Not for publication or presentation€¦ · Not for publication or presentation d. CK06-01 Ballen K, Arora M, Woolfrey A, Agovi M, Zhu X, Kalaycio M, Maziarz RT, Cortes J, Horowitz

Not for publication or presentation

AGENDA CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Honolulu, Hawaii Friday, February 18, 2011, 12:15 pm – 2:15 pm Co-Chair: Matt Kalaycio, MD, Cleveland Clinic Foundation, Cleveland, OH Telephone: 216-444-3705; Fax: 216-445-7444; E-mail: [email protected] Co-Chair: Richard Maziarz, MD, Oregon Health and Science University, Portland, OR

Telephone: 503-494-6345; Fax: 503-494-1552; E-mail: [email protected] Co-Chair: Jorge Cortes, MD, M.D. Anderson Cancer Center, Houston, TX

Telephone: 713-794-5783; Email: [email protected] Statisticians: Xiaochun Zhu, MS, CIBMTR Statistical Center, Milwaukee, WI

Telephone: 414-805-0649; Fax: 414-805-0714; E-mail: [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI Telephone: 414-456-7386; E-mail: [email protected] Scientific Directors: Mukta Arora, MD, University of Minnesota, Minneapolis, MN Telephone: 612-626-4105; Fax: 612-625-6919; E-mail: [email protected] Wael Saber, MD, MS, CIBMTR, Medical College of Wisconsin Milwaukee, WI Telephone: 414-805-0677; Fax: 414-805-0714; E-mail: [email protected] 1. Introduction Minutes of February, 2010 meeting (Attachment 1)

2. Accrual summary (Attachment 2) 3. Presentations, published or submitted papers

a. CK00-02 Ballen KK, Shrestha S, Sobocinski KA, Zhang M-J, Bashey A, Bolwell BJ, Cervantes F, Devine SM, Gale RP, Gupta V, Hahn TE, Hogan WJ, Krцger N, Litzow MR, Marks DI, Maziarz RT, McCarthy PL, Schiller G, Schouten HC, Vivek Roy V, Wiernik PH, Horowitz MM, Giralt SA, Arora M. Outcome of transplantation for Myflofibrosis. Biology of Blood & Marrow Transplantation 16:358-367, 2010.

b. CK03-01b Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora K, Gupta V, Rizzieri DA, George B, DM, Armand Keating, Gale RP, Marks DI, McCarthy PL, Woolfrey A, Szer J, Giralt SA, Maziarz RT, Cortes J, Horowitz MM, Lee SJ. Impact of Pre-Transplant Imatinib Mesylate on Outcomes of Allogeneic Transplantation in Advanced Phase Chronic Myeloid Leukemia: Analysis from the CIBMTR. Submitted.

c. CK03-02 Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M, Horowitz MM, Rizzo JD. Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase. Journal of Clinical Oncology 28 (11): 1888-95, 2010.

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d. CK06-01 Ballen K, Arora M, Woolfrey A, Agovi M, Zhu X, Kalaycio M, Maziarz RT, Cortes

J, Horowitz M, Saber W. Results of allogeneic transplantation for polycythemia vera and essential thrombocythemia. Presented at the American Society of Hematology in Orlando, Florida, 2010.

e. CK07-02 Kalaycio ME, Kukreja M, Woolfrey AE, Szer J, J Cortes J, Maziarz RT, Bolwell BJ, Buser A, Copelan E. Allogeneic hematopoietic cell transplant for prolymphocytic leukemia. Biology of Blood & Marrow Transplantation 16:543-547, 2010.

4. Studies in progress (Attachment 3)

a. CK02-03 Matched pair intravenous vs oral Busulfan (M Horowitz/ E Copelan) Manuscript Preparation

b. CK06-01 Outcomes after alloHCT for PV and ET (K Ballen) Manuscript Preparation c. CK02-01 BuCy vs CyTBI for leukemia (E Copelan)

(Attachment 4) Data File Preparation d. CK07-01 TBI based vs chemo based regimen for CLL

(M Sabloff) (Attachment 5) Data File Preparation e. CK06-03 NST/RIC for CLL/SCLL (J Leis/R Maziarz/

R Sobecks) (Attachment 6) Protocol Development f. CK06-04 Decision analysis/allo vs non-BMT Rx for

myelofibrosis (K Ballen) (Attachment 7) Protocol Development g. CK08-01 Outcome of allogeneic stem cell for imitanib resistant

CML (J Szer) (Attachment 8) Protocol Development h. CK08-02 Allo HCT for Hairy Cell Leukemia (R Kreitman/

S Pavletic) (Attachment 9) Protocol Development i. CK09-01 Minimal intensity vs RIC conditioning for

myelofibrosis (V Gupta) (Attachment 10) Protocol Development j. CK10-01 Update - impact of prior Gleevec on HCT for CML in

era of TKIs (R Maziarz) (Attachment 11) Protocol Development k. CK10-02 Impact of 2nd generation TKIs on HCT for CML

(R Maziarz) (Attachment 12) Protocol Development 5. Future/ Proposed studies

a. PROP 1210-32 Allogeneic hematopoietic stem cell transplantation with or without pre-transplant azacitidin in the treatment of myelodysplastic syndrome (R Olsson) (Attachment 13) (Deferred because of small number of patients received Azacitidin, n=41.)

b. PROP 1010-01 A decision analysis for performing allogeneic hematopoietic stem cell transplant in patients with chronic lymphocytic leukemia (B Hill) (Attachment 14)

c. PROP 1210-40 Donor lymphocyte infusion after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for chronic leukemia and chronic myeloproliferative diseases (R Sobecks) (Attachment 15)

d. PROP 1210-24 Development of a prognostic scoring system to predict relapse of chronic lymphocytic leukemia/small lymphocytic lymphoma after allogeneic hematopoietic stem cell transplantation (B Shaffer) (Attachment 16)

e. PROP 0510-01 Trends in allogeneic stem cell transplantation for myelodysplastic syndromes over the last decade: Impact of novel agents, predictive models, and reduced conditioning intensity (E Warlick) (Attachment 17)

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f. PROP 1210-25 Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation (B Shaffer) (Attachment 18)

g. PROP 0810-01 Allogeneic hematopoietic stem cell transplant for chronic myelomonocytic leukemia (H Duong) (Attachment 19-1) and PROP 1210-42 Outcomes of allogeneic hematopoietic stem cell transplantation for adult chronic myelomonocytic leukemia (M Akhtari) (Attachment 19-2)

h. PROP 1210-18 The role of EBMT score in predicting outcome of second allogeneic hematopoietic stem cell transplantation for relapse of hematological malignancies after first allogeneic or autologous transplantation (K Rezvani/R Szydlo) (Attachment 20)

6. Other business

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR CHRONIC LEUKEMIA Orlando, Florida Saturday, February 27, 2010, 2:45 pm - 4:45 pm Co-Chair: Jeffrey Szer, MD, Royal Melbourne Hospital

Phone : 61-3-9342-7737; Fax: 61-3-9342-7386; E-mail: [email protected] Co-Chair: Richard Maziarz, MD, Oregon Health and Science University

Phone: 503-494-6345; Fax: 503-494-1552; E-mail: [email protected] Co-Chair: Jorge Cortes, MD, M.D. Anderson Cancer Center, Texas

Phone: 713-794-5783; Fax: 713-794-4297; E-mail: [email protected] Statisticians: Xiaochun Zhu, MS, CIBMTR Statistical Center

Phone: 414-805-0649; Fax: 414-805-0714; E-mail: [email protected] Kwang Woo Ahn, PhD, CIBMTR Statistical Center Telephone: 414-456-7386; E-mail: [email protected] Scientific Director: Mukta Arora, MD, University of Minnesota, Minneapolis, MN Phone: 612-626-4105; Fax: 612-625-6919; E-mail: [email protected] 1. Introduction

The CIBMTR Working Committee for Chronic Leukemia was held on Saturday, February 27, 2010 at 2:45 pm. Dr. Jorge Cortes introduced all the three co-chairs, scientific director, and the statistician were introduced. Dr. Matt Kalaycio, from the Cleveland Clinic was introduced as newly appointed chair of the working committee and will replace outgoing chair Dr. Jeffrey Szer. A gift from CIBMTR was presented to Dr. Jeffrey Szer by Dr. Richard Maziarz to appreciate Dr. Szer’s contribution to Chronic Leukemia Working Committee. Xiaochun Zhu was introduced to Working Committee as a new MS statistician. Dr. Jeffrey Szer, Dr. Jorge Cortes and Dr. Richard Maziarz co-chaired the meeting. The minutes from the 2009 Tandem meeting held in Tampa, Florida, were approved by committee members. Attendees were asked to sign the attendance sheet in order to maintain committee membership and to use paper ballot voting sheets for the new proposals and studies in progress.

2. Accrual Summary

Accrual table has been updated.

3. Published or submitted papers a. CK00-02 Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ, Cervantes

F, Devine SM, Gale RP, Gupta V, Hahn TE, Hogan WJ, Kröger N, Litzow MR, Marks DI, Maziarz RT, McCarthy PL, Schiller G, Harry CS, Roy V, Wiernik PH, Horowitz MM, Giralt SA, Arora M. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2009. In press.

b. CK03-01b Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora K, Gupta V, Rizzieri DA, George B, DM, Armand Keating, Gale RP, Marks DI, McCarthy PL, Woolfrey A, Szer J, Giralt SA, Maziarz RT, Cortes J, Horowitz MM, Lee SJ. Impact of Pre-Transplant Imatinib Mesylate on

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Outcomes of Allogeneic Transplantation in Advanced Phase Chronic Myeloid Leukemia: Analysis from the CIBMTR. Submitted to JCO

c. CK03-02 Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M, Horowitz MM, Rizzo JD. Myeloablative Allogeneic Hematopoietic-Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase: Incidence of Relapse and Late Mortality in 5-year Survivors. Journal of Clinical Oncology 2009. In press.

d. CK07-02 Kalaycio ME, Kukreja M, Woolfrey AE, Szer J, Cortes J, Maziarz RT, Bolwell BJ, Buser A, Copelan E, Gale RP, Gupta V, Maharaj D, Marks DI, Pavletic SZ, Horowitz MM, Arora M. Allogeneic Hematopoietic Cell Transplant for Prolymphocytic Leukemia. Biol Blood Marrow Transplant. 2009. In press.

Dr. Cortes briefly mentioned above publications.

4. Studies in progress

a. CK02-01 Comparison of results using BuCy compared to CyTBI as preparation for allotx in in early phase AML and CML (E Copelan) Dr. Cortes briefly mentioned about this study. The TED follow up forms need to be updated this year. The next step is to begin the analysis as soon as the data file is updated with center’s follow up information.

b. CK02-03 Matched pair analysis of IV vs oral busulfan (Horowitz/Copelan)

Dr. Copelan mentioned that this study will only do descriptive analysis.

c. CK04-01 Comparison of outcome of allo SCT and Imatinib Mesylate therapy in patients with CML (F Ravandi/J Cortes) Dr. Kebriaei on behalf of Dr. Ravandi presented the characteristic of patients of the study.Year of transplantation was from 1995 to 1999. Dr. Cortes mentioned that two data sets have been cleaned and will do comparison.

d. CK06-01 Outcomes after HSCT for Polycythemia Vera and Essential Thrombocytopenia (K Ballen)

Dr. Ballen presented the characteristic of patients in this descriptive study. The current issue is that a small number of patients were available. The goal is to complete abstract by the end of this year. Dr. Arora clarified one inclusion criteria that patient would not be included if patient progressed to AML.

e. CK06-03 NST/RIC allogeneic HSCT for CLL/small cell lymphocytic lymphoma (J Leis/R Sobecks)

Dr Jose Leis presented this study, and highlighted the potential numbers of cases who underwent HLA-identical sibling or unrelated donor transplant and received myeloablative /non-myeloablative or RIC for CLL/SCLL between 1995 and 2006 and reported to CIBMTR. This protocol was updated after the committee’s decision was to not collect additional data on cytogenetics and NCI criterion for remission rate, as that might delay the study because of limited resources and funds. Therefore the updated protocol with tables was presented with main objective of the study being to compare the clinical outcomes (like Overall survival, Progression, TRM, and PFS) between patients undergoing HLA-identical sibling or unrelated donor stem cell transplantation using conventional (N=410) versus reduced intensity/nonmyeloblative (N=525). One of the suggestions from the committee was to add a breakdown of unrelated donor and HLA identical siblings, and also state HLA classification for unrelated donor transplants. The study is in protocol development. The committee has discussed for two years that supplemental form for collecting cytogenetic information was not needed. However, the new version of the form includes this information. So this information will be available for future studies.

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f. CK06-04 Decision analysis of allogeneic BMT for myelofibrosis (K Ballen)

Dr. Ballen presented the study. The objective of the study is to compare overall survival with HCT and with non-transplantation therapies for myelofibrosis. The idea is to use the year between 1989 and 2004 in CIBMTR and Fred Hutchinson cancer center database. The patients will be matched for age and date of diagnosis with non-transplant patients under age 70. The table only included patients from CIBMTR till 2002. The idea is to extend year to 2004, which will include more reduced intensity patients and also include patients from Fred Hutchinson. Dr. Ballen will cooperate with Dr. Tefferi who has database for non-transplant patients. Samples for NMDP patients (N=74) may be used for JAK 2 analysis.

g. CK07-01 TBI vs chemo based regimen for CLL (M Sabloff) Dr. Sabloff presented the study. The objective is to compare the outcomes of patients from CIBMTR database who had a myeloblative allogeneic hematopoietic stem cell transplant for CLL using either a TBI-based vs. chemotherapy-based conditioning regimen. Missing data is a concern. The outcomes are overall survival and disease free survival.

h. CK08-01 Outcomes of Allogeneic HSCT for imatinib (J Szer) Dr. Szer briefly presented the updates on this study. The information of mutation has been included in new CML form. Funding source is being sought for conducting mutation analysis.

i. CK08-02 Allogeneic HSCT for Hairy cell leukemia (R Kreitman/S Pavletic)

Dr. Pavletic presented the table with characteristic of patients and mentioned that study aims to look at the outcomes of allogeneic HCT in hairy cell leukemia patients. Registry is the way to get the retrospective data on rare disease like this. Currently CIBMTR registration database has 17 patients available from 1980 to 2007. Dr. Pavletic mentioned that European center may provide extra two patient’s information. One of attendees said he also has information available on two patients.

j. CK09-01 A comparison of outcomes of reduced intensity and non-myeloablative conditioning

regimen for patients with Myelofibrosis (V Gupta) Dr. Gupta briefly outlined the primary objective of this study, which is to evaluate and compare the clinical outcomes of non-myeloablative and reduced intensity conditioning regimens in patients with myelofibrosis. He summarized the characteristics of all the patients with Myelofibrosis who underwent Non-myeloablative or Reduced intensity allogeneic transplants from related or unrelated donors, reported to the CIBMTR, from 1997 to 2007. Total of 175 patients were available: 141 in RIC arm and 34 in non-myeloablative arm. The current database does not include all patients from Fred Hutchison cancer center. Dr. Gupta will ask Dr. Deeg from Fred Hutchinson (FH) cancer center for cooperation. 15 to 18 patients may be available from FH.

5. Future/ Proposed studies:

a. PROP 1209-43 An updated assessment of the impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors (TKIs) (R Maziarz) Dr. Maziarz presented this proposal. The specific aims are to determine the overall survival after allogeneic stem cell transplantation for patients with CML in the current era and to determine patient-, disease-, and transplantation-specific variables which may influence the outcome of patients with CML treated with tyrosine kinase inhibitors as primary and subsequent allogeneic stem cell transplantation. Between 2001 and 2007 there were 254 CML patients from 115 centers who only received imatinib from the time of diagnosis reported to CIBMTR.

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b. PROP 1209-44 The impact of treatment with second-generation tyrosine kinase inhibitors on

the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia (R Maziarz) The specific aims are to determine the overall survival after allogeneic transplantation for patients with CML with a history of treatment with second-generation tyrosine kinase inhibitors and to determine patient-, disease-, and transplantation-specific variables which may influence the outcome of patients with CML undergoing allogeneic stem cell transplantation, treated with second generation tyrosine kinase inhibitors either as primary or as salvage therapy. Between 2001 and 2007 there were 60 CML patients from 39 centers who had exposure to second-generation tyrosine kinase inhibitor reported to CIBMTR. Dr. Maziarz suggested that supplemental forms were needed for actively collecting data for both studies, and mentioned the possibility of applying for a grant from Novartis for this purpose.

6. Other business:

Update on data collection on chronic leukemia forms: Dr Cortes presented chronic leukemia data collection forms. He mentioned that modification of medication in old form has been discussed in last year Tandem meeting. The information of PCR and mutation analysis was not available in old form but now included in new form. The form for CML has been developed but CLL not yet. Comments on the new form can be sent to Dr. Arora. All comments will be combined and passed to committee for new form release.

7. Voting results:

Studies in progress Study Voting Rank CK02-03 1 CK06-01 2 CK08-01 3 CK06-03 4 CK02-01 5 CK09-01 6 CK06-04 7 CK08-02 8 CK04-01 9 CK07-01 10

Proposal Proposal Voting Rank Prop1209-44 1 Prop1209-43 2

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Accrual Summary for Chronic Leukemia Working Committee

Characteristics of recipients of allogeneic transplant for CLL reported to the CIBMTR between 1990 and 2010

Characteristics of patients Registration only Research Number of patients 1996 1474Number of centers 253 192Age, median (range), years 54 (<1 - 80) 53 (2 - 75)Sex

Male 1460 (73) 1085 (74)Female 533 (27) 389 (26)Missing 3 (<1) 0

Graft type Bone marrow 319 (16) 420 (28)PBSC 1602 (80) 992 (67)Missing 75 ( 4) 62 ( 4)

Donor type Twin 6 (<1) 19 ( 1)HLA-identical sibling 1256 (63) 616 (42)Other relative 119 ( 6) 32 ( 2)Unrelated donor 560 (28) 786 (53)Missing 55 ( 3) 21 ( 1)

Year of transplant 1990-1991 12 (<1) 21 ( 1)1992-1993 19 (<1) 39 ( 3)1994-1995 31 ( 2) 77 ( 5)1996-1997 61 ( 3) 109 ( 7)1998-1999 110 ( 6) 99 ( 7)2000-2001 240 (12) 134 ( 9)2002-2003 267 (13) 193 (13)2004-2005 295 (15) 221 (15)2006-2007 334 (17) 287 (19)2008-2009 a 353 (18) 280 (19)2010 a 274 (14) 14 (<1)

a Cases continue to be reported in this interval.

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Characteristics of recipients of autologous transplant for CLL reported to the CIBMTR between 1990 and 2010

Characteristics of patients Registration only Research Number of patients 123 469Number of centers 43 115Age, median (range), years 50 (29 - 73) 52 (18 - 81)Sex

Male 96 (78) 345 (74)Female 27 (22) 123 (26)Missing 0 1 (<1)


Year of transplant 1990-1991 1 (<1) 10 ( 2)1992-1993 17 (14) 11 ( 2)1994-1995 12 (10) 28 ( 6)1996-1997 31 (25) 43 ( 9)1998-1999 39 (32) 120 (26)2000-2001 5 ( 4) 127 (27)2002-2003 5 ( 4) 60 (13)2004-2005 6 ( 5) 38 ( 8)2006-2007 1 (<1) 23 ( 5)2008-2009 a 5 ( 4) 3 (<1)2010 a 1 (<1) 6 ( 1)


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Characteristics of recipients of allogeneic transplant for CML reported to the CIBMTR between 1990 and 2010

Characteristics of patients Registration only Research Number of patients 12244 11538Number of centers 438 388 Age, median (range), years 38 (<1 - 74) 37 (1 - 76)Sex

Male 7293 (60) 6847 (59)Female 4877 (40) 4690 (41)Missing 74 (<1) 1 (<1)


Donor type Twin 76 (<1) 58 (<1)HLA-identical sibling 8438 (69) 5421 (47)Other relative 354 ( 3) 121 ( 1)Unrelated donor 2583 (21) 5350 (46)Missing 793 ( 6) 588 ( 5)

Year of transplant 1990-1991 544 ( 4) 1599 (14)1992-1993 1062 ( 9) 1718 (15)1994-1995 1309 (11) 1610 (14)1996-1997 1970 (16) 1673 (14)1998-1999 2427 (20) 1550 (13)2000-2001 1955 (16) 985 ( 9)2002-2003 1302 (11) 743 ( 6)2004-2005 712 ( 6) 814 ( 7)2006-2007 499 ( 4) 402 ( 3)2008-2009 a 256 ( 2) 346 ( 3)2010 a 208 ( 2) 98 (<1)


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Characteristics of recipients of autologous transplant for CML reported to the CIBMTR between 1990 and 2010

Characteristics of patients Registration only Research Number of patients 247 416Number of centers 56 122Age, median (range), years 47 (2 - 65) 47 (4 - 70)Sex

Male 162 (66) 239 (57)Female 85 (34) 177 (43)

Graft type Bone marrow 117 (47) 87 (21)PBSC 112 (45) 253 (61)Missing 18 ( 7) 76 (18)

Year of transplant 1990-1991 24 (10) 30 ( 7)1992-1993 51 (21) 8 ( 2)1994-1995 63 (26) 51 (12)1996-1997 55 (22) 92 (22)1998-1999 44 (18) 123 (30)2000-2001 4 ( 2) 83 (20)2002-2003 2 (<1) 21 ( 5)2004-2005 4 ( 2) 6 ( 1)2006-2007 0 2 (<1)

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Characteristics of recipients of allogeneic transplant for MDS reported to the CIBMTR between 1990 and 2010

Characteristics of patients Registration only Research Number of patients 5389 4312*Number of centers 388 333Age, median (range), years 49 (<1 – 81) 46 (<1 – 78)Sex

Male 3165 (59) 2508 (58)Female 2211 (41) 1801 (42)Missing 13 (<1) 3 (<1)


Donor type Twin 37 (<1) 18 (<1)HLA-identical sibling 3116 (58) 1500 (35)Other relative 299 ( 6) 95 ( 2)Unrelated donor 1709 (32) 2588 (60)Missing 228 ( 4) 111 ( 3)

FAB claasification MDS, NOS 1352 (25) 452 (10)RA 977 (18) 1026 (24)RAEB 1254 (23) 1267 (29)CMML 482 ( 9) 387 ( 9)RARS 158 ( 3) 159 ( 4)RAEB-1 283 ( 5) 216 ( 5)RAEB-2 413 ( 8) 250 ( 6)RCMD 184 ( 3) 142 ( 3)RCMD/RS 26 (<1) 28 (<1)Other MDS 260 ( 5) 385 ( 9)

Year of transplant 1990-1991 76 ( 1) 152 ( 4)1992-1993 149 ( 3) 206 ( 5)1994-1995 281 ( 5) 250 ( 6)1996-1997 358 ( 7) 317 ( 7)1998-1999 479 ( 9) 309 ( 7)2000-2001 521 (10) 408 ( 9)2002-2003 634 (12) 459 (11)2004-2005 679 (13) 590 (14)2006-2007 687 (13) 623 (14)2008-2009 a 819 (15) 699 (16)2010 a 706 (13) 299 ( 7)

a Cases continue to be reported in this interval. * 3092 cases are reported as having MDS at diagnosis and prior HCT (no transformation to other disease).

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Characteristics of recipients of autologous transplant for MDS reported to the CIBMTR between 1990 and 2010

Characteristics of patients Registration only Research Number of patients 41 141*Number of centers 37 82Age, median (range), years 47 (3 - 68) 47 (2 - 70)Sex

Male 17 (41) 76 (54)Female 24 (59) 65 (46)

Graft type Bone marrow 10 (24) 21 (15)PBSC 26 (63) 61 (43)Missing 5 (12) 59 (42)

FAB classification MDS, NOS 3 ( 7) 47 (33)RA 17 (41) 27 (19)RAEB 18 (44) 47 (33)CMML 1 ( 2) 6 ( 4)RARS 1 ( 2) 3 ( 2)RAEB-2 0 1 (<1)RCMD 0 1 (<1)Other MDS 1 ( 2) 9 ( 6)

Year of transplant 1990-1991 3 ( 7) 5 ( 4)1992-1993 6 (15) 11 ( 8)1994-1995 4 (10) 17 (12)1996-1997 12 (29) 12 ( 9)1998-1999 9 (22) 30 (21)2000-2001 2 ( 5) 22 (16)2002-2003 2 ( 5) 23 (16)2004-2005 2 ( 5) 15 (11)2006-2007 1 ( 2) 3 ( 2)2008-2009 a 0 1 (<1)2010 a 0 2 ( 1)

a Cases continue to be reported in this interval. * 12 cases are reported as having MDS at diagnosis and prior HCT (no transformation to other disease).

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TO: Chronic Leukemia Working Committee Members FROM: Wael Saber, MD, MS, Scientific Director for the Chronic Leukemia WC Mukta Arora, MD, MS, Scientific Director for the Chronic Leukemia WC RE: Studies in Progress Summary CK02-03: Pretransplant conditioning therapy using oral or IV Busulfan in hemopoietic stem cell transplantation (Horowitz/Copelan): This study is to to determine whether patients receiving IV Bu as part of a Busulfan/Cytoxan (BuCy) conditioning regimen have less toxicity than similar patients receiving oral BuCy. The manuscript is under review by chairs with recommendations to restrict to early post transplant outcomes. CK06-01: Outcomes after HSCT for Polycythemia Vera and Essential Thrombocytopenia (K Ballen): This study is to determine overall and disease-free survival, hematopoietic recovery, acute and chronic GVHD, and transplant related mortality after allogeneic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia. The univariate analysis has been completed. A poster was presented at ASH 2010. Additional data may be needed from Fred Hutchinson Cancer Center for further analysis. CK02-01: Comparison of results using Busulfan/Cyclophosphamide compared to TBI/Cyclophosphomide as preparation for allogeneic transplantation in chronic myelogenous leukemia and acute myelogenous leukemia (E Copelan): The objectives of this study are 1) to compare transplant-related mortality, relapse, overall survival and leukemia-free survival in patients receiving preparation with Oral Bu/Cy, IV Bu/Cy, and Cy/TBI; 2) to determine the impact of patient, disease and transplamt specific variables on these outcomes. The current status of the study is data file preparation. The follow-up completeness was very low. Now CRC has provided some follow-up update. Data cleaning is under way. CK07-01: A comparison of total body irradiation (TBI) - based conditioning vs. chemotherapy-based conditioning in myeloablative allogeneic stem cell transplants for chronic lymphocytic leukemia (CLL) (M Sabloff): This study it to compare the outcomes of patients who had a myeloablative allogeneic hematopoietic stem cell transplant for CLL using either a TBI based or chemotherapy-based conditioning regimen; to evaluate the impact of TBI dose (<=1200 vs. >1200) on endpoints. The status of this study is protocol development. The protocol has been presented at the statistical meeting. Due to the fact that many missing data requests have been sent out to the centers a new version of the protocol will be coming soon. CK06-03: NST/RIC allogeneic HSCT for CLL/small cell lymphocytic lymphoma (J Leis): This study is to compare the clinical outcomes between patients undergoing HLA-identical sibling or unrelated donor stem cell transplantation using conventional versus reduced intensity/nonmyeloablative (RIC/NST) conditioning regimen for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); to determine patient-, disease- and transplant-related variables associated with favorable progression-free and overall survival outcomes; to assess the impact of disease prognostic factors on relapse rate, progression-free survival, and overall survival among patients receiving conventional versus RIC/NST

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conditioning regimen for CLL. The current status is protocol development. The protocol has been presented at the stat meeting. Studies previously proposed, but not initiated CK06-04: Decision analysis of allogeneic bone marrow transplantation for myelofibrosis: comparison of allogeneic stem cell transplantation and non transplantation therapies for myelofibrosis (K Ballen): This study is to compare overall survival with hematopoietic cell transplantation (HCT) and with nontransplantation therapies for myelofibrosis; to determine appropriate patient-,disease-, and transplant-related selection criteria for transplantation in patients with myelofibrosis. A draft protocol is available for review. CK08-01: Evaluation of the outcome of allogeneic stem cell transplantation for chronic myeloid leukemia (CML) in patients with resistance to Imatinib or second generation tyrosine kinase inhibitors (TKIS) either (I) associated with abl kinase domain mutations or (II) not associated with mutations (J Szer): This study is to assess the progression free and overall survival of patients undergoing an allograft for CML who have resistance to imatinib or second generation TKIs, either due to mutations or other mechanisms. The key issue is whether conditioning and/or graft vs. leukemia (GVL) effects are sufficiently powerful to overcome the otherwise poor prognosis of this condition. A draft protocol is available for review. CK08-02: Results of allogenic hematopoietic stem cell transplantation in patients with hairy cell leukemia (R Kreitman): The primary endpoint of this study is to analyze overall and progression-free survival. The secondary endpoint is to analyze engraftment, acute and chronic GVHD, disease response, progression, and non-relapse mortality. A draft protocol is available for review. CK09-01: A comparison of outcomes of minimal intensity and reduced intensity conditioning regimens for patients with myelofibrosis (V Gupta): This study is to evaluate and compare the outcomes of minimal intensity and reduced intensity conditioning regimens in patients with myelofibrosis. The secondary objective is to study the graft-versus-myelofibrosis effect. A draft protocol is available for review. CK10-01: An updated assessment of the impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors (TKIs)(R Maziarz): The objectives of this study are 1) to determine the overall survival after allogeneic stem cell transplantation for patients with CML in the current era; 2) to determine progression free survival, event free survival, relapse rate and non-relapse mortality of patients with CML undergoing allogeneic stem cell transplantation in the current era; 3) to determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML treated with tyrosine kinase inhibitors as primary therapy and subsequent allogeneic stem cell transplantation. A draft protocol is available for review. CK10-02: The impact of treatment with second-generation tyrosine kinase inhibitors on the outcome of hematopoietic cell transplantation for patients with chronic myeloid leukemia (R Maziaz): The specific aims of this study are: 1) to determine the overall survival after allogeneic stem cell transplantation for patients with CML with a history of treatment with second-generation tyrosine kinase inhibitors 2) to determine progression free survival, event free survival, relapse rate and non-relapse mortality of patients with CML undergoing allogeneic stem cell transplantation with a history of treatment with second-generation tyrosine kinase inhibitors 3) to determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML undergoing allogeneic stem cell

15


transplantation, treated with second tyrosine kinase inhibitors either as primary or as salvage therapy. A draft protocol is available for review.

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CIBMTR CK02-01 COMPARISON OF RESULTS USING BUSULFAN/CYCLOPHOSPHAMIDE COMPARED TO TBI/CYCLOPHOSPHOMIDE AS PREPARATION FOR ALLOGENEIC TRANSPLANTATION

IN CHRONIC MYELOGENOUS LEUKEMIA AND ACUTE MYELOCYTIC LEUKEMIA

REVISED PROTOCOL Study Chair: Edward Copelan, MD Cleveland Clinic

Hematologic Oncology and Blood Disorder 9500 Euclid Ave R-35

Cleveland, Ohio 44195 Telephone: 216-445-5647 Fax: 216-444-9464 E-mail: [email protected]

Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD, The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd Milwaukee, WI 53226 Telephone: 414-456-7386 Fax: 414-456-6513 E-mail: [email protected]

17


Scientific Director: Mukta Arora, MD University of Minnesota Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 Telephone: 612-626-4105 Fax: 612-625-6919 E-mail: [email protected] Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Matt Kalaycio, MD The Cleveland Clinic Main Campus Mail Code R35 9500 Euclid Ave Cleveland, OH 44195 Telephone: 216-444-3705 Fax: 713-794-4297 E-mail: [email protected] Richard T. Maziarz, MD Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-6345 Fax: 503-494-1552 E-mail: [email protected]

Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX 77030 Telephone: 713-794-5783 Fax: 713-794-4297 E-mail: [email protected]

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1.0 OBJECTIVES:

1.1 Compare estimated rates of transplant-related mortality, relapse, overall survival and leukemia-free survival in patients receiving preparation with Oral Bu/Cy, IV Bu/Cy, and Cy/TBI.

1.2 Determine the prognostic significance of variables such as age, interval from diagnosis to

transplant, abnormal pretransplant LFTs, stem cell source, degree of match, and GVHD prevention method.

2.0 SCIENTIFIC JUSTIFICATION:

Acute myelogenous leukemia and chronic myelogenous leukemia are diseases for which patients commonly undergo allogeneic hematopoietic stem cell transplantation. Randomized studies comparing Bu/Cy to Cy/TBI have not demonstrated significantly different outcomes, but significantly decreased toxicity (e.g. duration of neutropenia) and relapse rates (as well as increased relapse rates) have been reported with busulfan. It is critical to analyze whether one regimen is associated with better overall results than the other and whether one regimen is better in specific settings, e.g., in older patients. Lastly it is important to determine whether better results are achieved using IV versus oral busulfan.

3.0 STUDY POPULATION:

The study population will include all patients who have undergone first allogeneic transplantation with an HLA-identical sibling donor or an unrelated donor from 2000 through 2005 for Ph+ CML in first CP or acute myelocytic leukemia in first CR and who received preparation with Cy/TBI or BuCy. Only patients who received CsA±other, MTX+CsA ±other, FK506+MTX±other or FK506±other for GVHD prophylaxis will be included. Patients with identical twin or cord blood donors will be excluded as will patients who underwent in vitro T cell depletion.

4.0 OUTCOMES:

4.1 Hematopoietic recovery: Time to neutrophils (ANC) > 0.5 x 109/L for three consecutive days will be the primary measure for comparisons of hematopoietic recovery. Time to platelets ≥30k will also be measured. 4.2 Incidence of acute and chronic GVHD: The number of patients who experience

grade II-IV, and III-IV acute GVHD, and limited and extensive chronic GVHD will be assessed.

4.3 Treatment-related mortality: death within the first 100 days and 1st year following transplant for any cause of death while in complete remission of primary disease. 4.4 Relapse: recurrence of disease for those in complete remission are events. Those who survive without recurrence are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with TRM as the competing risk. 4.5 Leukemia-free survival: time to treatment failure (death or relapse). Patients are censored at time of last follow-up.

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4.6 Overall survival: time to death. Death from any cause will be considered an event. Surviving patients will be censored at time of last follow-up. 4.7 Other outcomes: development of hepatic VOD, duration of neutropenia post transplant,

interstitial pneumonia, diffuse alveolar hemorrhage, bronchiolitis, permanent alopecia, cataracts, second malignancies.

5.0 VARIABLES TO BE ANALYZED:

Patient-related:

- Age at transplant: continous, 1-10 vs 11-20 vs 21-30 vs 31-40 vs 41-50 vs >50 - Gender: male vs female - Karnofsky performance score at transplant: <90% vs ≥90%

Disease-related:

- Disease: AML, CML - Pre transplant LFT ( Bilirubin and SGOT): Abnormal (3 times normal) vs normal vs

missing - Time from diagnosis to transplant: continuous

Transplant-related:

- Donor recipient gender match: M-M vs M-F vs F-M vs F-F - Donor type: HLA identical sibling vs unrelated - Donor-recipient HLA match: match vs mismatch, degree of mismatch - Donor-recipient CMV status: +/+ vs +/- vs -/+ vs -/- - Donor age: continous and 1-10 vs 11-20 vs 21-30 vs 31-40 vs 41-50 vs >50 - Graft type: bone marrow vs peripheral blood vs BM+PB - TBI dose: non-fractionated, # 1000 cGy vs >1000 cGy; fractionated, # 1200 cGy vs

>1200 cGy - Cyclophosphamide dose: continuous - Busulfan dose: continuous - Year of transplant: 2000-2001 vs. 2002-2003 vs. 2004-2005 - GVHD prophylaxis: CsA ±other vs CsA+MTX±other vs. FK506+MTX±other vs.

FK506±other - G-CSF or GM-CSF growth factors post transplant: yes vs no

Data collected in the CIBMTR Report Forms would be used. No additional data would be needed.

6.0 STUDY DESIGN:

Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. These factors will be compared between the three treatment groups (Oral Bu/Cy vs IV Bu/Cy vs Cy/TBI) using the Chi-Square test for categorical variables and the Mann-Whitney test for continuous variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. Probability of leukemia-free survival and overall survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Values for other

20


endpoints included in section 4.0 will be generated using cumulative incidence estimates to account for competing risks. Comparison of survival curves will be done using the log-rank test. Multivariate analyses will be performed using proportional hazards models. These analyses will fit models to determine which risk factors (Sec 5.0) may be related to a given outcome. All variables will first be examined to assure that they comply with the proportional hazards assumption. Factors found to have non-proportional hazards will be adjusted for in subsequent analyses. A stepwise model building approach will then be used to develop models for relapse, treatment-related mortality, leukemia-free survival and overall survival.

7.0 REFERENCES:

1. Cox RD. Regression analysis and life tables. J of Royal Statist Soc 1972; B 34:187-220.

21


Table 1. Characteristics of patients who underwent first allogeneic transplantation with an HLA- identical sibling donor or an unrelated donor for CR1 AML and CP1 Ph+ CML and received preparation with Cy/TBI, oral or IV Bu/Cy, reported to CIBMTR from 2000 to 2005a.

Cy TBI

Oral BuCy

IV BuCy

Variable

N eval

N (%)

N eval

N (%)

N eval

N (%)

P-valueb

Patient-related Number of patients 855 719 308 Number of centers 135 107 87 Age, median (range), years 855 35 (1-63) 719 33 (1-63) 308 39 (1-65) <0.001 Age at transplant, years 855 719 308 <0.001 ≤10 42 ( 5) 57 ( 8) 30 (10) 11 - 20 96 (11) 110 (15) 45 (15) 21 - 30 162 (19) 146 (20) 44 (14) 31 - 40 228 (27) 169 (24) 43 (14) 41 - 50 210 (25) 156 (22) 86 (28) >50 117 (13) 81 (11) 60 (19) Male sex 855 477 (56) 719 412 (57) 308 161 (52) 0.331 Karnofsky score at transplant

810 699 297 <0.001

<90% 146 (18) 65 ( 9) 60 (20) ≥90% 664 (82) 634 (91) 237 (80) Disease-related Disease 855 719 308 <0.001 AML 529 (62) 376 (52) 204 (66) CML 326 (38) 343 (48) 104 (34) Pretransplant LFT 855 719 308 0.111

Normal 778 (91) 640 (89) 287 (93) Abnormal (3 times normal)

62 ( 7) 70 (10) 16 ( 5)

Missing 15 ( 2) 9 ( 1) 5 ( 2) Time from diagnosis to transplant, median (range), months

854

6 (1-170)

719

6 (2-107)

308

5 (1-68)

0.121

22


Table 1. Continued.

Cy TBI

Oral BuCy

IV BuCy

Variable N

eval

N (%) N

eval

N (%) N

eval

N (%)

P-valueb Transplant-related Donor/recipient gender match 852 713 308 0.373

M-M 308 (36) 250 (35) 106 (34) M-F 200 (23) 168 (24) 89 (29) F-M 166 (20) 158 (22) 55 (18) F-F 178 (21) 137 (19) 58 (19)

Donor 855 719 308 <0.001

HLA-identical sibling 267 (31) 527 (73) 127 (41) Unrelated 588 (69) 192 (27) 181 (59)

Donor-recipient HLA match 855 719 308 <0.001

Match 771 (90) 691 (96) 280 (91) Mismatch 84 (10) 28 ( 4) 28 ( 9)

Donor-recipient CMV status 791 688 291 <0.001 +/+ 222 (28) 364 (53) 106 (37) +/- 102 (13) 48 ( 7) 35 (12) -/+ 212 (27) 121 (18) 71 (24) -/- 255 (32) 155 (22) 79 (27) Donor age 836 706 302 <0.001 ≤10 10 ( 1) 45 ( 6) 14 ( 5) 11 - 20 24 ( 3) 107 (15) 17 ( 6) 21 - 30 217 (26) 166 (24) 68 (23) 31 - 40 279 (33) 191 (27) 98 (32) 41 - 50 224 (27) 137 (19) 77 (25) >50 82 (10) 60 ( 9) 28 ( 9) Donor age, median (range), years

836

36 (1-66)

706

32 (1-70)

302

36 (2-64)

<0.001

Graft type 855 719 308 0.009

BM 474 (55) 364 (51) 141 (46) PB 381 (45) 355 (49) 167 (54)

Bu dose, median (range),mg/Kg

NA

712

16 (4-35)

306

12 (3-27)

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Table 1. Continued.

Cy TBI

Oral BuCy

IV BuCy

Variable N

eval

N (%) N

eval

N (%) N

eval

N (%)

P-valueb Cy dose, median (range),mg/Kg

844 119 (33-201) 713 119 (40-232) 306 114 (14-222) 0.066

TBI dose 849 NA NA Non-fractionated≤1000cGy 67 ( 8) Non-fractionated>1000cGy 3 ( 1) Fractionated ≤ 1200 cGy 504 (59) Fractionated > 1200 cGy 275 (32) Year of transplant 855 719 308 <0.001

2000-2001 378 (44) 298 (42) 38 (12) 2002-2003 230 (27) 239 (33) 71 (23) 2004-2005 247 (29) 182 (25) 199 (65)

GVHD prophylaxis 855 719 308 <0.001 MTX+CsA ± others 498 (58) 604 (84) 149 (48) FK506+MTX ± others 246 (29) 56 ( 8) 113 (37) CsA ± others 79 ( 9) 48 ( 7) 22 ( 7) FK506 ± others 32 ( 4) 11 ( 1) 24 ( 8) Growth factors post transplant: G-CSF or GM-CSF

855 719 308 <0.001

Yes 279 (33) 218 (30) 156 (51) No 576 (67) 501 (70) 152 (49)

Median follow-up of survivors, months

489

24 (3-78)

497

24 (3-79)

212

12 (3-62)

Abbreviations: CML = chronic myelogenous leukemia; AML= acute myelogenous leukemia; GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus; BM = bone marrow; PB = peripheral blood; CMV = cytomegalovirus; LFT= Liver function test; TBI=Total body irradiation; Bu=Busulfan; Cy=cyclophosphamide; GM-CSF=granulocyte macrophage colony stimulating factor; G-CSF= granulocyte colony stimulating factor; CP1=chronic phase 1; CR1= first complete remission.

aSelection criterion: - First allogeneic transplant with HLA identical siblings and unrelated donor from 2000 to 2005 - Ph+ CML in first chronic phase and AML in first CR who received preparation with Cy/TBI or Bu/Cy - Only patients who received CsA+/-other, MTX+CsA+/-other, FK506+MTX ± others or FK506 ± others as GVHD prophylaxis included - Patients with twin transplant and graftype cord blood excluded - IBMTR cases (n=1223) and NMDP (n=659) bThe chi-square test is used for discrete covariates; the Kruskal-Wallis test is used for continuous covariates. Follow up completeness index=83% One year of complete follow-up [Cy/TBI (95%); Oral Bu/Cy (96%); IV Bu/Cy (87%)] Three year of complete follow-up [Cy/TBI (87%); Oral Bu/Cy (83%); IV Bu/Cy (67%)] Five year of complete follow-up [Cy/TBI (78%); Oral Bu/Cy (59%); IV Bu/Cy (69%)]

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CIBMTR CK07-01

A COMPARISON OF TOTAL BODY IRRADIATION (TBI) - BASED CONDITIONING VS. CHEMOTHERAPY-BASED CONDITIONING IN MYELOABLATIVE ALLOGENEIC STEM

CELL TRANSPLANTS FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

DRAFT PROTOCOL Study Chair: Mitchell Sabloff, MD

The Ottawa Hospital, Ottawa, Ontario, Canada, K1H 8L6 Telephone: 613-737-8899 ext 71284 Fax: 613-737-8861 E-mail: [email protected]

Study Statisticians: Wael Saber, MD, MS CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700

Fax: 414-805-0714 Email: [email protected]

Kwang Woo Ahn, PhD CIBMTR

The Medical College of Wisconsin 8701 Watertown Plank Rd

Milwaukee, WI 53226 Telephone: 414-456-7386 Fax: 414-456-6513 Email: [email protected]

25


Scientific Director: Mukta Arora, MD University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 Telephone: 612-626-4105 Fax: 612-625-6919

E-mail: [email protected]

Working Committee Chairs: Matt Kalaycio, MD The Cleveland Clinic Main Campus Mail Code R35 9500 Euclid Ave Cleveland, OH 44195 Telephone: 216-444-3705 Fax: 713-794-4297 E-mail: [email protected]

Richard T. Maziarz, MD

Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-6345 Fax: 503-494-1552 E-mail: [email protected] Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX 77030 Telephone: 713-794-5783 Fax: 713-794-4297 E-mail: [email protected]

26


1.0 OBJECTIVES:

1.1 To compare the outcomes of patients extracted from the CIBMTR database that underwent a myeloablative allogeneic hematopoietic stem cell transplant for CLL using either a TBI-based or chemotherapy-based conditioning regimen.

Primary endpoint:

− Disease-free survival (DFS)

Secondary endpoints: − Hematopoietic recovery − Incidence of acute GVHD or chronic GVHD − Treatment-related mortality (TRM) − Recurrence or progression − Overall survival (OS)

1.2 To evaluate the impact of TBI dose (<=1200 vs. >1200) on endpoints.


Treatment options for CLL have been evolving, recently, from the standard conservative management to more aggressive approaches. This has been possible due to the identification of novel prognostic markers and the development of more effective treatments. These include such agents as purine analogues, antibodies such as Rituximab and Alemtuzumab, combinations of the above and autologous and allogeneic stem cell transplants1-4. Intensive treatments such as allogeneic hematopoietic stem cell transplants have demonstrated some promising results; however, the optimal conditions regimen has not been identified yet. Both myeloablative and reduced-intensity hematopoietic stem cell transplants have been performed5-8. Although the more intense myeloablative transplants appear to be effective on the disease they have been complicated by high treatment related mortality9. This has been reduced by reduced-intensity transplants but they may be hindered by more frequent relapse and reduced effect on more resistant disease , particularly those who present with bulky adenopathy10. Radiotherapy, is very effective at treating non-Hodgkin’s lymphoma, particularly chemotherapy resistant lymphoma11-13. There have been examples of even low-dose radiotherapy having a useful effect in treating localized CLL, irrespective of the previous chemotherapy14;15. Total body irradiation (TBI), which is used routinely in a variety of stem cell transplant for hematological diseases and in autologous stem cell transplants for CLL, is only used in a subset of allogeneic stem cell transplants for CLL5;16;17. Those receiving reduced intensity regimen transplants have received very low dose or no radiotherapy7. There have been some recent reports comparing myeloablative radiotherapy-based conditioning regimens and chemotherapy regimens but both were retrospective and very small sample sizes5;16. In addition, no difference was detected in one of the reports and the other suggested a difference in favor of TBI but it appeared to be more because of a difference in toxicity rather than disease relapse, which may be attributable to oral busulfan.

It would be of interest to know if the addition of radiation to the conditioning regimen is important to a relatively radiation naïve but sensitive disease, in order to overcome some of the

27


obstacles of resistance in chemotherapy based conditioning regimens. This might help guide future transplants in terms of adding radiation to the transplant if it is found useful in overcoming these obstacles or continuing with the current trends, employing primarily chemotherapy-based regimens. Such a question would require a large database to draw on such as the CIBMTR.


All patients who have been reported to the CIBMTR who received a first myeloablative allogeneic stem cell transplant (per CIBMTR consensus criteria) in the past 10 years for B-CLL, non-transformed, from a related or unrelated donor. Excluded from the population are any transplants with a TBI dose of ≤500 cGy as a single fraction or ≤800 cGy, if fractionated, twin transplants, and cord blood transplants.

4.0 OUTCOMES:

4.1 Hematopoietic recovery: The primary measures for hematopoietic recovery will be:

4.1.1 Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive days within 28 and 100 days posttransplant. This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution. This event is summarized by the cumulative incidence estimate with death as the competing risk.

4.1.2 Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 3 consecutive days, and (b) >50 x 109/L independent of platelet transfusions for 3 consecutive days within 28 and 100 days posttransplant. This event is summarized by the cumulative incidence estimate with death as the competing risk.

4.2 Incidence of acute and chronic GVHD: Occurrence of grade II, III and/or IV skin,

gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD and limited and extensive chronic GVHD. This event is summarized by the cumulative incidence estimate with death as the competing risk.

4.3 Treatment-related mortality (TRM): Any death within the first 28 days of transplant or any

death occurring after day 28 in the absence of disease progression. This event is summarized by the cumulative incidence estimate with relapse as the competing risk.

4.4 Relapse/Progression: progressive disease or recurrence of disease are events except death

occurred within the first 28 days of transplant. Those who survive without recurrence or progressive disease are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with TRM as the competing risk.

4.5 Disease-free survival (DFS): survival without recurrence or tumor progression.

Recurrence or progression of disease and death are events. Those who survive without recurrence or progression are censored at last contact.

4.6 Overall survival: time to death. Death from any cause will be considered an event.

Surviving patients will be censored at time of last follow-up.

28



5.1 Patient-related: − Age at transplant: in decades − Gender: (male vs. female) − Karnofsky performance score at transplant: (<90% vs. ≥90%)

5.2 Disease-related:

5.2.1 At diagnosis: − Rai stage: (0/I/II vs. III/IV) − B-symptoms: (y/n)

5.2.2 Between diagnosis and transplant:

− Number of prior treatments: (≤2 vs. ≥3) − Prior fludarabine therapy: (y/n) − Fludarabine-refractory: (y/n) − Chemotherapy-refractory: (y/n) − Best response after any therapy prior to transplant (molecular CR/continuing

CR/CR/Nodular PR/PR vs. Stable disease/progressive disease vs. Not evaluable/not tested)

5.2.3 At transplant:

− Hemoglobin: (≥ or <110 g/L) − Platelets count: (≥ or < 100 x 109/L) − Lymphocytosis: (>50 x 109/L) − Splenectomy: (y/n) − Rai stage: (0/I/II vs. III/IV) − Bulky lymphadenopathy: (< or ≥ 5cm) − State of disease: (molecular CR/continuing CR/CR/Nodular PR/PR vs. Stable

disease/progressive disease vs. not evaluable/not tested) − Extramedullary or extra-nodal disease: (y or n)

5.3 Transplant-related:

− Time from diagnosis to transplant: (continuous) − Donor recipient gender match: (M-M vs. M-F vs. F-M vs. F-F) − Donor type: (related vs. unrelated) − Donor-recipient HLA match − Donor-recipient CMV status: (+/+ vs. +/- vs. -/+ vs. -/-) − Donor age − CD34 stem cell dose: (< or ≥ 5 x 106 cells/Kg) − Graft type: BM vs. PB − Year of transplant: − GVHD prophylaxis − ATG (y or n)

29


6.0 STUDY DESIGN:

From the data collected as described in the study population above the group will be divided into 2 groups: those that received TBI vs. those that did not. Differences between the 2 groups (i.e. TBI containing vs. chemotherapy only) will be identified using chi-squared analysis for categorical variables and the Mann-Whitney test for continuous variables. The Kaplan-Meier product limit method will be used to assess for OS and PFS. The overall follow-up completeness index is 72% (79% @ 5yrs). Thus, the survival curves after 5 years for OS and PFS should be interpreted with a caution. Values for the other outcomes listed in Section 4.0 will be calculated by cumulative incidence estimate to account for competing risks. Multivariate analyses will be performed using the proportional hazards model. To see whether there is statistical difference between TBI (<=1200) and TBI (>1200), the subgroup analysis will be performed first. If it shows statistically significant difference between the two subgroups, the proportional hazards model with TBI (<=1200) vs. TBI (>1200) vs. chemotherapy only will be employed. If it shows no statistically significant difference between the two, the proportional hazards model with TBI vs. chemotherapy only will be used. The interaction between the main effect and the other covariates will be checked. Factors violating the proportional hazard assumptions will be included in the model as time-dependent covariates.

7.0 REFERENCES:

1. Shanafelt TD, Kay NE. Comprehensive management of the CLL patient: a holistic approach. [Review] [63 refs]. Hematology 2007324-331.

2. Tam CS, Khouri I. The role of stem cell transplantation in the management of chronic lymphocytic leukaemia. [Review] [52 refs]. Hematological Oncology 2009;27:53-60.

3. Gribben JG. Stem cell transplantation in chronic lymphocytic leukemia. [Review] [30 refs]. Biology of Blood & Marrow Transplantation 2008;15:Suppl-8.

4. Gribben JG. Role of allogeneic hematopoietic stem-cell transplantation in chronic lymphocytic leukemia.[comment]. Journal of Clinical Oncology 2008;26:4864-4865.

5. Toze CL, Galal A, Barnett MJ et al. Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplantation 2005;36:825-830.

6. Malhotra P, Hogan WJ, Litzow MR et al. Long-term outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years.[see comment]. Leukemia & Lymphoma 2008;49:1724-1730.

7. Sorror ML, Storer BE, Sandmaier BM et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.[see comment]. Journal of Clinical Oncology 2008;26:4912-4920.

8. Caballero D, Garcia-Marco JA, Martino R et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clinical Cancer Research 2005;11:7757-7763.

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9. Pavletic SZ, Khouri IF, Haagenson M et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. Journal of Clinical Oncology 2005;23:5788-5794.

10. Dreger P, Brand R, Milligan D et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 2005;19:1029-1033.

11. Kahn ST, Flowers CR, Lechowicz MJ, Hollenbach K, Johnstone PA. Refractory or relapsed Hodgkin's disease and non-Hodgkin's lymphoma: optimizing involved-field radiotherapy in transplant patients. Cancer Journal 2005;11:425-431.

12. Wadhwa PD, Fu P, Koc ON et al. High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: an effective regimen with low morbidity and mortality. Biology of Blood & Marrow Transplantation 2005;11:13-22.

13. Girinsky T, Lapusan S, Ribrag V et al. Phase II study of concomitant chemoradiotherapy in bulky refractory or chemoresistant relapsed lymphomas. International Journal of Radiation Oncology, Biology, Physics 2005;61:476-479.

14. Johannsson J, Specht L, Mejer J, Jensen BA. Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia.[see comment]. International Journal of Radiation Oncology, Biology, Physics 2002;54:1466-1470.

15. Sawyer EJ, Timothy AR. Low dose palliative radiotherapy in low grade non-Hodgkin's lymphoma. Radiotherapy & Oncology 1997;42:49-51.

16. Doney KC, Chauncey T, Appelbaum FR, Seattle Bone Marrow Transplant Team. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplantation 2002;29:817-823.

17. Pavletic ZS, Arrowsmith ER, Bierman PJ et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplantation 2000;25:717-722.

31


Table 1. Characteristics of 396 CLL patients that underwent a myeloablative HCT from 1995-2007 and reported to the CIBMTR based on type of conditioning regimen (TBI based vs. chemotherapy based)

Variable TBI Chemotherapy P-value*Number of patients 302 94 Number of centers 273 89 Age at transplant, median (range), years 48 (24-64) 50 (27-72) 0.007**Age at transplant, years 0.01

21-40 70 (23) 12 (13) 41-50 146 (48) 42 (45) >51 86 (28) 40 (43)

Male sex 206 (68) 64 (68) 0.98Karnofsky score prior to transplant 0.72

<90 91 (30) 30 (32) >=90 197 (65) 58 (62) missing 14 ( 5) 6 ( 6)

Disease-related: Rai stage at diagnosis 0.31

Early (stages 0, I and II) 144 (48) 37 (39) Late (III and IV) 36 (12) 11 (12) missing 122 (40) 46 (49)

Symptoms at diagnosis 0.97A 126 (42) 40 (43) B 41 (14) 12 (13) missing 135 (45) 42 (45)

Prior radiation between diagnosis and tx 0.55No 157 (52) 44 (47) Yes 16 ( 5) 4 ( 4) missing 129 (43) 46 (49)

Number of prior lines of treatments 0.81≤2 63 (21) 19 (20) ≥3 99 (33) 28 (30) missing 140 (46) 47 (50)

Fludarabine therapy between diagnosis and transplant 0.04No 45 (15) 8 ( 9) Yes 152 (50) 41 (44) missing 105 (35) 45 (48)

Fludarabine-refractory between diagnosis and transplant 0.96No 48 (16) 13 (14) Yes 73 (24) 24 (26) Not applicable 172 (57) 54 (57) missing 9 ( 3) 3 ( 3)

32


Table 1. Continued.

Variable TBI Chemotherapy P-value*Chemotherapy-refractory between diagnosis and transplant

0.62

No 62 (21) 15 (16) Yes 92 (30) 28 (30) Not applicable 131 (43) 47 (50) missing 17 ( 6) 4 ( 4)

Best response after any therapy prior to tx 0.70continuing CR - CR - nodular PR - PR 127 (42) 35 (37) stable - progressive 28 ( 9) 9 (10) unknown 147 (49) 50 (53)

Hemoglobin level at transplant (g/dL) 0.41hgb > = 11 78 (26) 26 (28) hgb < 11 46 (15) 19 (20) missing 178 (59) 49 (52)

Platelets at transplant (x103/mm3) 0.38platelets > = 100 78 (26) 25 (27) platelets < 100 50 (17) 21 (22) missing 174 (58) 48 (51)

ANC at transplant 0.01Neutrophils = > 0.5 x 10^9/L at tx 108 (36) 40 (43) Neutrophils < 0.5 x 10^9/L at tx 6 ( 2) 7 ( 7) missing 188 (62) 47 (50)

Lymphocyte count at transplant (x 109/L) 0.64Lymphocyte count < 50 x 10^9/L at tx 110 (36) 39 (41) Lymphocyte count = > 50 x 10^9/L at tx 35 (12) 9 (10) missing 157 (52) 46 (49)

Splenectomy 0.91no 180 (60) 56 (60) yes 19 ( 6) 7 ( 7) missing 103 (34) 31 (33)

B symptoms present at transplant 0.01No 30 (10) 20 (21) Yes 14 ( 5) 4 ( 4) missing 258 (85) 70 (74)

Rai stage at transplant 0.72Early (CR; stages 0, I and II) 121 (40) 34 (36) Late (stages III and IV) 64 (21) 23 (24) missing 117 (39) 37 (39)

33


Table 1. Continued. Variable TBI Chemotherapy P-value* Bulky LAD at transplant: (< or ≥ 5cm) 0.59

No 159 (53) 47 (50) Yes 36 (12) 15 (16) missing 107 (35) 32 (34)

Extramedullary or extra-nodal disease at transplant 0.59No 128 (42) 37 (39) Yes 68 (23) 26 (28) missing 106 (35) 31 (33)

State of disease at transplant± 0.43CR/PR at tx 111 (37) 28 (30) Stable/Progressive at tx 82 (27) 30 (32) Unknown/Not evaluable/missing at tx 109 (36) 36 (38)

Transplant-related: Time from diagnosis to transplant, median (range), months 43 (2-236) 41 (6-198) 0.47** missing 3 0 Donor age, median (range), years 42 (13-69) 41 (18-67) 0.23**Donor age, years 0.76

<31 55 (18) 20 (21) 31-40 82 (27) 26 (28) >40 159 (53) 45 (48) missing 6 ( 2) 3 ( 3)

Donor recipient gender match 0.79M-M 118 (39) 41 (44) M-F 58 (19) 19 (20) F-M 88 (29) 23 (24) F-F 38 (13) 11 (12)

Donor-recipient CMV status 0.06Pos-pos 88 (29) 41 (44) Pos-neg 28 ( 9) 8 ( 9) Neg-pos 79 (26) 24 (26) Neg-neg 92 (30) 17 (18) Not tested/inconclusive 15 ( 5) 4 ( 4) Donor-recipient HLA match 0.68HLA-id sib and Related partially matched 159 (53) 47 (50) Related mismatched and Related matching unknown 15 ( 5) 3 ( 3) URD well-matched and URD partially matched 101 (33) 37 (39) URD mismatched and URD matching unknown and URD matching TBD

27 ( 9) 7 ( 7)

34


Table 1. Continued. Variable TBI Chemotherapy P-value*CD34 stem cell dose: (< or ≥ 5 x 106 cells/Kg) <.0001

<5 71 (24) 39 (41) >5 54 (18) 28 (30) missing 177 (59) 27 (29)

Graft type <.0001Bone marrow 179 (59) 32 (34) Peripheral blood 123 (41) 62 (66)

Year of transplant <.00011995 48 (16) 6 ( 6) 1996 45 (15) 6 ( 6) 1997 38 (13) 7 ( 7) 1998 23 ( 8) 7 ( 7) 1999 36 (12) 3 ( 3) 2000 14 ( 5) 8 ( 9) 2001 12 ( 4) 2 ( 2) 2002 12 ( 4) 7 ( 7) 2003 17 ( 6) 12 (13) 2004 13 ( 4) 13 (14) 2005 19 ( 6) 7 ( 7) 2006 18 ( 6) 8 ( 9) 2007 7 ( 2) 8 ( 9)

Year of transplant (grouped) <.00011995-1998 154 (51) 26 (28) 1999-2002 74 (25) 20 (21) 2003-2005 49 (16) 32 (34) 2006-2007 25 ( 8) 16 (17) GVHD prophylaxis 0.01none and other║ 5 ( 2) 3 ( 3) T-cell depletion 58 (19) 7 ( 7) FK506+MTX+-oth and FK506+MTX+-oth 82 (27) 38 (40) CsA+MTX+-oth and CsA+-oth 157 (52) 46 (49) ATG at conditioning or as GVHD prophylaxis <.0001No 284 (94) 67 (71) Yes 18 ( 6) 27 (29) Median (range) follow-up of survivors, m 84(3-159) 43(3.0-132) ---

*Chi-Square **Wilcoxon two-sample Test

The completeness index FU as of 12-31-08 is 72%. The completeness index FU at 1, 3, and 5 years is 96%, 88% and 79%, respectively. Additional follow up information is being sought from the centers. ║Centers will be contacted ±Additional information is being sought to reduce the proportion of missing data.

35


Table 1a. Characteristics of 396 CLL patients that underwent a myeloablative HCT from 1995-2007 and reported to the CIBMTR based on type of conditioning regimen (TBI based vs. chemotherapy based) and radiation dose intensity (TBI>1200 cGy vs. TBI ≤1200 cGy)

TBI = < 1200 TBI > 1200 Chemotherapy

Characteristics of patients: N (%) N (%) N (%) P-value*Number of patients 226 76 94 Number of centers 211 62 89 Age at transplant, median (range), years 49 (24-64) 44 (27-60) 50 (27-72) <0.0001**Age at transplant, years <0.0001

21-40 44 (19) 26 (34) 12 (13) 41-50 104 (46) 42 (55) 42 (45) >51 78 (35) 8 (11) 40 (43)

Male sex 149 (66) 57 (75) 64 (68) 0.34Karnofsky score prior to transplant 0.94

<90 68 (30) 23 (30) 30 (32) >=90 148 (65) 49 (64) 58 (62) missing 10 ( 4) 4 ( 5) 6 ( 6)

Disease-related: Rai stage at diagnosis 0.18

Early (stages 0, I and II) 113 (50) 31 (41) 37 (39) Late (III and IV) 29 (13) 7 ( 9) 11 (12) missing 84 (37) 38 (50) 46 (49)

Symptoms at diagnosis 0.16A 103 (46) 23 (30) 40 (43) B 31 (14) 10 (13) 12 (13) missing 92 (41) 43 (57) 42 (45)

Prior radiation between diagnosis and tx 0.25No 125 (55) 32 (42) 44 (47) Yes 12 ( 5) 4 ( 5) 4 ( 4) missing 89 (39) 40 (53) 46 (49)

Number of prior lines of treatments 0.07≤2 48 (21) 15 (20) 19 (20) ≥3 83 (37) 16 (21) 28 (30) missing 95 (42) 45 (59) 47 (50)

Fludarabine therapy between diagnosis and transplant

0.18

No 33 (15) 12 (16) 8 ( 9) Yes 115 (51) 37 (49) 41 (44) missing 78 (35) 27 (36) 45 (48)

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Table 1a. Continued. TBI = < 1200 TBI > 1200 Chemotherapy

Characteristics of patients: N (%) N (%) N (%) P-value*Fludarabine-refractory between diagnosis and transplant

0.60

No 38 (17) 10 (13) 13 (14) Yes 60 (27) 13 (17) 24 (26) not applicable 122 (54) 50 (66) 54 (57) Missing 6 ( 3) 3 ( 4) 3 ( 3)

Chemotherapy-refractory between diagnosis and transplant

0.12

No 50 (22) 12 (16) 15 (16) Yes 76 (34) 16 (21) 28 (30) not applicable 89 (39) 42 (55) 47 (50) missing 11 ( 5) 6 ( 8) 4 ( 4)

Best response after any therapy prior to tx 0.05continuing CR - CR - nodular PR - PR 103 (46) 24 (32) 35 (37) stable - progressive 24 (11) 4 ( 5) 9 (10) unknown 99 (44) 48 (63) 50 (53)

Hemoglobin level at transplant (g/dL) 0.17hgb > = 11 65 (29) 13 (17) 26 (28) hgb < 11 35 (15) 11 (14) 19 (20) missing 126 (56) 52 (68) 49 (52)

Platelets at transplant (x103/mm3) 0.05platelets > = 100 67 (30) 11 (14) 25 (27) platelets < 100 37 (16) 13 (17) 21 (22) missing 122 (54) 52 (68) 48 (51)

ANC at transplant 0.002Neutrophils = > 0.5 x 10^9/L at tx 89 (39) 19 (25) 40 (43) Neutrophils < 0.5 x 10^9/L at tx 6 ( 3) 0 7 ( 7) missing 131 (58) 57 (75) 47 (50)

Lymphocyte count at transplant (x 109/L) 0.26Lymphocyte count < 50 x 10^9/L at tx 88 (39) 22 (29) 39 (41) Lymphocyte count = > 50 x 10^9/L at tx 22 (10) 13 (17) 9 (10) missing 116 (51) 41 (54) 46 (49)

Splenectomy 0.04no 144 (64) 36 (47) 56 (60) yes 16 ( 7) 3 ( 4) 7 ( 7) missing 66 (29) 37 (49) 31 (33)

B symptoms present at transplant 0.01No 27 (12) 3 ( 4) 20 (21) Yes 10 ( 4) 4 ( 5) 4 ( 4) missing 189 (84) 69 (91) 70 (74)

37


Table 1a. Continued.

TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value*Rai stage at transplant 0.86

Early (CR; stages 0, I and II) 91 (40) 30 (39) 34 (36) Late (stages III and IV) 50 (22) 14 (18) 23 (24) missing 85 (38) 32 (42) 37 (39)

Bulky LAD at transplant: (< or ≥ 5cm) 0.03No 124 (55) 35 (46) 47 (50) Yes 32 (14) 4 ( 5) 15 (16) missing 70 (31) 37 (49) 32 (34)

Extramedullary or extra-nodal disease at transplant

0.004

No 103 (46) 25 (33) 37 (39) Yes 57 (25) 11 (14) 26 (28) missing 66 (29) 40 (53) 31 (33)

State of disease at transplant± 0.21CR/PR at tx 78 (35) 33 (43) 28 (30) Stable/Progressive at tx 68 (30) 14 (18) 30 (32) Unknown/Not evaluable/missing at tx

80 (35) 29 (38) 36 (38)

Transplant-related: Time from diagnosis to transplant, median (range), months

45 (4-236) 37 (2-137) 41 (6-198) 0.49**

Donor age, median (range), years 43 (13-69) 39 (13-66) 41 (18-67) 0.10**Donor age, years 0.50

<31 41 (18) 14 (18) 20 (21) 31-40 56 (25) 26 (34) 26 (28) >40 123 (54) 36 (47) 45 (48) missing 6 ( 3) 0 3 ( 3)

Donor recipient gender match 0.67M-M 88 (39) 30 (39) 41 (44) M-F 46 (20) 12 (16) 19 (20) F-M 61 (27) 27 (36) 23 (24) F-F 31 (14) 7 ( 9) 11 (12)

Donor-recipient CMV status 0.17Pos-pos 70 (31) 18 (24) 41 (44) Pos-neg 20 ( 9) 8 (11) 8 ( 9) Neg-pos 61 (27) 18 (24) 24 (26) Neg-neg 65 (29) 27 (36) 17 (18) Not tested/inconclusive 10 ( 4) 5 ( 7) 4 ( 4)

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TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value*Donor-recipient HLA match 0.16

HLA-id sib and Related partially matched

129 (57) 30 (39) 47 (50)

Related mismatched and Related matching unknown

11 ( 5) 4 ( 5) 3 ( 3)

URD well-matched and URD partially matched

69 (31) 32 (42) 37 (39)

URD mismatched and URD matching unknown and URD matching TBD

17 ( 8) 10 (13) 7 ( 7)

CD34 stem cell dose: (< or ≥ 5 x 106 cells/Kg)

<0.0001

<5 53 (23) 18 (24) 39 (41) >5 44 (19) 10 (13) 28 (30) missing 129 (57) 48 (63) 27 (29)

Graft type <0.0001Bone marrow 127 (56) 52 (68) 32 (34) Peripheral blood 99 (44) 24 (32) 62 (66)

Year of transplant <.00011995 38 (17) 10 (13) 6 ( 6) 1996 33 (15) 12 (16) 6 ( 6) 1997 31 (14) 7 ( 9) 7 ( 7) 1998 14 ( 6) 9 (12) 7 ( 7) 1999 20 ( 9) 16 (21) 3 ( 3) 2000 10 ( 4) 4 ( 5) 8 ( 9) 2001 8 ( 4) 4 ( 5) 2 ( 2) 2002 9 ( 4) 3 ( 4) 7 ( 7) 2003 12 ( 5) 5 ( 7) 12 (13) 2004 11 ( 5) 2 ( 3) 13 (14) 2005 17 ( 8) 2 ( 3) 7 ( 7) 2006 16 ( 7) 2 ( 3) 8 ( 9) 2007 7 ( 3) 0 8 ( 9)

Year of transplant (grouped) <.00011995-1998 116 (51) 38 (50) 26 (28) 1999-2002 47 (21) 27 (36) 20 (21) 2003-2005 40 (18) 9 (12) 32 (34) 2006-2007 23 (10) 2 ( 3) 16 (17)

39



TBI = < 1200 TBI > 1200 Chemotherapy Characteristics of patients: N (%) N (%) N (%) P-value*GVHD prophylaxis 0.03

none and other║ 4 ( 2) 1 ( 1) 3 ( 3) T-cell depletion 40 (18) 18 (24) 7 ( 7) FK506+MTX+-oth and FK506+MTX+-oth

66 (29) 16 (21) 38 (40)

CsA+MTX+-oth and CsA+-oth 116 (51) 41 (54) 46 (49) ATG at conditioning or as GVHD prophylaxis

<.0001

No 215 (95) 69 (91) 67 (71) Yes 11 ( 5) 7 ( 9) 27 (29)

Median (range) follow-up of survivors, m

75(3.5-159) 84(3.2-157) 43(3.0-132) ---

║Centers will be contacted. ±Additional information is being sought to reduce the proportion of missing data.

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CIBMTR CK06-03

COMPARISON OF CONVENTIONAL MYELOABLATIVE VS. NONMYELOABLATIVE OR REDUCED-INTENSITY CONDITIONING ALLOGENEIC HEMATOPOIETIC STEM CELL

TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA

REVISED PROTOCOL

Study Chairs: Jose F. Leis, MD, PhD

Adult Blood & Marrow Transplant Program Mayo Clinic 5777 East Mayo Boulevard Phoenix, Arizona 85054 Telephone: 480-342-2088 Fax: 480-342-2085 E-mail: [email protected]

Richard T. Maziarz, MD

Center for Hematologic Malignancies Oregon Health & Science University 3181 S.W. Sam Jackson Park Road Mail Code: UHN73C Portland, Oregon 97239 Telephone: 503-494-4606 Fax: 503-494-1552 E-mail: [email protected]

Ronald M. Sobecks, MD Taussig Cancer Center

The Cleveland Clinic 9500 Euclid Ave. R35 Cleveland, OH 44195 Telephone: 216-445-4626 Fax: 216-444-9464 E-mail: [email protected]

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Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin

CIBMTR 9200 West Wisconsin Ave Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin CIBMTR

8701 Watertown Plank Rd Milwaukee, WI 53226 Telephone: 414-456-7386 Fax: 414-456-6513 E-mail: [email protected] Scientific Directors: Mukta Arora, MD University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 Telephone: 612-626-4105 Fax: 612-625-6919 E-mail: [email protected] Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR

9200 W. Wisconsin Ave Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700

Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Matt Kalaycio, MD

The Cleveland Clinic Main Campus Mail Code R35 9500 Euclid Ave Cleveland, OH 44195 Telephone: 216-444-3705 Fax: 713-794-4297 E-mail: [email protected]

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Working Committee Chairs: Richard Maziarz, MD Oregon Health and Science University 3181 S W Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-6345 Fax: 503-494-1552 E-mail: [email protected] Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX 77030 Telephone: 713-794-5783 Fax: 713-794-4297 E-mail: [email protected]

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1.0 OBJECTIVES:

1.1 To compare the clinical outcomes between patients undergoing HLA-identical sibling or unrelated donor stem cell transplantation using conventional versus reduced intensity/nonmyeloblative (RIC/NST) conditioning regimen for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) as to the following:

− 30-day mortality; − 100-day mortality; − Engraftment (neutrophil recovery & platelet recovery); − Incidence and severity of acute graft-versus-host disease; − Incidence and severity of chronic graft-versus-host disease; − Treatment-related mortality; − Disease recurrence or progression; − Progression-free survival; − Overall survival.

1.2 To determine patient-, disease- and transplant-related variables associated with favorable

progression-free and overall survival outcomes among patients receiving conventional versus RIT/NST conditioning regimen for CLL.


Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia occurring in the western world (1). CLL represents 25-30% of the reported leukemia cases in the United States with 8,000 to 10,000 new cases diagnosed annually. CLL typically occurs in older people with a median age of onset in the seventh decade of life. CLL is characterized by accumulation of mature-appearing but biologically immature B lymphocytes. Etiologic factors of CLL remain undetermined. Unlike the acute leukemias and chronic myelogenous leukemia (CML), it is not associated with chemical exposure, radiation, or alkylating agents. The precise origin of the CLL lymphocyte remains unclear. CLL cells express pan-B cell antigens (e.g. CD19, CD20), as well as other characteristic surface antigens (CD5, CD23, CD25, CD71). Antigens common to terminally differentiated plasma cells are not present. However, the B-CLL cell phenotype differs from normal B cells in two ways. B-CLL cells express CD5, a pan-T cell antigen also expressed in a small subpopulation of B lymphocytes which do not undergo somatic hypermutation, and express low levels of surface immunoglobulin. Recently CD5+ B cells have been shown to be present in the mantle zone of normal lymph nodes. These CD5+ B cells are in increased in number in patients with autoimmune disorders such as rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus. These observations suggest that B-CLL may be a clonal proliferation of anergic CD5+ self-reactive B cells from the mantle zone which are involved in production of polyreactive autoantibodies. Specific clonal chromosomal abnormalities have been found using standard cytogenetic studies in the majority of patients with CLL (2). However, karyotypic analysis has been limited because of the slow growth kinetics of CLL and the difficulty in obtaining metaphases for analysis. The most common chromosomal abnormalities involve trisomy 12, a deletion in the long arm of chromosome 13 near the Rb (retinoblastoma gene) gene locus, and translocations into the Ig heavy-chain gene locus on chromosome 14q. Trisomy 12 has been associated with atypical morphology, progressive disease and decreased survival.

44


More recently molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH) have allowed more efficient detection of numerical and structural chromosome aberrations in the slow growing CLL. FISH analysis allows for the identification of chromosomal abnormalities in the interphase nuclei of non-dividing cells (“interphase cytogenetics”). These studies have demonstrated that prognosis of patients varies greatly depending on the genomic aberration present. Patients with mutations in chromosome 17p (p53 gene) or 11q (ATM) have markedly poorer survivals (median 2-3 years and 5-6 years respectively) and have limited responsiveness to standard therapies (3,4). New approaches utilizing molecular diagnostic assays can distinguish clinical subgroups of the disease. Immunoglobulin variable heavy chain gene mutational status reveal that there are two patient populations, characterized by variable chain mutational status with markedly different clinical outcomes with the unmutated subgroup having significantly shorter overall survival (4-7). Studies using gene expression profiling suggest that both the mutated and unmutated forms of CLL arise from memory B cells. These studies have also demonstrated that a protein called Zap-70 is the most differentially expressed protein between the different mutational subgroups and may serve as a surrogate marker for the unmutated form of B-CLL (8). Treatment of asymptomatic, early stage CLL patients with stable disease is usually not warranted (9). Alkylating agents (especially chlorambucil and cyclophosphamide) with or without steroids have historically been the first line of treatment for CLL. During the past 2 decades the purine analogs deoxycoformycin, cladribine and fludarabine have demonstrated promising results in multiple phase II and III studies in previously treated and untreated CLL patients and made fludarabine an acceptable first-line therapy in patients with symptomatic CLL. Recently humanized monoclonal antibodies directed at surface antigens on CLL cells (rituximab, anti-CD20 and alemtuzamab, anti-CD52) have improved the results of standard treatments with fludarabine and led to a doubling of the complete remission rates (60%-70%) and full molecular remissions. However, longterm followup is not available. Despite these advances the disease remains incurable with standard therapies. Multiple single institution and transplant registry studies have demonstrated that conventional myeloablative HLA-matched sibling donor stem cell transplantation can achieve high complete remission rates (70%) and durable 40-60% three to five-year overall survival in selected patients with relapsed CLL. Relapse rates after transplantation have been low presumably due to a graft versus leukemia (GVL) effect from the donor graft. However, conventional myeloablative transplantation has been associated with significant transplant related morbidity and mortality (30-40%) with graft versus host disease and infection being major causes of mortality (10). Although allogeneic bone marrow transplantation represents a potentially curative therapy its use is limited by significant procedure-related mortality, a lack of suitable HLA-matched donors, and the fact that with a median age of onset in the seventh decade most patients with CLL are ineligible for standard transplants. Recently RIT/NST has been applied to patients with CLL with encouraging results (11-14). RIT/NST has the potential benefits of:

− Lower acute toxicities and early transplant related mortality − Treatment of elderly patients feasible − Suitable for treatment of patients with co-morbid conditions − More readily applicable to the outpatient setting − Faster recovery with fewer complications and lower infection rate − Lower anticipated late effects

45


Evaluation of early phase II RIT/NST trials for relapsed CLL suggest decreased toxicity and treatment related mortality (15-25%) with durable 2 year PFS and OS in the 50-60% range despite an older patient cohort at time of transplant. In these early reports acute and chronic GVHD appear to remain a significant problem, possibly related to more rapid tapering of immune suppression therapy to achieve a GVL effect. Based on these preliminary reports that suggest decreased early toxicity and high rates of durable remission in CLL, there is increasing interest in the use of reduced intensity/nonmyeloblative conditioning for the treatment of CLL. This has led to the hypothesis that GVL mechanisms are the prime determinant of outcome in allogeneic transplantation for CLL and that the intensity of the conditioning regimen may be of secondary importance. Reduced intensity/nonmyeloblative conditioning is increasingly used around the world, but no single center has sufficient follow-up or sufficient patient numbers to identify the impact of this type of conditioning in particular disease entities. An analysis of large numbers of patients reported to the CIBMTR may allow us to effectively address this issue.


All CLL/SLL patients reported to the CIBMTR who underwent HLA-identical sibling or unrelated donor myeloablative or RIC/NST transplantation for relapsed/refractory CLL/SLL between 1999 and 2008.

4.0 OUTCOMES:

4.1 30-day mortality: time to death from any cause within 30 days post-transplant. 4.2 100-day mortality: time to death from any cause within 100 days post transplant 4.3 Hematopoietic recovery: The primary measures for hematopoietic recovery will be:

4.3.1 Time to neutrophils (ANC) > 0.5 x109/L sustained for three consecutive days.

This endpoint does not specify whether recovery is engraftment of donor cells or autologous reconstitution.

4.3.2 Time to achieve a platelet count of (a) >20 x 109/L independent of platelet transfusions for 3 consecutive days.

4.4 Incidence of acute GVHD: grade II-IV and grade III-IV 4.5 Incidence of chronic GVHD: limited and extensive. 4.6 Treatment-related mortality: death within the first 28 days of transplant from any cause or

death in complete remission of primary disease. 4.7 Relapse/ Progression: progressive disease or recurrence of disease are events.

Those who survive without recurrence or progressive disease are censored at the date of last contact. This event is summarized by the cumulative incidence estimate with TRM as the competing risk.

4.8 Progression-free survival: survival in continuous complete remission of primary disease.

Disease relapse, progression or death from any cause are events. Patients surviving without disease will be censored at time of last follow-up.

4.9 Overall survival: time to death. Patients are censored at time of last follow-up.

46



Patient-related: − Age at transplant: continuous − Gender: male vs. female − Karnofsky performance status at transplant: <=90% vs 90-100%

Disease-related:

− Disease stage at transplant: Rai stage 0/I/II vs. III/IV. Binet A will be considered equivalent to Rai stages 0/I/II. Binet B will correspond to Rai stage III and Binet C will be equivalent to Rai stage IV.

− B-symptoms at transplant: present vs. absent. − Elevated LDH at transplant: yes vs. no − Splenomegaly: yes vs. no − Bulky adenopathy (lymph nodes > vs. < 5 cm) − Number of prior chemotherapy regimens received: median and range − Relapse/Refractory to prior therapies: alkylating agents, fludarabine, rituximab,

alemtuzumab, and other regimens. − Extent of bone marrow involvement at transplant: > vs. < 50% − Disease status at transplant: CR1, PIF, CR2, etc − Prior antibody therapy: yes vs. no

Transplant-related:

− Time from diagnosis to transplant: − CD34+ cell dose infused − CD3+ cell dose infused − Proposed conditioning regimens and doses are:

− Traditional ablative: − CY+TBI (TBI dose > 500 cGy single or > 800 cGy fractionated) − CY+VP16+TBI (TBI dose > 500 cGy) − BU+CY − BU > 9 mg/kg − TBI > 500 cGy single or > 800 cGy fractionated − Melphalan > 150 mg/m2

− Non-myeloablative/ reduced-intensity:

− TBI dose = 200 cGy − Fludarabine + TBI dose = 200 cGY − Fludarabine + Ara-C + Ida − Fludarabine + cyclophosphamide − BU < 9 mg/kg − Melphalan < 150 mg/m2 − TBI < 500 cGy single fraction or < 800 cGy fractionated

− Donor-recipient gender match: M-M vs. M-F vs. F-M vs. F-F − Source of stem cells: bone marrow vs. peripheral blood − Year of transplant − ATG given for conditioning or GVHD prophylaxis − GVHD prophylaxis:

47


− Cyclosporin + methotrexate − Tacrolimus + methotrexate − Cyclosporine + mycophenolate − Other

− Donor-recipient HLA disparities 6.0 STUDY DESIGN:

The goal of this study is to compare the clinical outcomes, as listed in Section 4.0, between patients undergoing conventional versus RIC/NST HLA-identical sibling or unrelated donors allogeneic stem cell transplants for CLL while adjusting for significant patient-, disease-, and transplant-related variables.

Patient-, disease- and transplant- related factors will be compared between groups using the Chi-square test for categorical variables and the Wilcoxon two sample test for continuous variables.

The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time.

The probabilities of 30-day mortality, 100-day mortality, progression-free, and overall survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula.

Values for other endpoints included in Sec. 4.0 will be generated using cumulative incidence estimates to account for competing risks.

Cox proportional hazards regression will be used to compare the two conditioning regimens.

The variables to be considered in the multivariate models are listed in Sections 5.2-5.4. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. When this indicates differential effects over time (nonproportional hazards), models will be constructed breaking the post transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. First order interactions between main effect and significant covariates will be tested before and after stepwise modeling. After modeling time-varying effects and interactions, the final multivariate model will be built using a forward stepwise model selection approach. Factors significantly associated with the outcome variable at a 5% level will be kept in the final model. All p-values will be two-sided.

7.0 REFERENCES:

1. Chiorazzi N, Rai KR, Ferrarini M. Chronic Lymphoctyic Leukemia. N Engl J Med 2005; 352:804-815.

2. Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ, Parker AC, Castoldi GL, Cuneo A, Knuutila S, Elonen E, Gahrton G. Prognostic subgroups in B-Cell Chronic Lymphocytic Leukemia defined by specific chromosomal abnormalities. N Engl J Med 1990; 323:720-724.

3. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Eng J Med 2000; 343:1910-1916.

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4. Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE, Corcoran MM, Chapman RM, Thomas PW, Copplestone JA, Orchard JA, Hamblin TJ. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 2002; 100:1177-1184.

5. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94:1848-1854.

6. Naylor M, Capra J D. Mutational status of Ig VH genes provides clinically valuable information in B-Cell chronic lymphocytic leukemia. Blood 1999; 94:1837-1839.

7. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840-1847.

8. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004; 351:893-901.

9. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S, Rai KR. Blood 1996; 87:4990-4997. National Cancer Institute-sponsored working group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-4997.

10. Dreger P, Montserrat E. Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia 2002; 16:985-992.

11. Ritgen M, Stilgenbauer S, von Neuhoff N, Humpe A, Bruggemann M, Pott C, Raff T, Krober A, Bunjes D, Schlenk R, Schmitz No, Dohner H, Kneba M, Dreger P. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104: 2600-2602.

12. Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Delilier GL, Martino R, Russel N, van Biezen A, Michallet M, Niederwieser D. Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 2003; 17:841-848.

13. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, Woolfrey AE, Chauncey TR, Flowers ME, Mielcarek M, Maloney DG, Storb R. Graft-Versus-Tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. JCO 2005; 23:1993-2003.

14. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. JCO 2005; 23:3819-3829.

49


Table 1. Characteristic of patients who underwent HLA-identical sibling or unrelated donor myeloablative or RIC/NST transplantation for relapsed/refractory CLL/SLL reported to the CIBMTR between 1999-2008

Characteristics HLA-iden sibs + MA

HLA-iden sibs +

RIC/NMA URD + MA URD +

RIC/NMA Patient-related

Number of patients 77 186 133 434Number of centers 45 71 57 100Age, median(range), years 51 (40 - 62) 57 (40 - 70) 51 (40 - 69) 57 (40 - 70)

40-49 34 (44) 32 (17) 55 (41) 81 (19)50-59 39 (51) 102 (55) 64 (48) 202 (47)60-70 4 ( 5) 52 (28) 14 (11) 151 (35)

Gender Male 55 (71) 133 (72) 90 (68) 341 (79)Female 22 (29) 53 (28) 43 (32) 93 (21)

Karnofsky score pretransplant <90% 24 (31) 61 (33) 39 (29) 122 (28)>=90% 51 (66) 117 (63) 83 (62) 269 (62)Missing 2 ( 3) 8 ( 4) 11 ( 8) 43 (10)

Disease-related Rai stage at diagnosis

Early Rai stages (0/I/II) 46 (60) 126 (68) 47 (35) 89 (21)Late Rai stages (III/IV) 19 (25) 33 (18) 24 (18) 33 ( 8)Missing 12 (16) 27 (15) 62 (47) 312 (72)

Rai stage prior to conditioning Complete remission 3 ( 4) 15 ( 8) 5 ( 4) 13 ( 3)0/I/II 44 (57) 86 (46) 43 (32) 54 (12)III/IV 29 (38) 70 (38) 25 (19) 47 (11)Missing 1 ( 1) 15 ( 8) 60 (45) 320 (74)

B-symptoms at diagnosis Absent 48 (62) 107 (58) 40 (30) 81 (19)Present 18 (23) 35 (19) 25 (19) 29 ( 7)Unknown 11 (14) 44 (24) 68 (51) 324 (75)

Elevated LDH at transplant No 33 (43) 83 (45) 32 (24) 63 (15)Yes 32 (42) 67 (36) 44 (33) 63 (15)Unknown 12 (16) 36 (19) 57 (43) 308 (71)

Splenectomy No 70 (91) 163 (88) 21 (16) 33 ( 8)Yes 5 ( 6) 12 ( 6) 0 3 (<1)Missing 2 ( 3) 11 ( 6) 112 (84) 398 (92)

50


Table 1. Continued.


HLA-iden sibs +


RIC/NMA Bulky adenopathy

>=5 cm 12 (16) 19 (10) 18 (14) 30 ( 7)<5 cm 26 (34) 52 (28) 27 (20) 55 (13)Unknown/missing 39 (51) 115 (62) 88 (66) 349 (80)

Number of lines of therapy received prior to transplant, median(range)

3 (1 - 5) 3 (1 - 5) 3 (1 - 5) 3 (1 - 5)

Prior therapy received or not No 1 ( 1) 1 (<1) 0 0Yes a 60 (78) 105 (56) 77 (58) 124 (29)Missing 16 (21) 80 (43) 56 (42) 310 (71)

Refractory to prior therapy Yes 40 (67) 70 (67) 29 (38) 45 (36)No 17 (28) 31 (30) 46 (60) 74 (60)Unknown/missing 3 ( 5) 4 ( 4) 2 ( 3) 5 ( 4)

CLL involvement of bone marrow prior to conditioning

<50% 20 (26) 59 (32) 28 (21) 66 (15)>=50% 8 (10) 46 (25) 26 (20) 41 ( 9)Missing 49 (64) 81 (44) 79 (59) 327 (75)

Disease status at transplant CR/PR/nPR 43 (56) 104 (56) 13 (10) 12 ( 3)Stable/progressive 32 (42) 77 (41) 10 ( 8) 22 ( 5)Unknown/untreated/not evaluable 2 ( 3) 5 ( 3) 110 (83) 400 (92)

Transplant-related Time from diagnosis to transplant, median (range),

months 45 (6 - 223) 56 (5 - 239) 46 (6 - 236) 63 (3 - 234)

Missing 0 0 2 ( 2) 11 ( 3)CD34+ cell dose, median(range), 10^6/kg 5 (1 - 13) 5 (1 - 43) 6 (1 - 22) 6 (1 - 37)

Missing 13 (17) 19 (10) 67 (50) 210 (48)CD3+ cell dose, median(range), 10^6/kg 11 (1 - 51) 3 (2 - 25) 10 (3 - 43) 23 (1 - 49)

Missing 57 (74) 176 (95) 120 (90) 411 (95)

51


Table 1. Continued.


HLA-iden sibs +


RIC/NMAProposed conditioning regimens and doses

cy+tbi>500cGY-single-tbi>800cGY-fract 44 (57) 0 82 (62) 0bu+cy 19 (25) 0 19 (14) 0tbi<500cGY-single-tbi<800cGY-fract 0 47 (25) 0 143 (33)lpam<=150 mg/m^2 0 23 (12) 0 66 (15)bu<=9 mg/kg 0 23 (12) 0 108 (25)tbi=200cGY 0 1 (<1) 0 0flud+cy 0 74 (40) 0 91 (21)tbi=>500cGY-single-tbi>=800cGY-fract 4 ( 5) 0 4 ( 3) 0lpam>150 mg/m^2 1 ( 1) 0 8 ( 6) 0bu>9 mg/kg 9 (12) 0 20 (15) 0CBV 0 2 ( 1) 0 3 (<1)arac+others 0 0 0 2 (<1)cy+cortico 0 0 0 1 (<1)flud+/-others 0 2 ( 1) 0 0flud+atg+/-others 0 1 (<1) 0 1 (<1)tbi+flud 0 2 ( 1) 0 0tai+cy 0 1 (<1) 0 0tli+atg 0 10 ( 5) 0 18 ( 4)Missing 0 0 0 1 (<1)

Donor-recipient sex match M-M 32 (42) 78 (42) 60 (45) 218 (50)F-F 9 (12) 27 (15) 18 (14) 35 ( 8)M-F 12 (16) 26 (14) 24 (18) 43 (10)F-M 23 (30) 55 (30) 23 (17) 90 (21)Missing 1 ( 1) 0 8 ( 6) 48 (11)

Source of stem cells Bone marrow 19 (25) 6 ( 3) 58 (44) 75 (17)Peripheral blood 58 (75) 180 (97) 75 (56) 359 (83)

Donor-recipient HLA disparities HLA-identical sibling 77 186 0 0Well-matched, unrelated 0 0 58 (44) 214 (49)Partially matched, unrelated 0 0 11 ( 8) 43 (10)Mismatched, unrelated 0 0 38 (29) 92 (21)HLA data unknown, unrelated 0 0 26 (20) 85 (20)

ATG given for conditioning or GVHD prophylaxis Yes 8 (10) 28 (15) 28 (21) 113 (26)No 69 (90) 157 (84) 105 (79) 321 (74)Missing 0 1 (<1) 0 0

52


Table 1. Continued.


HLA-iden sibs +


RIC/NMA GVHD prophylaxis

T-cell depletion 10 (13) 2 ( 1) 7 ( 5) 4 (<1)FK506+MTX +/- other 15 (19) 39 (21) 56 (42) 160 (37)FK506 +/- other 5 ( 6) 23 (12) 17 (13) 113 (26)CsA+MTX +/- other 39 (51) 47 (25) 45 (34) 26 ( 6)CsA +/- other 6 ( 8) 71 (38) 4 ( 3) 117 (27)Other b 0 2 ( 1) 4 ( 3) 6 ( 1)Missing 2 ( 3) 2 ( 1) 0 8 ( 2)

Year of transplant 1999 20 (26) 8 ( 4) 11 ( 8) 4 (<1)2000 12 (16) 20 (11) 9 ( 7) 16 ( 4)2001 5 ( 6) 25 (13) 5 ( 4) 15 ( 3)2002 9 (12) 25 (13) 10 ( 8) 23 ( 5)2003 8 (10) 24 (13) 16 (12) 44 (10)2004 4 ( 5) 22 (12) 18 (14) 46 (11)2005 8 (10) 27 (15) 19 (14) 45 (10)2006 9 (12) 26 (14) 16 (12) 80 (18)2007 2 ( 3) 9 ( 5) 13 (10) 67 (15)2008 0 0 16 (12) 94 (22)

Median follow-up of survivors, range, months 76 (3 - 133) 46 (2 - 113) 49 (3 - 121) 37 (<1 - 110)a 25 patients received antibody therapy in HLA-iden sibs+MA; 55 patients received antibody therapy in HLA-iden sibs+RIC/NMA; 6 patients received antibody therapy in URD+MA; 9 patients received antibody therapy in URD+RIC/NMA. b Other includes MMF/MTX. Abbreviations: FK506 = tacrolimus; CSA = cyclosporine; MTX = methosrexate; TBI = total body radiation; Cy = cyclophosphamide; Bu = Busulfan Completeness index as of 12/31/2009 Follow-up Overall population

(%) HLA-iden Sibs +

MA (%) HLA-iden Sibs + RIC/NMA (%)

URD + MA (%)

URD + RIC/NMA

(%) Overall 82 76 63 79 88 1-year 97 92 93 96 98 2-year 94 89 87 92 95 3-year 79 87 82 87 70 5-year 60 77 67 74 45

Selection/exclusion steps # Excluded # Remaining cases

First transplant for CLL/SLL reported 1999-2008 973 Excluded twin and other relative 17 956 Excluded cord blood 31 925 Restrict age between 40 - 70 73 852 Excluded missing survival status 1 851 Excluded regimen intensity unknown 21 830

53


CIBMTR CK06-04

DECISION ANALYSIS OF ALLOGENEIC BONE MARROW TRANSPLANTATION FOR MYELOFIBROSIS: COMPARISON OF ALLOGENEIC STEM CELL TRANSPLANTATION

AND NON TRANSPLANTATON THERAPIES FOR MYELOFIBROSIS

DRAFT PROTOCOL Study Chair: Karen Ballen, MD

Hematology/Oncology Division Massachusetts General Hospital Zero Emerson, Suite 118 Boston, MA 02114 Telephone: 617-724-1124 Fax: 617-724-1126 E-mail: [email protected]

Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-7387 Fax: 414-456-6513 E-mail: [email protected]

54


Scientific Directors: Mukta Arora, MD University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 Telephone: 612-626-4105 Fax: 612-625-6919 E-mail: [email protected] Wael Saber, MD, MS

The Medical College of Wisconsin CIBMTR

9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Matt Kalaycio, MD The Cleveland Clinic Main Campus Mail Code R35 9500 Euclid Ave Cleveland, OH 44195 Telephone: 216-444-3705 Fax: 713-794-4297 E-mail: [email protected] Richard T. Maziarz, MD Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-6345 Fax: 503-494-1552 E-mail: [email protected]

Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX 77030 Telephone: 713-794-5783 Fax: 713-794-4297 E-mail: [email protected]

55


1.0 OBJECTIVES:

1.1 To compare overall survival with hematopoietic cell transplantation (HCT) and with non-transplantation therapies for myelofibrosis.

1.2 To determine appropriate patient-,disease-, and transplant-related selection criteria for transplantation in patients with myelofibrosis.


Myelofibrosis is a presenting feature of or develops in advanced stages of rmyeloproliferative disorders. Characteristics include splenomegaly, marrow fibrosis, and the presence of circulating immature white and red blood cells. (1) The pathology of myelofibrosis is related to abnormal clonal myeloproliferation with collagen fibrosis, osteosclerosis, and neo-angiogenesis in the bone marrow. (2) Several investigators have described prognostic factors in myelofibrosis; for example, in one series age greater than 60 years, weight loss, hemoglobin < 10g/dl, white blood count <4 or >30 x 109/l, and an abnormal karyotype were associated with shortened survival. (3,4) The Mayo prognostic scoring system identified a platelet count <100,000 and a monocyte count >1000 as indicative of poor prognosis. (5) Recently, patients with normal cytogenetics, sole 20q-, and sole 13q- deletions were found to have favorable survival. (6) In 2006, a consensus group published International Working Group criteria for treatment response in patients with myelofibrosis. (7) Recently, the myeloproliferative disorders polycythemia vera and essential thrombocythemia have been linked to a gain-of-function mutation in the Janus Kinase 2 (JAK2) gene located on chromosome 9. (8) About 50% of patients with primary myelofibrosis are positive for the JAK2 mutation. However the significance of this mutation for the prognosis of myelofibrosis and for the choice of treatment options is not known. Most strategies for treatment of myelofibrosis are supportive, including blood transfusions, hydroxyurea, and androgens. (9) There are ongoing trials of interferon and thalidomide. (10,11) Thalidomide is effective in some patients with idiopathic myelofibrosis treated early in the disease. (11) In one study of 63 patients, half of the patients tolerated daily doses of more than 100 mg, 39% become transfusion independent for variable periods of time, and 19% had a reduction in spleen size. (12) Allogeneic HCT is the only known treatment modality with curative potential. Reported three year probabilities of survival have ranged from 38% to 56 %. (13,14) Recently, the CIMBTR has analyzed the outcome in 320 patients undergoing allogeneic HCT for myelofibrosis. (15) Overall survival at four years was 43% for HLA identical sibling donor transplants, 34% for transplants from an alternative related donor, and 31% for patients receiving unrelated donor grafts. Younger patients with a good performance status and no circulating blasts did better. However, this study did not address how to select appropriate patients or how to decide the appropriate timing for transplant. Reduced intensity or nonmyeloablative conditioning regimens may be best suited to the older population of patients with myelofibrosis. In the CIBMTR study cited above, 57 patients received a nonmyeloablative regimen. (15) Additional patients were transplanted in years 2003 and 2004. Several small series have also reported on nonmyeloablative HCT for myelofibrosis. Twenty-one patients received a fludarabine based conditioning regimen, and 17 of 21 were alive and in remission, with a median follow up of 31 months. (16)

56


The CIBMTR has analyzed outcomes for transplantation and non-transplant therapies in another disease group, myelodysplastic syndromes. In that study, a Markov decision analysis was used to determine the optimal timing of HCT. (17) Delayed transplantation maximized survival in low risk patients, but reduced the number of life years in patients with more advanced disease. The study proposed here seeks to establish similar guidelines for patients with myelofibrosis, which could provide guidance to transplant physicians and non-transplant hematologists.


The study population includes all patients with myelofibross reported to the CIBMTR between 1989 and 2004 or to the Fred Hutchinson Cancer Center database and who received an allogeneic transplant. Patients receiving HCT from a sibling, other related, or unrelated donors after either an ablative or nonmyeloablative conditioning will be included. This represents the database already analyzed for the ongoing myelofibrosis study, but with the addition of patients transplanted in the years 2003 and 2004 and with the addition of patients from the same time period transplanted in Seattle. (15) These additions will results in the inclusion of more patients conditioned with nonmyeloablative regimens. These patients will be matched for age and date of diagnosis with non-transplant patients under the age of 70 years from the database of the Mayo clinic (Dr. Tefferi) and Italian database (Dr. Barosi).

4.0 OUTCOMES:

Overall Survival: Time to death from any cause. Overall survival at one, three, five, and ten years after diagnosis will be presented.

5.0 VARIABLES TO BE DESCRIBED:

Patient-related: − Age − Gender − Performance status

Disease-related:

− Disease (primary vs post- polycythemia vera or post-essential thrombocythemia) − Disease stage − Dupriez score/Mayo score − Time from diagnosis to transplant − Circulating blasts − Hb <10 g/dl − WBC > 30 x 109/l − Platelet count <100,000 − Monocyte count >1000 − Cytogenetics—favorable (normal, sole 20q-, sole 13q-) vs all others − JAK 2 mutation if available − Splenomegaly

Treatment-related: − Transplant

− Donor − HLA match

57


− Source of stem cells (BM vs PBPC) − Conditioning Regimen (ablative vs nonmyeloablative) − Year of HCT − Splenectomy, yes/no

− Non transplant − Splenectomy, yes/no − Hydroxyurea − Other medical therapies − Supportive care

6.0 STUDY DESIGN:

The major objective is to compare the outcomes between transplant and non transplant groups. The data needed is currently on the CIBMTR data collection forms; no additional data collection would be needed. However, stored samples for NMDP patients (N=74) may be used for JAK 2 analysis An analysis similar to that by Cutler et al, which studied treatment strategies for patients with MDS, will be performed. (16) A Markov decision model will be constructed. Dr. Cutler has agreed to assist with this analysis.

7.0 SAMPLE SIZE:

There are 320 patients from the initial analysis of transplantation outcomes. Additional patients will be added from 2003 and 2004. Additional patients from the same time period will be added from the Seattle database. Patients will be matched with the population that did not receive HCT that is represented from the Italian and Mayo clinic databases. Only patients under the age of 70 will be included.

8.0 REFERENCES:

1. Mesa R, Steensma, Pardanani A, et al: A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelodysplasia with myeloid metaplasia. Blood 2003; 101:2534-2541.

2. Dupriez B, Mrel P, Demary JL, et al: Prognostic factors in agnogenic myeloid metaplasia: a report of 195 cases with a new scoring system. Blood 1996; 88: 1013-18.

3. Cervantes F, Pereria A, Esteve J, et al: Identification of “short-lived” and “long- lived” patients at presentation of idiopathic myelofibrosis. Brit J Hematol 1997; 97: 635-37.

4. Tefferi A, Huang J, Schwager S, et al: Validation and comparison of contemporary prognostic models in primary myelofibrosis. Cancer 2007; 109: 2083-8.

5. Dingli D, Schwager SM, Mesa RA, Li CY, Dewald GW, Tefferi A: Presence of unfavorable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis. Cancer 2006; 106: 1985-9.

6. Tefferi A, Barosi G, Mesa RA, et al: International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT) Blood 2006; 108: 1497-1503.

7. Kralovics R, Passamonti F, Buser AS, et al: A gain-of-function mutation of JAK2 kinase in myeloproliferative disorders. New Engl J Med 2005; 352: 1779-90.

8. Smith BD, Moliterno AR: Biology and management of idiopathic myelofibrosis. Current Opinion in Oncology 2001; 13: 91-4.

58


9. Bachleitner-Hofmann T, Gisslinger H: The role of interferon alpha in the treatment of idiopathic myelofibrosis. Annals of Hematology 1999; 78: 533-38.

10. Canepa L, Ballerina F, Valardo R, et al: Thalidomide in agnogenic and secondary myelofibrosis. Brit J Hematol 2001; 115: 313-315.

11. Marchetti, Barosi G, Balestri F, et al: Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a Phase II trial. J Clin Oncol 2004; 22: 424-31.

12. Deeg HJ, Gooley TA, Flowers MED, et al: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102: 3912-3918.

13. Guardiola P, Anderson JE, Bandini G, et al: Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Societe Francaise de Greffe de Moelle, Gruppos Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood 1999; 93: 2831-39.

14. Ballen KK, Sobocinski KA, Zhang MJ, et al: Outcome of bone marrow transplantation for myelofibrosis. Blood 2005; 106: 170a.

15. Rondelli D, Barosi G, Bacigalupo A, et al: Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 2005; 105: 4115-4119.

16. Cutler CC, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104: 579-85.

59


Table 1. Characteristics of all the patients who underwent allogeneic transplantation for Myelofibrosis and reported to the CIBMTR, from 1989 to 2002

Variable

N eval

Identical sibling

N eval

Other related

N eval

Unrelated

Number of patients 170 33 117Age at transplant, N (%) 170 45 (<1 - 73) 33 40 (<1 - 65) 117 47 (1 - 69) < 10 years 5 (3) 5 (15) 5 (4) 10 – 19 years 3 (2) 3 (9) 4 (3) 20 – 29 years 14 (8) 2 (6) 7 (6) 30 – 39 years 38 (22) 6 (18) 15 (13) 40 – 49 years 64 (38) 8 (24) 40 (34) 50 – 59 years 36 (21) 7 (21) 39 (33) ≥ 60 years 10 (5) 2 (6) 7 (6)Male sex, N (%) 170 106 (62) 33 21 (64) 117 65 (56)Karnofsky score prior to transplant, N (%)

166 32 113

< 90 64 (39) 9 (28) 56 (50) ≥ 90 102 (61) 23 (72) 57 (50)Time from diagnosis to transplant, N (%)

170 11 (<1 - 196) 33 10 (2 - 157) 115 13 (<1 - 317)

Graft type, N (%) 170 33 117 BM 102 (60) 20 (61) 86 (73) PBSC / BM + PBSC 68 (40) 13 (39) 31 (27)Regimen types, N (%) 170 33 117 Traditional ablative 138 (81) 29 (88) 83 (71) RIC 20 (12) 3 (9) 16 (14) Non-myeloablative 4 (2) 0 14 (12) Non-traditional ablative 3 (2) 1 (3) 4 (3) Unknown 5 (3) 0 0GVHD prophylaxis 166 28 116 MTX + CsA ± other 108 (65) 15 (54) 62 (53) MTX ± other 13 (8) 1 (4) 18 (16) CsA ± other 34 (20) 4 (14) 19 (16) T-depletion ± other 4 (2) 7 (25) 13 (11) Other or none 7 (4) 1 (4) 4 (3)Year of transplant, N (%) 170 33 117 1989 - 1995 56 (33) 6 (18) 16 (14) 1996 - 2002 114 (67) 27 (82) 101 (86)Median (range) follow-up of survivors, months 76 41 (3 - 136)

1132 (7 - 118) 37

48 (4 - 124)

Abbreviations: EVAL = evaluable; BM = bone marrow; PBSC = peripheral blood stem cells. Note: overall completeness is 85%.

60


CIBMTR CK08-01

EVALUATION OF THE OUTCOME OF ALLOGENIC STEM CELL TRANSPLANTATION FOR CHRONIC MYELOID LEUKEMIA (CML) IN PATIENTS WITH RESISTANCE TO

IMATINIB OR SECOND GENERATION TYROSINE KINASE INHIBITORS (TKIS) EITHER (I) ASSOCIATED WITH ABL KINASE DOMAIN MUTATIONS OR (II) NOT ASSOCIATED

WITH MUTATIONS.

DRAFT PROTOCOL

Study Chairs: Andrew Grigg, MD Royal Melbourne Hospital Grattan Street, Victoria Melbourne, Australia 3050 Telephone: 61-3-342-7695 Fax: 61-3-342-7386 E-mail: [email protected]

Tim Hughes, MD The Hanson Center for Cancer Research Frome Road Adelaide, Australia 5000 Telephone: 61-88-222-3330 Fax: 61-88-222-3139 E-mail: [email protected]

Jeffrey Szer, MD

Royal Melbourne Hospital Grattan Street, Parkville Victoria 3050 Australia Telephone: 61-3-9342-7737 Fax: 61-3-9342-7386

E-mail: [email protected] Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected]

61


PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-7387 Fax: 414-456-6513 E-mail: [email protected] Scientific Directors: Mukta Arora, MD University of Minnesota Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 Telephone: 612-626-4105 Fax: 612-625-6919 E-mail: [email protected]

Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700

Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Matt Kalaycio, MD

The Cleveland Clinic Main Campus Mail Code R35 9500 Euclid Ave Cleveland, OH 44195 Telephone: 216-444-3705 Fax: 713-794-4297 E-mail: [email protected] Richard T. Maziarz, MD Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-6345 Fax: 503-494-1552 E-mail: [email protected] Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX 77030 Telephone: 713-794-5783 Fax: 713-794-4297


62


1.0 OBJECTIVES: To assess the progression free and overall survival of patients undergoing an allograft for CML who have with resistance to imatinib or second generation TKIs, either due to mutations or other mechanisms. The key issue is whether conditioning and/or graft vs. leukemia (GVL) effects are sufficiently powerful to overcome the otherwise poor prognosis of this condition.


2.1 The commonest underlying mechanism of secondary imatinib resistance in CML is emergence of point mutations in the ABL kinase domain (reviewed by Kantarjian, Ann Int Med 2006; 149:913-923). These mutations can directly impede contact between BCR-ABL and imatinib or alter the spatial conformation of the protein (ATP-binding phosphate or “P” loop mutations and activation loop mutations) which results in the inability to assume the inactive conformation required for imatinib binding. These mutations may confer only a moderate degree of resistance and be overcome by dose escalation or be associated with absolute resistance to imatinib (reviewed by Shah, Haematology 2005; 183-187). P-loop mutations are associated with a significantly worse survival than other mutations (Branford et al, Blood 2003; Nicolini, Leukemia 2006; 20:1061-1066), although second generation TKIs such as dasatinib or nilotinib may be effective in some cases. E225K/V and Y253H mutations, for example, are highly resistant to imatinib, are partially resistant to nilotinib/dasatinib and have greater transformation potency. T3151 mutations are resistant to currently available TKIs and may also have a poor prognosis.

2.2 Current recommendations for allografting in CML is now largely restricted to patients with

imatinib resistance (Grigg, BBMT 2006 12:795-807). The effectiveness of allografting in this context is not well described and in particular there is a paucity of information about the relative impact of the different sorts of mutations on outcome, whether these mutations are differentially sensitive to GVL effects and whether they are of additional prognostic significance to the EBMT risk score (Gratwohl, Lancet 1998;352:1087-1092). The investigators are aware of only two peer-reviewed published reports in this area, each with a small number of patients. A recent publication (Oehler Blood 2007; 109:1782-1789) found that (i) pre-transplant exposure to imatinib did not increase early hepatotoxicity or engraftment delay and (ii) mortality was higher in CP patients transplanted with a suboptimal response or loss of response to imatinib compared with patients transplanted in complete or major cytogenetic response. Mutations were identified in only 12 of 103 evaluated patients in the study (but note that 38/72 patients in CP were transplanted with imatinib-responsive disease), with relapse occurring in two patients with a P-loop or T3151 mutation. Jabbour et al (Blood 2006; 108: 1421-1423) described 9 CML patients with imatinib-resistance due to kinase mutations who underwent an allograft. Two relapsed (T3151, E225K mutations in AP, BP respectively at transplant); the remaining 7 patients remained alive in complete molecular response at a median of 19 months post-transplant.

2.3 A less frequent, but still significant proportion of imatinib resistant disease is not associated

with mutations, especially in patients with primary resistance. A proportion of these are attributable to overproduction of BCR-ABL and the others to a mechanism independent of BCR-ABL (Shah 2005). The Oehler paper only partially addresses the issue of allograft outcome. Of the 72 patients transplanted in CP or better, less than half (31 patients; 45%) had imatinib resistance. Survival was inferior in patients transplanted with a suboptimal

63


cytogenic response (minor or minimal) or loss of response to imatinib, but was not evaluated separately within these categories or within the mutation vs. non mutation patients.

3.0 PATIENT ELIGIBILITY CRITERIA:

− Patients of any age undergoing an allograft for imatinib-resistant CML

Resistance is defined as follows using the European recommendations (Baccarini Blood 2006) as a guideline. − Primary resistance:

− Failure – no haematological response or < 1log reduction in BCR-ABL (>10% on international scale) by 3 months, Ph+ >95% at 6 months, Ph+>35% at 12 months

− Suboptimal response - < CHR at 3 months, Ph+ 36-95% at 6 months, Ph+1-35% at 12 months.

Note, that ideally these groups (failure vs. suboptimal) should be evaluated separately as the outlook for each is quite distinct.

− Secondary resistance: any of the following − Loss of CHR − Loss of major cytogenetic response (MCR): ≥ 20% increase in Ph+ cells to > 35% Ph+

cells in a marrow sample containing at least 20 metaphases in a patient in previous MCR.

− Loss of complete cytogenetic response (CCR): an increase to ≥ 10 % Ph+ cells in a marrow sample containing at least 20 metaphases in a patient in previous CCR

− Loss of molecular response: ≥ 5 fold rise in BCR-ABL transcripts in peripheral blood from nadir to a level > 1%.

− Any disease stage, donor source, conditioning regimen and type of reconstituting stem cell

source will be allowed.

Note that the investigators would like the advice of the CIBMTR about whether other organisation(s) e.g. EBMT should be involved and, if so, the logistics of so doing.


− “Standard” pre-transplant information already available i.e. date of transplant, age, sex of recipient and donor source, conditioning regimen, stem cell source, GVHD prophylaxis etc.

− CML specific information

− time of diagnosis to transplant − CML therapy prior to TKI (e.g. interferon, excluding hydroxyurea) − mutation detected group:

− summary of initial response to imatinib (haematological, cytogenic, molecular) and whether resistance is primary to secondary. Includes duration of imatinib therapy prior to detection of mutation and when it was first detected

− type of mutation and whether it is minor (<50%) or predominant (>50%). − therapeutic change in response to mutation detection (e.g. imatinib dose increase,

change to second generation TKI etc, response to this change and duration of this altered therapy prior to transplant.

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– mutation not detected group: − summary of initial response to imatinib and documentation whether resistance is

primary or secondary, incuding duration and dose of imatinib therapy − details of therapeutic change in response to resistance (e.g. second generation TKI),

as above. − Specific disease status at BMT: CP vs. AP vs. BC, complete haematological response

(CHR) or not, cytogenetic status and, if available, BCR-ABL % using international standardised scale.

− Post-transplant outcome

− achievement of CR based on cytogenetic and molecular criteria − PFS and overall survival − relapse – time, disease status, mutation status, clonal evolution. − response (haematological, cytogenetic, molecular) in cases of relapse to immunological

manipulation (cessation of I/S, DLI etc) and further therapy, in particular commencement of other TKIs.

− influence of acute and chronic GVHD on relapse risk. − early TRM not related to GVHD (ie. to detect unexpected organ toxicity from prior TKI

exposure, including dasatinib and nilotinib )

The data are bold font above do not appear to be currently collected on the CML-specific insert of the CIBMTR forms. Accordingly, protocol-specific CRFs will need to be designed and sent out to participating institutions.

5.0 STUDY DESIGN:

The following key analyses are suggested: 5.1 Generation of Kaplan-Meier curves of PFS and OS for all patients and for the following

subsets 5.1.1 Presence of a kinase domain mutation pre-transplant: all patients subdivided (a)

according to the anatomical type of mutation (T315I, P-loop, non-P-loop) and (b) the type of mutation based on resistance profile: fully resistant mutation - T315I (approximately 13%), highly resistant mutations - E255K/V and Y253H/F (approximately 20%) and partially resistant mutations (approximately 67%)

5.1.2 Resistance not associated with a mutation. Subject to numbers, curves will be generated for this group (a) as a whole and (b) according to the following subsets: primary resistance (failure vs. sub-optimal) and secondary resistance.

5.2 Multivariate analysis of pre-transplant factors influencing PFS and OS in the study population, including proven variables such as EBMT score (donor source, stage, age and F→M), but with the addition of (i) mutation type (ii) conditioning regimen (standard vs. reduced intensity) (iii) T cell depletion and (iv) PBPC vs. marrow. In addition in patients in CHR at transplant, the impact of % Ph+ (no vs. minor vs. major vs. complete cytogenetic response) and % BCR-ABL (< major vs. major molecular response) may be analysed if the numbers are sufficient.

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5.3 Statistical analysis of the impact of acute GVHD (grades 0-1, 2-4) and chronic GVHD (nil vs. limited vs. extensive) on relapse. In addition, description analysis of the outcome of relapse in response to (i) cessation of I/S, DLI etc. and, if feasible, statistical analysis of the impact of any subsequent GVHD on response and its durability (ii) the commencement of newer TKIs (e.g. dasatinib for a non-T3151 mutation)

5.4 Descriptive analysis of the causes of d100 TRM 5.5 Subject to feasibility and advice from the CIBMTR, a comparison of the outcome of the

study population with appropriate historical controls (e.g. matched for EBMT score) from the CIBMTR database who were transplanted in the pre-imatinib era.

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Table 1. Characteristics of all the patients who underwent allogeneic transplantation for CML in patients with resistance to Imatinib and reported to the CIBMTR, from 1999 to 2006a

Variable N eval N (%)Number of patientsa 579Number of centers 124Age, median (range), years 579 42 (10-71)Age at transplant, years 579 ≤10 1 (<1) 11-20 35 ( 6) 21-30 82 (14) 31-40 138 (24) 41-50 154 (27) >50 169 (29)Male sex 579 368 (64)Karnofsky score at transplant 160 (30) < 90% 368 (70) >= 90% Interval from diagnosis to transplant (months) 579 20 (1-343)Disease stage 579

Early 122 (21)Intermediate/advanced 457 (79)

Donor 579 HLA-identical sibling 233 (40)Twin 2 (<1)related 21 ( 4)unrelated 320 (56)

Conditioning regimen 579 Traditional ablative 374 (65)

RIC 119 (20)Non-myeloablative 24 ( 4)Non-traditional ablative 45 ( 8)TBD 17 ( 3)

Graft type 579 BM 206 (36)PBSC 373 (64)

Donor-recipient CMV status 546 +/+ 215 (39) +/- 55 (10) -/+ 133 (24) -/- 143 (26)Donor/recipient gender match 575

M-M 225 (39)M-F 120 (21)F-M 139 (24)F-F 91 (16)

TBI for conditioning regimen 579 Yes 240 (41)No 339 (59)

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Table 1. Continued. Variable N eval N (%)Year of transplant 579

1999 2 (<1)2000 9 ( 2)2001 53 ( 9)2002 104 (18)2003 132 (23)2004 153 (26)2005 91 (16)2006 35 ( 6)

GVHD prophylaxis 579 MTX+CsA ± others 280 (48) FK506+MTX ± others 161 (28) CsA ± others 63 (11) FK506 ± others 31 ( 5) T-cell depletion 25 ( 4)

Other 7 ( 1)None 11 ( 2)Missing 1 (<1)

Median follow-up of survivors, months 285 24 (2-73)Abbreviations: GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus; BM = bone marrow; PB = peripheral blood; FK506 = tacrolimus; a Selection criterion: All cases who underwent first allogeneic tx from year 1999 to 2006 for imatinib resistant CML (N=607), Twin tx excluded (N=579). Imatinib resistance: CP1 patients who either had clonal abnormality/other cytogenetic abnormality in addition to original Ph-chromosome;All >CP1 patients; All the patients from 1999 to 2004 who reported imatinib resistance on gleevec supplemental form (CK03-01). **IBMTR (n=394); NMDP (n=185) N=509 imatinib resistant CML from CIBMTR database (1999-2006) N=180 imatinib resistant CML from gleevec supplemental forms (1999-2004) Two data set merged and duplicates excluded (N=607) Twin tx excluded (N=579)

Suggestion from last meeting: only NMDP unrelated population on which samples might be available are to be selected. Steve Spellman sent information on the IDs with samples available through the NMDP Research Sample Repository. There are 152 out of 186 NMDP unrelated (~82%) with sufficient material for analysis. Next step: Final approval for use of the samples requires a protocol review by the NMDP Histocompatibility Advisory Group that serves as the repository oversight committee.

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CIBMTR CK08-02

RESULTS OF ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANTIONTION IN PATIENTS WITH HAIRY CELL LEUKEMIA

DRAFT PROTOCOL

Study Chairs: Robert J. Kreitman, MD

National Cancer Institute 9000 Rockville Pike Bethesda, MD 20892 Telephone: 301-496-6947 Fax: 240-255-0739 E-mail: [email protected]

Steven Pavletic, MD

National Cancer Institute National Institutes of Health 10 Center Drive Building 10, Hatfield CRC, Room 4-3130 Bethesda, MD 20892 Telephone: 301-402-4899 Fax: 302-480-4354 E-mail: [email protected]

Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin

CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-7387 Fax: 414-456-6513 E-mail: [email protected]

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Scientific Directors: Mukta Arora, MD University of Minnesota Division of Hematology/Oncology & Transplant Box 480 Mayo Building 420 Delaware Street SE Minneapolis, MN 55455 Office: 612-626-4105 Fax: 612-625-6919 E-Mail: [email protected] Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Matt Kalaycio, MD

The Cleveland Clinic Main Campus Mail Code R35 9500 Euclid Ave Cleveland, OH 44195 Telephone: 216-444-3705 Fax: 713-794-4297


Richard T. Maziarz, MD Oregon Health and Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-6345 Fax: 503-494-1552 E-mail: [email protected] Jorge Cortes, MD M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, TX 77030 Telephone: 713-794-5783 Fax: 713-794-4297 E-mail: [email protected]

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Hairy cell leukemia (HCL) is B-cell malignancy comprising 2% of all leukemias (1, 2), and is highly responsive but not curable with known therapy. Recent studies have shown response rates of 95-100% with either pentostatin or cladribine. CR rates are > 79-95%, and most patients remain in CR at median follow-up times of 9-15 years (3-5). Moreover, 50-70% of patients undergoing a 2nd course of cladribine achieve CR (3, 4, 6). Despite these excellent results, refractory hairy cell leukemia is a problem with increasing clinical importance. This is based on the absence of a plateau in the disease free survival curves for HCL patients treated with either pentostatin or cladribine (3, 4, 6), indicating that these agents are not curative. PCR and Southern blot analyses of patients in CR after cladribine also confirm lack of cure (7, 8). Rituximab has significant activity in HCL, with a total of 18 CRs out of 60 patients (30%) treated on 4 small trials (9-12). Trials with the highest CR rates (53-55%) were small and included patients without pre-existing cytopenias. Rituximab was reported to eradicate circulating HCL cells by PCR (13, 14). However, the PCR test, which used consensus primers, is less sensitive than flow cytometry of the blood, a test capable of detecting 1 HCL cells out of 10,000 cells normal cells. Although rituximab also eradicates circulating HCL by flow cytometry (14), high sensitivity PCR utilizing clonogenic primers and probes is capable of detecting HCL in flow-negative samples (15). Less effective treatments for HCL include splenectomy and interferon (16) which are now used palliatively. LMB-2 and BL22 are recombinant immunotoxins targeting CD25 and CD22 with truncated Pseudomonas exotoxin, and with response rates > 80% in HCL patients who are resistant to purine analogs (17-20). CRs are observed with both agents and are reported in >60% of patients after BL22 (20). Since purine analogs are not curative for HCL, and repeat remissions generally occur with decreasing likelihood and durability, HCL patients over time become resistant and require alternative innovative therapies. Allogeneic hematopoietic stem cell transplantation (HSCT) has shown potent immunotherapeutic effects in patients with indolent B-cell malignancies, such as CLL or follicular lymphoma, and it is plausible to investigate it’s efficacy in patients with HCL. Since the median age of patients with HCL is 54, a high percentage of patients can be expected, eventually, to die of their disease. Non-myeloablative stem cell transplantation is potentially an attractive option for patients suffering life-threatening complications of HCL, as it not only offers the goal of transfusion independence and remission, but also of cure. It may also be argued that patients with HCL might respond better to allogeneic transplantation if it were undertaken prior to the development of life-threatening complications. Bone marrow transplantation, either syngeneic or allogeneic, was reported in 1985 and suggested to be curative for this disease (21, 22). However, very few details are known about these patients and there are no other reports in the literature providing guidance about the possible efficacy of allogeneic HSCT in refractory HCL. We therefore propose analyzing the CIBMTR registry data for all patients with HCL who have undergone allogeneic (or syngeneic) HSCT and to describe their characteristics prior to transplant and their outcomes.


Patients with HCL who received allogeneic or identical twin HSCT reported to CIBMTR.

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Information would be obtained from the standard CIBMTR data collection forms and from the chronic leukemia disease-specific forms.

We would propose collecting:

− Age at original diagnosis − CBC, spleen and lymph node, bone marrow status at diagnosis − prior treatments for HCL − Responses and complications of prior treatments for HCL − Age and disease status at transplant, including CBCs, spleen, lymph node, bone marrow

status and infections if any − HLA matching characteristics of donor graft, including gender and relationship, stem cell

source, cell dose − Type of transplant conditioning regimen − GVHD prophylaxis − Post-transplant outcomes: engraftment, acute and chronic GVHD, major toxicities,

survival, causes of death − Disease response and assessment of minimal residual disease.

If feasible a consideration will be given to consenting survivors for obtaining bone marrow and peripheral blood samples for the real time assessment of minimal residual disease.

4.0 ENDPOINTS:

− Primary: Overall and Progression-free survival. − Secondary: engraftment, acute and chronic GVHD, disease response and progression, non-

relapse mortality. 5.0 STUDY DESIGN:

Descriptive, KM curves, cumulative incidence curves. 6.0 REFERENCES:

1. Cheson, B.D.Martin, A.: 1987.Clinical trials in hairy cell leukemia. Current status and future directions [published erratum appears in Ann Intern Med 1987 Oct;107(4):604], Ann Intern Med. 106: 871-878

2. Bouroncle, B.A., Wiseman, B.K.Doan, C.A.: 1958.Leukemic reticuloendotheliosis, Blood. 13: 609-630

3. Else, M., Ruchlemer, R., Osuji, N., DelGiudice, I., Matutes, E., Woodman, A., Wotherspoon, A., Swansbury, J., Dearden, C.Catovsky, D.: 2005.Long remissions in hairy cell leukemia with purine analogs - A report of 219 patients with a median follow-up of 12.5 years, Cancer. 104: 2442-2448

4. Chadha, P., Rademaker, A.W., Mendiratta, P., Kim, B., Evanchuk, D.M., Hakimian, D., Peterson, L.C.Tallman, M.S.: 2005.Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term follow-up of the Northwestern University experience, Blood. 106: 241-246

5. Goodman, G.R., Burian, C., Koziol, J.A.Saven, A.: 2003.Extended follow-up of patients with hairy cell leukemia after treatment with cladribine, J Clin Oncol. 21: 891-896.

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6. Saven, A., Burian, C., Koziol, J.A.Piro, L.D.: 1998.Long-term follow-up of patients with hairy cell leukemia after cladribine treatment, Blood. 92: 1918-1926

7. Filleul, B., Delannoy, A., Ferrant, A., Zenebergh, A., Van Daele, S., Bosly, A., Doyen, C., Mineur, P., Glorieux, P., Driesschaert, P., Sokal, C., Martiat, P.Michaux, J.L.: 1994.A single course of 2-chloro-deoxyadenosine does not eradicate leukemic cells in hairy cell leukemia patients in complete remission, Leukemia. 8: 1153-1156

8. Carbone, A., Reato, G., Di Celle, P.F., Lauria, F.Foa, R.: 1994.Disease eradication in hairy cell leukemia patients treated with 2- chlorodeoxyadenosine [letter], Leukemia. 8: 2019-2020

9. Hagberg, H.Lundholm, L.: 2001.Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia, Br J Haematol. 115: 609-611.

10. Lauria, F., Lenoci, M., Annino, L., Raspadori, D., Marotta, G., Bocchia, M., Forconi, F., Gentili, S., La Manda, M., Marconcini, S., Tozzi, M., Baldini, L., Zinzani, P.L.Foa, R.: 2001.Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia, Haematologica. 86: 1046-1050.

11. Nieva, J., Bethel, K.Saven, A.: 2003.Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia, Blood. 102: 810-813

12. Thomas, D.A., O'Brien, S., Bueso-Ramos, C., Faderl, S., Keating, M.J., Giles, F.J., Cortes, J.Kantarjian, H.M.: 2003.Rituximab in relapsed or refractory hairy cell leukemia, Blood. 102: 3906-3911

13. Cervetti, G., Galimberti, S., Andreazzoli, F., Fazzi, R., Cecconi, N., Caracciolo, F.Petrini, M.: 2004.Rituximab as treatment for minimal residual disease in hairy cell leukaemia, European Journal of Haematology. 73: 412-417

14. Ravandi, F., Jorgensen, J.L., O'Brien S, M., Verstovsek, S., Koller, C.A., Faderl, S., Giles, F.J., Ferrajoli, A., Wierda, W.G., Odinga, S., Huang, X., Thomas, D.A., Freireich, E.J., Jones, D., Keating, M.J.Kantarjian, H.M.: 2006.Eradication of minimal residual disease in hairy cell leukemia, Blood. 107: 4658-4662

15. Arons, E., Margulies, I., Sorbara, L., Raffeld, M., Stetler-Stevenson, M., Pastan, I.Kreitman, R.J.: 2006.Minimal residual disease in hairy cell leukemia patients assessed by clone-specific polymerase chain reaction, Clin Cancer Res. 12: 2804-2811

16. Habermann, T.M.: 2006.Splenectomy, interferon, and treatments of historical interest in hairy cell leukemia, Hematol Oncol Clin North Am. 20: 1075-1086

17. Kreitman, R.J., Wilson, W.H., Robbins, D., Margulies, I., Stetler-Stevenson, M., Waldmann, T.A.Pastan, I.: 1999.Responses in refractory hairy cell leukemia to a recombinant immunotoxin, Blood. 94: 3340-3348

18. Kreitman, R.J., Wilson, W.H., White, J.D., Stetler-Stevenson, M., Jaffe, E.S., Waldmann, T.A.Pastan, I.: 2000.Phase I trial of recombinant immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies, J. Clin. Oncol. 18: 1614-1636

19. Kreitman, R.J., Wilson, W.H., Bergeron, K., Raggio, M., Stetler-Stevenson, M., FitzGerald, D.J.Pastan, I.: 2001.Efficacy of the Anti-CD22 Recombinant Immunotoxin BL22 in Chemotherapy-Resistant Hairy-Cell Leukemia, New. Engl. J. Med. 345: 241-247

20. Kreitman, R.J., Squires, D.R., Stetler-Stevenson, M., Noel, P., Fitzgerald, D.J., Wilson, W.H.Pastan, I.: 2005.Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies, J Clin Oncol. 23: 6719-6729

21. Cheever, M.A., Fefer, A., Greenberg, P.D., Appelbaum, F., Armitage, J.O., Buckner, C.D., Sale, G.E., Storb, R., Witherspoon, R.P.Thomas, E.D.: 1982.Treatment of hairy-cell leukemia with chemoradiotherapy and identical-twin bone-marrow transplantation, N Engl J Med. 307: 479-481

22. Appelbaum, F.R.Thomas, E.D.: 1985.Treatment of acute leukemia in adults with chemoradiotherapy and bone marrow transplantation, Cancer. 55: 2202-2209

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Table 1. Characteristics of Hair Cell Leukemia patients receiving allogeneic HCT registered to the CIBMTR, 1980-2006.

Variables N eval N (%)Number of patients 16 Number of teams 14 Age, median (range), years 16 42 (20 – 62) Age at transplant, years 16 20 – 29 2 (13) 30 – 39 5 (31) 40 – 49 5 (31) 50 – 59 2 (13) 60 – 69 2 (13) Male sex 16 12 (75) Year of transplant 16 1983-1989 5 (31) 1990-1999 6 (38) 2000-2006 5 (31) Graft type 16 BM 9 (60) PBSC 6 (40) Missing (n=1) Donor 16 HLA-identical sibling 11 (69) Other related donor 4 (25) Unrelated donor 1 ( 6) Conditioning regimen 16

CY + TBI +- oth 6 (37)Busulf+CY+-oth 3 (19)CY +- other 2 (13)Other** 5 (31)

GVHD prophylaxis 16 CsA +- other (not MTX) 4 (25)MTX +- other (not CsA) 1 ( 6)MTX + CsA +- other 6 (38)CsA + MMF +- Other 1 ( 6)Other 1 ( 6)None 3 (19)

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Table 1. Continued.

**Other (n=5): Flud+Radmab+other (n=1); ATG+Bleo (n=1); TLI+ATG (n=1); other (n=2)

Variables N eval N (%)Form due status 16 Report form recieved 7 (44) Report form due 3 (19) Exempted for research 4 (25) Registration team 2 (12) Survival status 16 Alive 7 (44) dead 7 (44) unknown 2 (12) Median follow-up of survivors, months 9 68 (11-200)

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CIBMTR CK09-01

A COMPARISON OF OUTCOMES OF MINIMAL INTENSITY AND REDUCED INTENSITY CONDITIONING REGIMENS FOR PATIENTS WITH MYELOFIBROSIS

DRAFT PROTOCOL

Study Chairs: Vikas Gupta, MD

Blood and Marrow Transplant Program Princess Margaret Hospital Suite 5-217, 610-University Avenue Toronto, M5G 2M9, Canada, Telephone: 416-946-4521 Fax: 416-946-6546 E-mail: [email protected]

Adriana K. Malone, MD Bone Marrow Transplant Program Mount Sinai Medical Center One Gustave L. Levy Place, Box 1410 New York, NY 10029

Telephone: 212-241-6021 Fax: 212-410-0978 E-mail: [email protected]

Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin . CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-7387 Fax: 414-456-6513 E-mail: [email protected]

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Scientific Directors: Mukta Arora, MD University of Minnesota 420 Delaware St. SE, MMC 480 Minneapolis, MN 55455 USA Telephone: 612-626-4105 Fax: 612-625-6919 E-mail: [email protected]

Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500

Milwaukee, WI 53226 Telephone: 414-805-0700 Fax: 414-805-0714 E-mail: [email protected] Working Committee Chairs: Matt Kalaycio, MD




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1.0 OBJECTIVES:

1.1 Primary: To evaluate and compare the outcomes of minimal intensity and reduced intensity conditioning regimens in patients with myelofibrosis. Outcomes of interest: − Hematopoietic recovery (neutrophil and platelet recovery) − Acute and chronic graft-versus-host disease (GVHD) − Relapse risk − Non-relapse mortality − Progression-free survival − Overall Survival

1.2 Secondary:

− To study the graft-versus-myelofibrosis effect


Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative treatment modality for patients with myelofibrosis. The curative potential of alloHCT is related to a combination of the reduction or eradication of the malignant clone by the conditioning regimen and a Graft-versus-Myelofibrosis effect.1,2 In the last decade, several studies have demonstrated the feasibility and curative potential of non-myeloablative transplants in the management of myelofibrosis.3-8 A recent study from the chronic leukemia working committee of the CIBMTR showed that patients undergoing transplants using non-myeloablative conditioning had similar outcomes to those treated with conventional intensity conditioning.9 Another multicenter retrospective study comparing the outcomes of conventional intensity and reduced intensity transplants showed equivalent survival outcomes and trend towards better survival for older patients treated with non-myeloablative conditioning.10 The median age of patients at the onset of myelofibrosis is 65 years.11 Given that non-myeloablative transplants have curative potential in patients with myelofibrosis, there has been increase in use of non-myeloablative transplants for older patients with myelofibrosis. A wide spectrum of intensity of chemotherapy and or radiation therapy has been used for non-myeloablative transplants for myelofibrosis and the optimum intensity is not known. For example Seattle group has used a minimal intensity protocol (truly non-ablative) with fludarabine in a dose of 90 mg/m2 with or without 200 cGy of TBI12; on the other hand other groups have used relatively more intense protocols using combinations of fludarabine and busulphan5,7,8 or fludarabine and melphalan.4,13 A previous study from MD Anderson compared the outcome of nonablative versus reduced intensity conditioning regimens in patients with AML/MDS and showed better outcomes with reduced intensity regimens compared to minimal intensity regimens.14 Whether or not a dose effect is relevant in patients with myelofibrosis is not known? Given the rarity of myelofibrosis and low transplant activity for this disease, a large data source such as CIBMTR will be required to answer such question. The outcomes of this study will assist a transplant physician to select the optimum conditioning intensity for non-myeloablative transplantation and provide useful information for the design of future prospective clinical trials.

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Using the CIBMTR database, patients with myelofibrosis who underwent transplant between 1997 and 2006 and meet the following criteria will be identified.

Eligible patients: Patients with idiopathic or primary myelofibrosis (PMF) or post-polycythemic –myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF), who meet the following criteria: − Inclusion criteria (should meet all the criteria):

− First allogeneic transplant − Treated with a conditioning regimen thought to be non-myeloablative* by the treating

centre − A related or unrelated donor

− Exclusion criteria − Patients whose disease had progressed to AML prior to transplant − Syngeneic transplants − Cord blood transplants − Haplo-identical transplants − In Vitro T-cell depletion

* We have used the term non-myeloablative transplants collectively for minimal intensity and reduced intensity transplants as we feel this will be the best way to identify these patients as transplant centres fill this information on the reporting forms. Non-myeloablative transplants will be divided in two cohorts of patients: minimal intensity and reduced intensity. The division of patients into minimal intensity and reduced intensity will be done on the basis of current working definition of CIBMTR.

4.0 OUTCOMES:

4.1 Hematopoietic recovery: Time to neutrophils (ANC) >0.5 x 109/L (first of 3 consecutive days) and time to platelets ≥20 x 109/L (first of 3 consecutive days and no platelet transfusions 7 days prior)

May also look at chimerism data if available (stats centre to advise about the availability of

chimerism data) 4.2 Acute GVHD: Occurrence of grade II, III and/or IV skin, gastrointestinal or liver

abnormalities fulfilling the Consensus criteria of acute GVHD.

4.3 Chronic GVHD: Occurrence of symptoms in any organ system fulfilling the criteria of chronic GVHD

4.4 Relapse: time to transformation to leukemia or disease progression. This event will be

summarized by cumulative incidence estimate with TRM as the competing risk 4.5 Treatment-related mortality: time to death without evidence of disease relapse. This event

will be summarized as cumulative incidence estimate with relapse/progression as the competing risk.

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4.6 Leukemia-free survival: will be defined as time to relapse, leukemia transformation or death from any cause. Patients are censored at last follow-up.

4.7 Overall survival: Time to death, patients censored at last follow-up


Patient-related: - Age: <40 vs. 40-60 vs. >60 years (will be studied as continuous variable also) - Gender - Performance scores: <90 vs ≥90 - Comorbidities: none versus one versus more than one versus unknown (which

comorbidity will be screened from the data base to be decided)

Disease-related: - Aetiology of myelofibrosis: Idiopathic vs. post polycythemia myelofibrosis versus post

ET myelofibrosis - Type of Myelofibrosis: acute myelofibrosis versus with myeloid metaplasia - Constitutional symptoms: present vs. absent vs. unknown - Osteomyelosclerosis: yes/no/unknown - Blasts in PB prior to transplant: absent vs. ≥1% vs. <1% vs. unknown - Splenectomy prior to transplant: yes/no/unknown - Splenomegaly prior to transplant (only among patients without splenectomy):

yes/no/unknown - Cytogenetics: abnormal versus normal versus unknown - Time from diagnosis to transplant: <12 months versus 12-24 months versus >24

months - Hb prior to transplant <10 versus ≥10 versus unknown - WBC count prior to transplant - Number of lines of treatment prior to transplant - Risk stratification (Lille score)15*: Low vs. Intermediate vs. high vs. unknown - Risk Stratification (new Cerventes score)16**: Low vs. Intermediate 1 vs. Intermediate

2 vs. High vs. unknown - JAK 2 mutation: present/absent/unknown

*Lille Score15: In patients where both Hb and WBC count available, scoring will be done based on published criteria: Hb <10g/DL will be score 1, and Hb≥10 will be score 0; WBC count <4 or >30 x 109/Lwill score 1 and anything else will be score 0. Based on the scores, patients will be divided in 3 categories: Low (score 0), intermediate (score 1) and high (score 2) ** New prognostic scoring system by Cervantes et al16: Age >65 years, Hb <10g/DL, PB Blasts ≥1%, presence of constitutional symptoms, WBC count >25 x 109/L will be scored 1, all others will be scored zero. Based on total score: patient will be divided in 4 categories: Low (score 0); Intermediate 1 (score 1); intermediate 2 (score 2); high (score 3 or more) or unknown

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Transplant-related: - Graft type: BM versus PB versus mixed - TBI in conditioning regimen (cGy): ≤200 versus >200 but <500 versus >500 - Donor type: HLA identical sibling versus other related versus well matched URD vs.

partially matched URD vs. mismatched URD - GVHD prophylaxis: Calcineurin inhibitor (CsA or FK 506) + Methotrexate versus

calcineurin inhibitor (CsA or FK 506) + mycophenolate versus others - Serotherapy used (ATG or alemtuzumab or campath): yes/no - Year of transplant: 1997-2001 versus 2002-2006 - Donor-recipient gender match: M-M vs M-F vs F-M vs F-F - Donor-recipient CMV serostatus: +/+ vs. +/- vs. -/+ vs. -/- - CD34+cell dose x 106/kg for PB Tx / TNC for BM grafts - ABO incompatibility: none vs. minor vs. major vs. bidirectional - Planned Growth factor initiated within 7 days post-transplant: yes/no

Post-transplant:

- Did patient receive DLI anytime post transplant (yes/no) - If yes, date of DLI - If yes, Indication of DLI – decreasing chimerism or graft failure / relapse or

progression / unknown - Outcome of DLI - Did patient receive second allograft (yes/no) - If yes, date of second graft - Indication of second allograft (relapse or progression / graft failure / unknown)

6.0 ANALYSIS PLAN:

Patient-, disease-, and transplant-related variables for patients receiving minimal intensity and reduced intensity transplants will be compared using chi-square statistic for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate probabilities of LFS and survival will be calculated using the Kaplan-Meier estimator; the log-rank test will be used for univariate comparisons. Probabilities of hematopietic recovery, acute and chronic GVHD, treatment-related mortality and relapse will be calculated using cumulative incidence curves to accommodate competing risks. Assessment of potential risk factors for outcomes of interest will be evaluated in multivariate analyses using Cox proportional hazards regression

7.0 REFERENCES:

1. Cervantes F, Rovira M, Urbano-Ispizua A, et al: Complete remission of idiopathic myelofibrosis following donor lymphocyte infusion after failure of allogeneic transplantation: demonstration of a graft-versus-myelofibrosis effect. Bone Marrow Transplant 26:697-9, 2000

2. Byrne JL, Beshti H, Clark D, et al: Induction of remission after donor leucocyte infusion for the treatment of relapsed chronic idiopathic myelofibrosis following allogeneic transplantation: evidence for a 'graft vs. myelofibrosis' effect. Br J Haematol 108:430-3, 2000

3. Rondelli D, Barosi G, Bacigalupo A, et al: Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 105:4115-9, 2005

4. Snyder DS, Palmer J, Stein AS, et al: Allogeneic hematopoietic cell transplantation following reduced intensity conditioning for treatment of myelofibrosis. Biol Blood Marrow Transplant 12:1161-8, 2006

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5. Kroger N, Zabelina T, Schieder H, et al: Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. Br J Haematol 128:690-7, 2005

6. Merup M, Lazarevic V, Nahi H, et al: Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens. Br J Haematol 135:367-73, 2006

7. Kroeger N, Holler E, Kobbe G, et al: Dose-Reduced Conditioning Followed by Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis. Results from a Multicenter Prospective Trial of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). ASH Annual Meeting Abstracts 110:683-, 2007

8. Kroger N, Holler E, Kobbe G, et al: Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 114:5264-70, 2009

9. Ballen KK, Shrestha S, Sobocinski KA, et al: Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant, 2009

10. Gupta V, Kroger N, Aschan J, et al: A retrospective comparison of conventional intensity conditioning and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis. Bone Marrow Transplant 44:317-20, 2009

11. Kvasnicka HM, Thiele J, Werden C, et al: Prognostic factors in idiopathic (primary) osteomyelofibrosis. Cancer 80:708-19, 1997

12. Kerbauy DM, Gooley TA, Sale GE, et al: Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplant 13:355-65, 2007

13. Snyder DS, Palmer J, Gaal K, et al: Improved Outcomes Using Tacrolimus/Sirolimus for Graft Versus Host Disease prophylaxis with a Reduced Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis. Biol Blood Marrow Transplant, 2009

14. de Lima M, Anagnostopoulos A, Munsell M, et al: Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 104:865-72, 2004

15. Dupriez B, Morel P, Demory JL, et al: Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 88:1013-8, 1996

16. Cervantes F, Dupriez B, Pereira A, et al: New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113:2895-901, 2009

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Table 1. Characteristics of patients with Myelofibrosis who underwent Non-myeloablative or Reduced intensity allogeneic transplants from related or unrelated donors, reported to the CIBMTR, from 1997 and 2006**

RIC a Non-myeloablative Variable N eval N (%) N eval N (%)Number of patients 97 49 Number of centers 46 20 Age, median (range), years 97 54 (31-73) 49 53 (33-74) Age at transplant, years 97 49 31 - 40 7 ( 7) 4 ( 8) 41 - 50 22 (23) 10 (20) >50 68 (70) 35 (72) Male sex 97 61 (63) 49 36 (73) Karnofsky score at transplant 91 45

<90% 39 (43) 13 (29) ≥90% 52 (57) 32 (71) Time from diagnosis to transplant, months 97 19 (2-316) 49 17 (2-198) Donor 97 49

HLA-identical sibling 36 (37) 13 (27)Unrelated 61 (63) 36 (73)

Graft type 97 49

BM 15 (15) 16 (33)PBSC 82 (85) 33 (67)

Year of transplant 97 49

1997-1998 5 ( 5) 1 ( 2)1999-2000 8 ( 8) 4 ( 8)2001-2002 16 (16) 14 (29)2003-2004 25 (26) 14 (29)2005-2006 43 (45) 16 (32)Donor-recipient CMV status 91 44 +/+ 31 (35) 12 (27) +/- 14 (15) 8 (18) -/+ 21 (23) 11 (25) -/- 25 (27) 13 (30)

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Table 1. Continued. RIC Non-myeloablative Variable N eval N (%) N eval N (%)Donor/recipient gender match 97 49

M-M 42 (43) 26 (54)M-F 21 (22) 9 (18)F-M 19 (20) 10 (20)F-F 15 (15) 4 ( 8)

Regimen 97 49 TBI<500cGY-single- TBI <800cGY-fract 8 ( 8) 0 lpam<=150 mg/m^2 37 (38) 0

bu<=9 mg/kg 51 (53) 0 TBI =200cGY 0 26 (53)flud+cy 0 23 (47)vp16+cy 1 ( 1) 0

GVHD prophylaxis 97 49

FK506+MTX +/- other 21 (22) 3 ( 6)FK506 +/- other 18 (19) 5 (10)MTX+CsA +/- other 37 (38) 16 (33)CsA +/- other 18 (19) 24 (49)Other 3 ( 2) 1 ( 2)

Median follow-up of survivors, months 61 17 (3-114) 23 18 (3-18) Abbreviations: CML = chronic myelogenous leukemia; AML= acute myelogenous leukemia; GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus; BM = bone marrow; PB = peripheral blood; Cy=cyclophosphamide

** Eligibility criterion: − Patients with Myelofibrosis who underwent first allogeneic transplants − from related or unrelated donors, reported to the CIBMTR, from 1997 and 2006 (N=339) − Cord blood excluded (N=335; 4 excluded) − Syngeneic and haploidentical transplant excluded (N=328, 7 excluded) − T-cell depletion excluded (N=319; 9 excluded) − Selecting only RIC and non-myeloablative (N=146: RIC=97, NMA=49)

*** 23 patients out of 146 were identified from other specified field of MPS, MFS, and MDS

a NMAR (non-myeloablative regimen) and RIC (Reduced intensity conditioning) were categorized as per CIBMTR working

definition.

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CIBMTR CK10-01

THE IMPACT OF TREATMENT WITH SECOND-GENERATION TYROSINE KINASE INHIBITORS ON THE OUTCOME OF HEMATOPOIETIC CELL TRANSPLANTATION FOR

PATIENTS WITH CHRONIC MYELOID LEUKEMIA

DRAFT PROTOCOL Study Chairs: Richard Maziarz, MD Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-5058 Fax: 503-494-1552 E-mail: [email protected] Jeffrey Szer, MD Royal Melbourne Hospital Grattan St. Victoria, 3050 Australia Telephone: 61-3-9342-7737 Fax: 61-3-9342-7386 E-mail: [email protected] Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin

CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-7387 Fax: 414-456-6513 E-mail: [email protected]

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Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave. Ste C5500





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1.0 OBJECTIVES:

− To determine the overall survival after allogeneic stem cell transplantation for patients with CML with a history of treatment with second-generation tyrosine kinase inhibitors

− To determine progression free survival, event free survival, relapse rate and non-relapse mortality of patients with CML undergoing allogeneic stem cell transplantation with a history of treatment with second-generation tyrosine kinase inhibitors

− To determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML undergoing allogeneic stem cell transplantation, treated with second tyrosine kinase inhibitors either as primary or as salvage therapy


Imatinib mesylate has become the standard of care as upfront treatment for patients newly diagnosed with chronic myeloid leukemia. For those patients who ultimately prove to have intolerance or resistance to imatinib mesylate, second-generation tyrosine kinase inhibitors are now available for use. These second-generation tyrosine kinase inhibitors (TKI) have become standard therapy in the CML world as demonstrated by the updated set of management recommendations from the European LeukemiaNet for patients with chronic phase CML (1). These guidelines define a standard and acceptable treatment pathway for patients who fail imatinib to proceed to second-generation TKI for treatment. Interestingly, it has been reported that these agents could even replace imatinib as first-line therapy (2), as recent data presented at the ASH 2009 meetings demonstrated superiority of nilotinib over imatinib in newly diagnosed patients. When one assesses current practice involving stem cell transplantation in adults with CML, within the algorithms provided by the European LeukemiaNet, transplantation has become third line. It has been proposed that patients should be put on a pathway towards allogeneic stem cell transplantation when they a) demonstrate failure to second-generation TKI, b) develop the T315I resistant mutation, or c) experience progression to accelerated or blast phase of their malignancy (3). It was still recommended for patients with primary presentation of accelerated phase or blast crisis to proceed to early transplantation, after appropriate disease reduction with TKI therapy (either imatinib or second-generation agents) is administered. This approach is consistent with many current institutional algorithms balancing drug therapy for CML and allogeneic transplantation (3). These are the standards by which most developed countries are utilizing TKI and hematopoietic stem cell transplantation as therapies for their patients, with recognition that some developing countries have reported that transplantation remains a primary consideration balancing the risk: benefit of therapy with the cost of the TKIs (4). Concern remains though that when transplantation is utilized as third line therapy (or even later) that patient outcomes will be compromised. Thus, there could be a direct deleterious effect of the multiple prior therapies administered prior to transplantation or alternatively, worse outcomes may be the natural expectation as only patients with advanced, resistant disease are pursuing the transplant course. Previously, several retrospective studies have been performed both at an institutional and at the registry level that have demonstrated that pre-transplantation exposure to imatinib do not negatively influence the transplant metrics of overall survival, progression-free survival and regimen-related toxicity including a recent investigation of the chronic leukemia committee of the CIBMTR (5). Similarly, there have been small, single institutional reports that suggest that there are no adverse outcomes on transplantation from pre-transplantation exposure to second-

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generation tyrosine kinase inhibitors (6). This would be very important substantiate in this modern era. In review of the current CIBMTR database, there have been identified 81 CML patients who have received second-generation tyrosine kinase inhibitors prior to HSCT. We believe that this cohort would be a valuable group for study in that it may be most predictive of what to expect from transplantation outcomes over the next decade.

3.0 PATIENT ELIGIBILITY POPULATION:

This study will include patients with available data undergoing their first allogeneic transplant for CML from 2001 through 2007, an interval which will allow the capture of all patients who possibly could have had exposure to second-generation TKI's. Related, matched unrelated and cord blood allogeneic transplants will be included. We will pattern the study based on the previous CIBMTR analysis of all CML patients with imatinib pretreatment. Patient-related variables of interest will include age, sex, race, performance status. Disease-related variables of interest will include stage, imatinib response prior to transplant, type of imatinib failures, dasatinib vs nilotinib exposure, duration of second generation TKI therapy, interval from last dose of TKI to transplant. Capture of pretreatment comorbidities associated with TKI therapy would be advantageous. Transplant-related variables of interest will include donor: recipient sex match, related versus unrelated donor (with sub-analysis between well-managed, partially matched and mismatched unrelated donors), donor: recipient CMV status, conditioning regimen (conventional versus reduced intensity), total body irradiation (yes vs no), marrow vs peripheral blood vs cord blood, year of transplantation, GVHD prophylaxis, time from diagnosis to transplant.

4.0 DATA COLLECTION:

This study we utilize data collected from the CIBMTR database via the pretransplant posttransplant essential data forms as well as from core research forms with detailed information obtained from the disease specific inserts for chronic myelogenous leukemia.

5.0 STUDY DESIGN:

This will be a retrospective study of transplantation after second-generation tyrosine kinase inhibitor use for CML patients who in all likelihood had been treated with imatinib and then found to either be intolerant or resistance to primary TKI therapy. The primary endpoint will be overall survival from time of transplantation. The secondary endpoints will be progression free survival, then free survival, incidence of acute GVHD, incidence of chronic GVHD, and non- relapse mortality. Progression-free survival will be defined as time to disease progression. Event-free survival will be defined as time to disease progression or death from any cause. Non-relapse mortality will be defined as any death not due to disease progression. Patients will be stratified by disease status, donor type and age group. The collected patient, disease, and treatment related variables will be compared using the chi-square statistic for categorical variables and the Wilcoxon 2-sample test for continuous variables. The probabilities of overall survival and leukemia-free survival and progression-free survival for all patients will be calculated using the Kaplan Meier estimator with the variance estimated by Greenwood's formula. Patients will be censored at date of last known follow-up. Cumulative incidence estimates will be determined for acute and chronic GVHD rates and relapse risk.

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6.0 REFERENCES: 1. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts

and management recommendations of European LeukemiaNet. J Clin Onc. 2009; 27: 6041-6051.

2. Saglio G, Kim D-W, Issaragrisil S, et al. Nilotinib demonstrate superior efficacy compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: results from the international randomized phase 3 ENESTnd trial. Late-Breaking Abstracts-1, American Society of Hematology, 2009.

3. Champlin R, de Lima M, Kebriaei P, et al. Nonmyeloablative allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era. Clinical Lymphoma and Myeloma. 2009; 9 Suppl 3: S261-265.

4. Ruiz-Arguelles GJ, Tarin-Arzaga LC, Gonzalez-Carrillo ML, et.al. Therapeutic choices in patients with Ph-positive CML living in Mexico in the tyrosine kinase inhibitor era: SCT or TKIs? Bone Marrow Transplant 2008; 42:23-28.

5. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. BLOOD. 2008; 112: 3500-3507.

6. Jabbour E, Cortes J, Kantarjian H, et.al. Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer 2007; 110(2):340-344.

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Table 1. Characteristics of allogeneic CML transplant patients who received second generation tyrosin kinase inhibitors as a part of pre-transpalant therapy prior to transplantation. Patients were transplanted between 2001 and 2007 and reported to the CIBMTR

Characteristics of patients* N (%)Total number of patients 60Number of centers 39Age at transplant, median (range), years 46 (10 - 76)

<10 1 ( 2)11 - 20 4 ( 7)21 - 30 6 (10)31 - 40 14 (23)41 - 50 17 (28)51 - 60 11 (18)≥61 7 (12)

Male sex 33 (55)Karnofsky score

≤90 37 (62)>90 22 (37)Missing 1 ( 2)

Donor type HLA-Identical sibling 5 ( 8)URD, well matched 38 (63)URD, partially matched 17 (28)

Graft type Bone Marrow 17 (28)Peripheral blood 42 (70)Cord blood 1 ( 2)

Donor-recipient sex match Male -Male 20 (33)Female-Female 16 (27)Male -Female 11 (18)Female-Male 13 (22)

Donor/Recipient CMVC match negative 22 (37)positive 17 (28)+ve/-ve 3 ( 5)-ve/+ve 16 (27)unknown 2 ( 3)

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Table 1. Continued. Characteristics of patients* N (%)Year of transplant

2003 1 ( 2)2005 1 ( 2)2006 14 (23)2007 44 (73)

GVHD prophylaxis none 1 ( 2)T-cell depletion 1 ( 2)CSA + MMF +-other 2 ( 3)CSA + MTX +- other 10 (17)CSA +-other (not mtx) 1 ( 2)CSA alone 1 ( 2)FK506 + MMF +- other 6 (10)FK506 alone 2 ( 3)MTX alone 16 (27)MTX +- other 2 ( 3)Other 2 ( 3)missing 16 (27)

Conditioning regimen CY + TBI 20 (33)Bu + CY 17 (28)TBI +- other 3 ( 5)Cy +- other 1 ( 2)Bu +-other 10 (17)Fludara + Lpam +-other 4 ( 7)Fludara + Atg +-other 3 ( 5)Fludara +- other 1 ( 2)other not specified 1 ( 2)

Median follow-up of survivors (range), months 13 (<1 – 27)Abbreviations: URD=unrelated; CY= cyclosphosphamide; GVHD=graft vs host disease; MTX=methotrexate; MMF=mycophenolate ; FK506=tacrolimus; CSA=cyclosporine; TBI=total body irradiation; BU=busulfan; ATG=ALG, ALS, ATG, ATS; Fludara=fludarabine.

* One patient was given “tyrosin kinase inhibitor” but not specified.

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CIBMTR CK10-02 AN UPDATED ASSESSMENT OF THE IMPACT OF PRIOR IMATINIB MESYLATE ON THE

OUTCOME OF HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN THE ERA OF TYROSINE KINASE INHIBITORS

(TKIS)

DRAFT PROTOCOL Study Chairs: Richard Maziarz, MD Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-5058 Fax: 503-494-1552 E-mail: [email protected] Michael Mauro, MD Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland, OR 97239 Telephone: 503-494-0376 Fax: 503-494-1552 E-mail: [email protected] Study Statistician: Xiaochun Zhu, MS The Medical College of Wisconsin CIBMTR 9200 West Wisconsin Ave. Ste C5500 Milwaukee, WI 53226 Telephone: 414-805-0649 Fax: 414-805-0714 E-mail: [email protected] PhD Statistician: Kwang Woo Ahn, PhD The Medical College of Wisconsin

CIBMTR 8701 Watertown Plank Rd. Milwaukee, WI 53226 Telephone: 414-456-7387 Fax: 414-456-6513 E-mail: [email protected]

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Wael Saber, MD, MS The Medical College of Wisconsin CIBMTR 9200 W. Wisconsin Ave Ste C5500





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1.0 OBJECTIVES:

− To determine the overall survival after allogeneic stem cell transplantation for patients with CML in the current era

− To determine progression free survival, event free survival, relapse rate and non-relapse mortality of patients with CML undergoing allogeneic stem cell transplantation in the current era

− To determine patient-, disease-, and transplantation- specific variables which influence the outcome of patients with CML treated with tyrosine kinase inhibitors as primary therapy and subsequent allogeneic stem cell transplantation


Imatinib mesylate has become the standard of care for patients newly diagnosed with chronic myeloid leukemia. In addition, there has been an expansion of treatment options with second-generation tyrosine kinase inhibitors now available for patients with intolerance or resistance to imatinib mesylate (1). Previously, several retrospective studies have been performed both at an institutional and at the registry level that have demonstrated that pre-transplantation exposure to tyrosine kinase inhibitors does not negatively influence the transplant metrics of overall survival, progression free survival and regimen related toxicity (2-4). Interestingly, there have been observations from these retrospective and as well from one prospective study (4,5), that suggest that there is a trend for pre-transplant imatinib mesylate, at least in patients with first chronic phase of CML, to be associated with a reduction of subsequent transplant regimen related mortality.

A previous investigation of the CIBMTR examined the outcomes of 185 patients in first chronic phase and 224 patients in advanced phase of CML who underwent allogeneic stem cell transplantation after imatinib exposure (4). These were compared to the cohort of 900 patients who had not received imatinib mesylate before transplantation in the immediate years prior to the availability of imatinib. Data obtained demonstrated that among patients in first chronic phase, pretransplant imatinib therapy was associated with improved survival, but no statistically significant differences in treatment related mortality, relapse, or leukemia free survival. In parallel, better HLA matched donors, utilization of bone marrow stem cell source and transplantation within one year of diagnosis were also associated with improved survival. A matched pair analysis confirmed a higher survival rate among CP1 patients receiving imatinib. However, for patients transplanted with advanced CML, the use of imatinib was not associated with any change in treatment related mortality, relapse, leukemia free survival or overall survival. These data confirmed the safety of utilizing imatinib in the pre-transplant setting. However, in that first analysis, many patients with CML who underwent transplantation had received imatinib mesylate as a salvage agent and not as primary therapy; documentation revealed that many patients were pretreated with a variety of agents including most commonly hydroxyurea , but also busulfan, interferon, and anagrelide. During subsequent discussions, what remained of interest to the CIBMTR Chronic Leukemia Committee was to identify those patients newly diagnosed in whom imatinib had been the primary therapy and to assess transplantation outcomes in that cohort. The reason for this focus was to acknowledge the reduction / disappearance of “late chronic phase” or CP CML patients treated with imatinb salvage and the emergence of a pure, dominant population of CML transplant cases with tyrosine kinase inhibitor exposure only. In review of the current CIBMTR database, there are 380 CML patients identified who have received no other therapeutic agent prior to the onset of imatinib therapy. We believe

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that this cohort would be a valuable index group for study, most predictive of transplantation expectations over the next decade.


This study will include patients with available data undergoing their first allogeneic transplant for CML from 2001 (date of imatinib FDA approval) through 2007. Related, matched unrelated, and cord blood allogeneic transplants will be included. Patients in whom there is documentation of pretreatment of their CML with agents other than imatinib would be excluded. We will pattern the study based on the previous CIBMTR analysis of all CML patients with imatinib pretreatment. We also will determine if the overlap of patients between the previous study and this proposed study is significant and will affect the current proposal’s feasibility and ability to provide new information. Patient-related variables of interest will include age, sex, race, and performance status. Disease related variables of interest will include stage at diagnosis and at transplant, best imatinib response prior to transplant, imatinib dose, duration of imatinib therapy, interval from last dose of imatinib to transplant, second generation tyrosine kinase utilization for salvage and type of imatinib failure. Transplant-related variables of interest will include donor-recipient sex match, related versus unrelated donor (with sub-analysis between well-matched, partially matched and mismatched unrelated donors), donor-recipient CMV status, conditioning regimen (conventional versus reduced intensity), total body irradiation (yes vs no), marrow vs peripheral blood vs cord blood, year of transplantation, GVHD prophylaxis, and time from diagnosis to transplant.

4.0 DATA COLLECTION:

This study will utilize data collected from the CIBMTR database via the pretransplant / posttransplant essential data forms as well as from core research forms with detailed information obtained from the disease specific inserts for chronic myelogenous leukemia.

5.0 STUDY DESIGN:

This will be a retrospective study of transplantation after imatinib for CML patients who were not treated with any other agent other than imatinib from the time of diagnosis. The primary endpoint will be overall survival from time of transplantation. The secondary endpoints will be progression free survival, event free survival, incidence of acute GVHD, incidence of chronic GVHD, and non-relapse mortality. Progression free survival will be defined as time to disease progression. Event free survival will be defined as time to disease progression or death from any cause. Non-relapse mortality will be defined as any death not due to disease progression. Patients will be stratified by disease status, donor type and age group. The collected patient, disease, and treatment related variables will be compared using the chi-square statistic for categorical variables and the Wilcox 2-sample test for continuous variables. The probabilities of overall survival, leukemia free survival, and progression free survival for all patients will be calculated using the Kaplan-Meier estimator with the variance estimated by Greenwood's formula. Patients will be censored at date of last known follow-up. Cumulative incidence estimates will be determined for acute and chronic GVHD rates and relapse risk.

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6.0 REFERENCES: 1. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and

management recommendations of European LeukemiaNet. J Clin Onc. 2009; 27: 6041-6051. 2. Oehler VG, Gooley T, Snyder DS, et al. The effect of imatinib mesylate treatment before

allogeneic transplant for chronic myeloid leukemia. BLOOD. 2007; 109: 1782-1789. 3. Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on

transplant related mortality. Hematologica. 2006; 76: 9-17. 4. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate on the outcome of

hematopoietic cell transplantation for chronic myeloid leukemia. BLOOD. 2008; 112: 3500-3507.

5. Saussele S, Lauseker M, Gratwohl A, et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era; evaluation of its impact within a subgroup of the randomized German CML Study IV. BLOOD, 2009 Nov 18. [Epub ahead of print].

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Table 1. Characteristics of allogeneic CML patients who received Gleevec only as part of pretransplant therapy prior to transplantation. Patients were transplanted between 2001 and 2007, reported to the CIBMTR

Characteristics of patients N (%)Total number of patients 254Number of centers 115Age at transplant, median (range), years 34 (1 - 63)

< 10 15 ( 6)11 - 20 45 (18)21 - 30 52 (20)31 - 40 59 (23)41 - 50 51 (20)51 - 60 31 (12)≥61 1 (<1)

Male sex 126 (50)Karnofsky score

≤90 131 (52)>90 113 (44)Missing 10 ( 4)

Donor type HLA-iden Sibling 112 (44)Other relative 7 ( 3)URD, well matched 95 (37)URD, mismatch 9 ( 4)URD, partial matched 31 (12)

Graft type Bone Marrow 113 (44)Peripheral blood 137 (54)Cord blood 4 ( 2)

GVHD prophylaxis none 5 ( 2)CSA + MMF +-other 6 ( 2)CSA + MTX +- other 86 (34)CSA +-other (not mtx) 9 ( 4)CSA alone 9 ( 4)FK506 + MMF +- other 23 ( 9)FK506 + MTX +- other 5 ( 2)FK506 +- other (not mtx) 2 (<1)FK506 alone 13 ( 5)MTX alone 73 (29)MTX +- other 10 ( 4)Other 7 ( 3)missing 6 ( 2)

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Table 1. Continued. Characteristics of patients N (%)Donor/recipient CMVC match

negative 64 (25)positive 85 (33)+ve/-ve 38 (15)-ve/+ve 62 (24)unknown 5 ( 2)

Donor-recipient sex match M-M 78 (31)F-F 50 (20)M-F 77 (30)F-M 47 (19)Missing 2 (<1)

Year of transplant 2001 6 ( 2)2002 11 ( 4)2003 36 (14)2004 73 (29)2005 69 (27)2006 47 (19)2007 12 ( 5)

Conditioning regimen CY + TBI 71 (28)Bu + CY 122 (48)TBI +- other 5 ( 2)Bu +-other 12 ( 5)Fludara + Lpam +-other 6 ( 2)Fludara + Atg +-other 17 ( 7)Fludara +- other 14 ( 6)Lpam +-other 1 (<1)other not specified 6 ( 2)

Median follow-up of survivors (range), months 36 (1 – 85) Abbreviations URD=unrelated; CY= cyclosphosphamide; GVHD=graft vs host disease; MTX=methotrexate; MMF=mycophenolate ; FK506=tacrolimus; CSA=cyclosporine; TBI=total body irradiation; BU=busulfan; ATG=ALG, ALS, ATG, ATS; Fludara=fludarabine.

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Study Proposal 1210-32 Study Title: Allogeneic hematopoietic stem cell transplantation with or without pre-transplant azacitidin in the treatment of myelodysplastic syndrome. Richard Olsson, MD, PhD, Karolinska University Hospital, Stockholm, Sweden Specific Aims: Investigate whether azacitidin treatment pre-allo-HSCT improves the clinical outcome in MDS patients. Scientific Justification: The myelodysplastic syndromes (MDS) encompass a group of heterogeneous clonal stem cell disorders characterized by apoptosis of marrow progenitors leading to peripheral cytopenia, and a high propensity for leukemic transformation arising from the stem cell population escaping apoptotic control. The “stemness” of this disease implies a high degree of resistance to chemotherapy, and cure by conventional induction chemotherapy is exceedingly rare.1 Patients with MDS may be cured by allogeneic hematopoietic stem cell transplantation (ASCT), but this treatment is feasible only for a fraction of the patient population due to high age, comorbidity, or lack of a suitable donor. The long-term survival rate after transplantation ranges between 25% and 45%.2-6. Despite advances in transplantation technology, a considerable mortality and risk of relapse still remain. Transplantation-related mortality (TRM) after myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) has been reported to be 32% and 22% and relapse rate 22% vs. 45%, respectively.2 Known risk factors for unfavorable outcome after ASCT for MDS encompass blast counts ≥5%3,7, high-risk karyotype8,9, high age3,5,7,10, low platelet counts3, therapy-related MDS10, comorbidity11 and elevated ferritin values12. The International Prognostic Score System (IPSS)10,13, as well as the recently established WHO-based Prognostic Score System (WPSS)6,14 has been able to predict outcome after ASCT3,9,10. SCT is indicated for patients with IPSS int-2 and high. For patients with IPSS int-1, SCT can be considered after individual assessment15. Azacitine16, a hypomethylating drug, was introduced in MDS-treatment approximately 5 years ago, and its contribution to the clinical outcome after allo-HSCT needs evaluation in a lager retrospective study.

Patient Eligibility Population: Inclusion Criteria: – Allogeneic HSCT during the time-period 2005 to 2010 – All ages – MDS – Conditioning

– Myeloablative conditioning (MAC) – Total body irradiation (TBI dose ≥5 Gy single dose, or fractionated TBI ≥8 Gy) – Busulfan (BU dose ≥9 mg/kg) – Melphalan (dose ≥150mg/m2)

– Reduced intensity conditioning (RIC) – TBI dose <5 Gy single or TBI dose <8 Gy fractionated – L-PAM dose ≤150 mg/m2 – BU dose ≤9 mg/kg – BEAM (upper limit of RIC)

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– Donor – Matched unrelated donor (genomic match 8/8) – HLA-identical sibling

– Stem cell source – Bone marrow (BM) or peripheral blood stem cells (PBSC)

Outcomes: – Overall survival – Acute graft-versus-host-disease (GVHD) – Chronic GVHD – Relapse – Non-relapse mortality

Variables to be Analyzed: – Patient-related:

– Age at transplant as a continuous variable – Gender: female vs. male – Karnofsky performance score: <90% vs. ≥90%.

– Disease-related: – Disease stage: IPSS int-1, int-2, high risk – Ferritin levels pre-transplant: continues variable

– Transplant-related: – Donor type: HLA-identical sibling vs. matched unrelated donor – Source of stem cells: BM vs. PBSC vs. cord blood – Cell dose (continuous variable) – CD34+ – Total nucleated cells (TNC) – Donor-recipient ABO incompatibilities: no vs. minor vs. major – Ex vivo T-cell depleted vs. repleted – Donor age as a continuous variable

– Donor-recipient gender match: F-M vs. M-F vs. M-M vs. F-F – Year of transplant: continuous variable

– GVHD prophylaxis: cyclosporine ± MTX ± other, Prograf ± MTX ± other vs. other. – Thymoglobulin vs. Campath vs. none – Azacitidin pre-transplant yes vs. no – Azacitidin post-transplant yes vs. no

Data Collection: Data will be collected from the CIBMTR registry. No additional data collection is required.

Study Design: To summarize the characteristics of the dataset, descriptive tables of patient, disease and transplant related variables will be reported. For discrete factors, the number of cases and their respective percentages will be calculated. For continuous factors, the median and ranges will be calculated.

The main objective of this study is to investigate whether azacitidin pre-transplant improves the overall survival after allo-HSCT in the treatment of MDS. Secondary objectives are to investigate whether azacitidin pre-transplant has any impact on incidences of acute or chronic GVHD, relapse or non-relapse mortality after allo-HSCT in the treatment of MDS.

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References: 1. Hofmann WK, Heil G, Zander C, et al: Intensive chemotherapy with idarubicin, cytarabine,

etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia. Ann Hematol 83:498-503, 2004

2. Martino R, Iacobelli S, Brand R, et al: Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108:836-46, 2006

3. Sierra J, Perez WS, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100:1997-2004, 2002

4. Castro-Malaspina H, Harris RE, Gajewski J, et al: Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 99:1943-51, 2002

5. de Witte T, Hermans J, Vossen J, et al: Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:620-30, 2000

6. Alessandrino EP, Della Porta MG, Bacigalupo A, et al: WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood 112:895-902, 2008

7. Sutton L, Chastang C, Ribaud P, et al: Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: a long-term study of 71 patients Societe Francaise de Greffe de Moelle. Blood 88:358-65, 1996

8. Nevill TJ, Fung HC, Shepherd JD, et al: Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation. Blood 92:1910-7, 1998

9. Deeg HJ, Shulman HM, Anderson JE, et al: Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95:1188-94, 2000

10. Appelbaum FR, Anderson J: Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 12 Suppl 1:S25-9, 1998

11. Zipperer E, Pelz D, Nachtkamp K, et al: The hematopoietic stem cell transplantation comorbidity index is of prognostic relevance for patients with myelodysplastic syndrome. Haematologica 94:729-32, 2009

12. Armand P, Kim HT, Cutler CS, et al: Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 109:4586-8, 2007

13. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-88, 1997

14. Malcovati L, Porta MG, Pascutto C, et al: Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 23:7594-603, 2005

15. NCCN Practical guidelines in oncology - www.nccn.org. 16. Fukuto JS, Greenberg PL, Management of patients with higher risk myelodysplastic

syndromes. Crit Rev Oncol Hematol. 2005 Nov;56(2):179-92.

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Characteristic of patients who received an allogeneic transplant for MDS reported to the CIBMTR between 2005 and 2008

Characteristics of patients No Azacitidin N(%) Azacitidin N(%) Number of patients 609 41 Number of centers 143 9 Age, median (range), years 53 (1 - 74) 56 (32 - 66)

0-10 26 ( 4) 0 11-20 33 ( 5) 0 21-30 45 ( 7) 0 31-40 56 ( 9) 4 (10) 41-50 115 (19) 5 (12) 51-60 203 (33) 22 (54) 61-70 125 (21) 10 (24) >=71 6 (<1) 0

Sex Male 363 (60) 24 (59) Female 246 (40) 17 (41) Karnofsky score <90% 189 (31) 14 (34) 90-100% 364 (60) 26 (63) Missing 56 ( 9) 1 ( 2)

Conditioning regimen Myeloablative 330 (54) 20 (49) Non-myeloablative 256 (42) 21 (51) TBD 23 ( 4) 0

Disease status pre transplant Early 177 (29) 7 (17) Advanced 293 (48) 29 (71) TBD 139 (23) 5 (12)

Donor type HLA identical-sibling 218 (36) 7 (17) HLA 8/8 matched URD 391 (64) 34 (83)

D-R sex match M-M 203 (33) 21 (51) M-F 134 (22) 13 (32) F-M 120 (20) 3 ( 7) F-F 98 (16) 4 (10) Missing 54 ( 9) 0

D-R CMV status +/+ 163 (27) 11 (27) +/- 46 ( 8) 3 ( 7) -/+ 167 (27) 14 (34)

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Continued. Characteristics of patients No Azacitidin N(%) Azacitidin N(%)

-/- 174 (29) 13 (32) Missing 59 (10) 0

Graft type Bone marrow 137 (22) 10 (24) Peripheral blood 472 (78) 31 (76)

Year of HCT 2005 177 (29) 12 (29) 2006 186 (31) 16 (39) 2007 149 (24) 13 (32) 2008 97 (16) 0

GVHD prophylaxis T-cell depletion 20 ( 3) 0 FK506+MTX+-other 257 (42) 21 (51) FK506+-other 99 (16) 10 (24) CsA+MTX+-other 136 (22) 4 (10) CsA+-other 71 (12) 6 (15) Other 21 ( 3) 0 Missing 5 (<1) 0

Treatment for MDS prior to conditioning No 211 (35) 0 Yes 383 (63) 41 (100) TBD/missing 15 ( 2) 0

Median follow-up of survivors, range, months 36 (<1 - 65) 38 (6 - 60)

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Study Proposal 1010-01

Study Title: A decision analysis for performing allogeneic hematopoietic stem cell transplant in patients with chronic lymphocytic leukemia (CLL). Brian T. Hill, MD, PhD, Cleveland Clinic, Cleveland, OH William Hogan, MD, Mayo Clinic, Rochester, MN

Specific Aims: To determine optimal CLL patient characteristics for allogeneic stem cell transplantation (SCT) compared to non-transplant treatment. Scientific Justification: The median age of patients diagnosed with chronic lymphocytic leukemia (CLL) is 72 years [1]. Many patients never require treatment for the disease and will die of other causes, but approximately 10% of CLL patients are diagnosed under the age of 55 and have a high likelihood of dying from the disease. Treatment with combination chemo-immunotherapy improves overall survival of patients with CLL but is not curative [2, 3]. Allogeneic hematopoietic stem cell transplantation (SCT) leads to long-term disease free survival as a result of the graft-versus-leukemia effect [4-6]. Even for younger patients allogeneic SCT is offered infrequently because of significant treatment-related mortality (TRM) and morbidity. Given the risks of transplantation, reduced intensity or nonmyeloablative conditioning regimens have been implemented with encouraging results [7, 8]. Allogeneic SCT is generally offered to younger patients who have failed fludarabine-based therapy. Currently, the most commonly accepted consensus recommendations for allogeneic SCT are poor-risk disease, as defined by non-response or early relapse (< 12 months) after purine analogue-containing therapy, relapse (< 24 months) after purine-analogue combination therapy, or presence of 17p (p53) deletion requiring treatment. These criteria are derived from expert opinion after review of a limited number of series with relatively few patients [9]. Given the encouraging long-term results of nonmyeloablative SCT for patients with fludarabine-resistant disease and poor cytogenetic risk factors, we propose a systematic comparison of SCT to non-transplant therapy with the goal of identifying patients who would most benefit from transplantation [10]. Patient Eligibility Population: This study will involve the comparison of two groups of patients treated for CLL: characteristics of patients with a diagnosis of CLL who underwent an nonmyeloablative allogeneic SCT recorded in the CIBMTR database (transplanted patients) will be compared to patients who have received non-transplant therapy for CLL as documented in the Mayo Clinic CLL database (non-transplanted patients).

The following inclusion criteria will be applied: - Age ≥18. - Diagnosis of CLL after 1990 requiring treatment. - For transplanted patients, an allogeneic transplant performed at CIBMTR institution between 1995 –

2008 with a nonmyeloablative preparative regimen. Data Requirements: For transplanted patients, CIBMTR data collection forms will be used to provide information on age and Rai stage as well as performance status at diagnosis and immediately prior to the preparative regimen. Results of fluorescence in situ hybridization (FISH) testing for common cytogenetic abnormalities such as 17p (p53) deletion will be assessed as available. Prior first-line and second-line therapies will be analyzed, such as treatment with purine analogues and monoclonal antibodies (alemtuzumab, rituximab) as well as details of the preparative regimen, donor type (HLA matched sibling vs. unrelated donor), and GVHD prophylaxis. Outcomes will include overall survival, non-relapse mortality, acute and chronic

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graft versus host disease (GVHD) and relapse requiring treatment. For non-transplanted patients, information from the Mayo Clinic CLL database will include age and Rai stage as well as performance status at diagnosis, results of FISH testing for cytogenetic abnormalities, time to treatment, treatment history and relapse requiring treatment. The primary outcomes measured will be overall survival and cause of death (due to CLL or other causes).

Sample Requirements: There are no tissue requirements proposed for this study.

Study Design (Scientific Plan): We will compare outcomes of transplant and non-transplant treatments for CLL using two approaches: (1) a matched-cohort analysis and (2) a Markov decision model. Matched Cohort Analysis: Overall survival as a function of age will be compared for transplanted and non-transplanted patients. Cohorts will be matched based on age, sex, Rai stage and presence or absence of a 17p deletion. As shown in the Figure 1, older patients can be expected to have inferior survival with transplant relative to non-transplant treatment. In contrast, for young CLL patients, the previously observed long-term survival after nonmyeloablative transplant of approximately 50% suggests that performing allogeneic SCT will improve survival relative to non-transplant treatment. Multivariable analysis will be used to calculate hazard ratios associated with survival after SCT relative to non-transplant treatment. Variables to be assessed will be age and stage at diagnosis and the time of SCT, period of time from diagnosis to treatment, response to treatment, and cytogenetic risk factors.

Figure 1: Gain/loss of discounted life expectancy with SCT as a function of age of CLL patients. Based on available data, SCT is expected to result in significantly decreased life expectancy for older patients but gains for younger patients. Matched-cohort analysis will be implemented to quantitate the number of quality-adjusted life years of benefit or harm for various ages.

Markov Decision Model: Because of the potentially limited number of older transplanted patients available for matched cohort analysis, a Markov decision model will be employed which tracks hypothetical subjects transition between clinically relevant states. This approach has been successfully applied to the decision about when to perform SCT for patients with myelodysplastic syndrome [11]. The Markov model will examine four treatment strategies for patients with CLL as a function of age: transplantation at the time

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or remission, at the time of relapse, with refractory disease, or no transplant. Analyses using from transplant and non-transplant databases will be performed separately for patients with non-response or early relapse (<12 months) after purine analogue-containing therapy as well early relapse (> 24 months) and those with 17p (p53) deletion requiring treatment. Because treatment of CLL both with and without transplant is associated with significant morbidity without mortality, the Markov model will utilize quality-of-life adjustments by incorporating utilities. Utilities are numerical values assigned to a given health state that are expressed as a value between 0 (death) and 1 (perfect health). A model of expected disease states for CLL is shown in Figure 2.

Figure 2: Markov Decision Model. Patients begin either with early stage not requiring treatment or advanced CLL requiring treatment. Under this model, no patients are treated immediately with SCT. Following non-transplant treatment, patients with refractory disease will either die or proceed to SCT. Patients in remission after non-transplant treatment can remain in remission until death, relapse, or proceed to SCT. The model necessitates transition from one state to the next after a fixed time interval.

Quality of life utilities will be based on global quality of life assessments using standardized questionnaires such as the FACT-G or EORTC QLQ-C30. The Total FACT-G score for early stage and advanced CLL has been previously published [12]. Importantly, the quality of life of patients treated with chemotherapy for CLL is equivalent to patients who have not been treated [13]. Although there are no published assessments of quality of life for relapsed/refractory CLL after non-SCT treatment, FACT scores have been reported for follicular lymphoma at diagnosis and various stages of treatment [14]. The utility of newly diagnosed follicular lymphoma was measured at 0.80 which is remarkably similar to advanced CLL (utility 0.77). Follicular lymphoma in complete remission was associated with the same quality of life as newly diagnosed disease but relapsed follicular lymphoma was associated with a 20% reduction in quality of life. This provides the basis for extrapolating the utility value of 0.62 for relapsed/refractory CLL after non-SCT treatment. Global quality of life after reduced-intensity transplantation has shown to be return to pre-transplant values (reported utility of 0.82) within 3 months after transplant and to be to be equal to age-matched population controls [15, 16]. Therefore, utilities scores for those patients alive with CLL in complete remission will be taken to be equivalent to the baseline value of those patients with early stage CLL. For patients with relapsed CLL after SCT, quality of life can be expected to be equivalent to that of the relapsed/refractory population (utility =0.62). Table I shows utilities for each stage in the Markov model.

Advanced

CLL

Alive after SCT

SCT

CLL in remission

non-transplant treatment

Relapsed CLL after non-SCT treatment

CLL relapse

after SCT SCT

Death

Refractory CLL

SCT

Early-stage

CLL

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Utilities for various stages in the Markov Decision Model Markov State Utility Value/Source Early stage CLL (Rai 0,I, II) 0.82 [12] Advanced stage CLL (Rai III, IV) 0.77 [12] CLL in remission 0.77 [13] Relapsed/Refractory CLL after non-SCT treatment 0.62 [14] Alive after SCT 0.82 [15] CLL relapse after SCT 0.62 [14] Death 0

References:

1. Altekruse SF, K.C., Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). , SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, . http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010., 2010.

2. Hallek, M., Fingerle-Rowson, G, Fink, AM, et al., First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group. Blood Abstract 535, 2009. 114: p. 223.

3. Parikh, S., Wierda, WG., Badoux, X., O'Brien, S. M., Ferrajoli, A., Faderl, S., Burger, JA., Lerner, S. Kantarjian, H., Keating, MJ. , Comparison of fludarabine (F) plus cyclophosphamide (C) versus FC plus rituximab (R) in previously untreated Rai stage III/IV chronic lymphocytic leukemia (CLL). JCO, 2010. 28(15s): p. abstract 6519.

4. Pavletic, S.Z., et al., Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol, 2005. 23(24): p. 5788-94.

5. Schetelig, J., et al., Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol, 2003. 21(14): p. 2747-53.

6. Toze, C.L., et al., Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplant, 2005. 36(9): p. 825-30.

7. Sorror, M.L., et al., Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood, 2008. 111(1): p. 446-52.

8. Dreger, P., et al., Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia, 2005. 19(6): p. 1029-33.

9. Dreger, P., et al., Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia, 2007. 21(1): p. 12-7.

10. Schetelig, J., et al., Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol, 2008. 26(31): p. 5094-100.

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11. Cutler, C.S., et al., A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood, 2004. 104(2): p. 579-85.

12. Shanafelt, T.D., et al., Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients. Br J Haematol, 2007. 139(2): p. 255-64.

13. Holzner, B., et al., Quality of life of patients with chronic lymphocytic leukemia: results of a longitudinal investigation over 1 yr. Eur J Haematol, 2004. 72(6): p. 381-9.

14. Pettengell, R., et al., The impact of follicular lymphoma on health-related quality of life. Ann Oncol, 2008. 19(3): p. 570-6.

15. Bevans, M.F., et al., Health-related quality of life in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant, 2006. 38(2): p. 101-9.

16. Deschler, B., et al., Prognostic factor and quality of life analysis in 160 patients aged > or =60 years with hematologic neoplasias treated with allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant, 2010. 16(7): p. 967-75.

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Characteristic of patients >=18 years of age who underwent a non-myeloablative/reduced-intensity transplant for CLL reported to the CIBMTR between 1995 and 2008

Characteristics of patients N (%)Number of patients 639Number of centers 136Age, median (range), years 56 (21 - 74)

18-29 5 (<1)30-39 22 ( 3)40-49 111 (17)50-59 293 (46)60-69 195 (31)>=70 13 ( 2)

Sex Male 485 (76)Female 154 (24)

Karnofsky score <90% 187 (29)90-100% 398 (62)Missing 54 ( 8)

Disease status at transplant CR/PR/nPR 119 (19)Stable/progressive 100 (16)Unknown/untreated/not evaluable 420 (66)

Type of donor HLA-id sibling 232 (36)URD well-matched 212 (33)URD partially matched 72 (11)URD mismatched 22 ( 3)URD matching to be classified 101 (16)

D-R sex match M-M 296 (46)M-F 73 (11)F-M 157 (25)F-F 63 (10)Missing 50 ( 8)

D-R CMV status +/+ 171 (27)+/- 69 (11)-/+ 171 (27)-/- 145 (23)Missing 83 (13)

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Continued. Characteristics of patients N (%)Graft type

Bone marrow 88 (14)Peripheral blood 531 (83)Cord blood 20 ( 3)

Year of HCT 1995-1996 3 (<1)1997-1998 7 ( 1)1999-2000 41 ( 6)2001-2002 86 (13)2003-2004 146 (23)2005-2006 178 (28)2007-2008 178 (28)

GVHD prophylaxis T-cell depletion 5 (<1)FK506+MTX+-other 212 (33)FK506+-other 136 (21)CsA+MTX+-other 80 (13)CsA+-other 187 (29)Other 16 ( 3)Missing 3 (<1)

Median follow-up of survivors, range, months 40 (<1 - 113)** Twin and other relative were excluded.

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Study Proposal 1210-40 Study Title: Donor lymphocyte infusion after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for chronic lymphocytic leukemia. Ronald M. Sobecks, MD, Cleveland Clinic, Cleveland, OH

Specific Aims:

– To determine the effect of DLI after RIC alloHSCT on achievement of T-cell complete donor chimerism, disease relapse/progression, disease-free survival, non-relapse mortality and overall survival for patients with chronic lymphocytic leukemia.

– To determine the incidence, time to occurrence and severity of acute and chronic graft-versus-host disease following DLI administered after RIC alloHSCT for patients with chronic lymphocytic leukemia.

– To assess the influence of the DLI CD3+ cell dose and the time of administration after RIC alloHSCT on each of these post-transplant outcomes (if data available).

Scientific Justification: RIC alloHSCT has become an effective alternative transplant modality for patients who are not candidates for myeloablative alloHSCT. However, disease relapse and progression remain important causes of transplant failure and death after RIC alloHSCT 1. In particular, patients who fail to achieve complete donor chimerism are unlikely to develop a graft-vs.-malignancy effect 2, 3. DLI has been an effective treatment strategy for patients with relapsed disease after myeloablative HSCT 4 as well as RIC alloHSCT 5-8. However, a major limitation of the reports on DLI after RIC alloHSCT is that there have been relatively small numbers of patients evaluated for each specific disease subtype. Important questions that remain for DLI in the RIC alloHSCT setting include:

1. Are certain disease subtypes more likely to benefit from DLI after RIC alloHSCT? 2. What is the optimal CD3+ cell dose needed to achieve complete donor

chimerism and a disease response without causing fatal acute or chronic GVHD? 3. At what time point after RIC alloHSCT should the DLI be administered? 4. Should the DLI’s be administered prophylactically or only for mixed chimerism and for

disease relapse/progression? 5. Are certain RIC alloHSCT preparative regimens associated with a greater need for DLI? 6. Are there differences in the requirements for DLI or the outcomes after

related vs. matched unrelated donor RIC alloHSCT patients? Patient Eligibility Criteria: The study population will include all patients reported to the CIBMTR who had received a RIC alloHSCT and a DLI from 2000 to 2010. Potential numbers of subjects are shown in Table 1. Outcomes:

– T-cell complete donor chimerism: achievement of T-cell hematopoiesis with > 95% DNA – of donor origin. – T-cell mixed donor chimerism: achievement of T-cell hematopoiesis with < 95% and

>1% DNA of donor origin. – Graft Failure: failure to ever achieve complete or mixed donor chimerism or – loss of donor-derived hematopoiesis after previously achieving complete – or mixed donor chimerism. – Relapse/Progression: the time of onset of disease recurrence or progression – after transplant. Patients will be censored at death if in continuous CR, if in – continuous CR at last follow-up or if they received a subsequent transplant.

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– Acute graft-vs.-host disease: time of onset of grades II-IV acute GVHD as – defined by the Glucksberg criteria. – Chronic graft-vs.-host disease: time of onset of any chronic GVHD in any – organ system. – Disease-free survival: time to treatment failure (death or relapse) and patients – are censored at time of last follow-up. – Non-relapse mortality: time to death without evidence of disease. – Patients are censored at time of relapse or last follow-up. – Overall survival: time to death. Patients are censored at time of last follow-up.

Variables to be Analyzed:

– Patient-related: – Age – Gender: male vs. female – Karnofsky performance score at transplant: <70 vs. 80-90 vs. 90-100

– Disease-related: – Underlying disease: CLL – Disease stage at time of transplant: Rai stage 0/I/II vs. III/IV. (Binet stage A/B will be – considered equivalent to Rai stage 0/I/II). – B-symptoms at transplant: present vs. absent – Elevated LDH at transplant: yes vs. no – Splenomegaly: yes vs. no – Bulky adenopathy (lymph nodes > vs. < 5 cm) – Disease status: CR1, CR2, >CR2, PR, refractory

– Transplant-related: – Donor-recipient gender relationship: M-M vs. M-F vs. F-M vs. F-F – Year of transplant – Donor source: matched related vs. matched unrelated – Hematopoietic stem cell source: PBSC vs. BM – Transplant preparative regimen: Low-dose TBI (200 cGy), Flu/TBI, Flu/Cy,

Mel/Flu, Bu/Flu/ATG, other. – Subset analysis of those who had ATG/T-cell depletion vs. no ATG/TCD – GvHD prophylaxis (calcineurin inhibitor + MMF, calcineurin inhibitor + MTX,

calcineurin inhibitor ± other) – Donor-recipient HLA disparities: yes (HLA-A, -B, -C, -DR, -DQ, or -DP) vs. none – T-cell chimerism post RIC alloHSCT: complete donor chimerism vs. mixed chimerism vs.

graft failure (if data available). – Donor lymphocyte infusion:

– Time interval after RIC alloHSCT that the DLI was administered: – < 6 months – > 6 months, < 12 months – > 12 months, < 24 months – > 24 months

– CD3+ cell doses for each DLI: – < 1 x 106 – > 1 x 106 , < 1 x 107 – > 1 x 107 , < 1 x 108 – > 1 x 108

– Indication for DLI: disease relapse/progression vs. mixed chimerism vs. prophylactic (if data available).

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Study Design: The incidence of DLI administration after RIC alloHSCT for each disease subtype will be established. Then a comparison of the characteristics will be made between each disease group regarding the DLI variables. For each disease subtype in which DLI’s were administered analyses will be performed to determine the influence of CD3+ cell dose and the timing of DLI administration on disease response, development of T-cell complete donor chimerism, acute and chronic GVHD, disease-free survival, no-relapse mortality and overall survival. Cox’s proportional hazards regression and Kaplan-Meier analyses will then be used to further evaluate these outcomes.

References:

1. Maris M, Niederwieser D, Sandmaier B, et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102:2021-2030, 2003.

2. Massenkeil G, Nagy M, Lawang M, et al. Reduced intensity conditioning and prophylactic DLI can cure patients with high-risk acute leukaemias if complete donor chimerism can be achieved. Bone Marrow Transplant 31:339-345, 2003.

3. Childs R, Clave E, Contentin N, et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: Full donor T-cell chimerism precedes alloimmune responses. Blood 94:3234-3241, 1999.

4. Kolb H, Schattenberg A, Goldman J, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86:2041-2050, 1995.

5. Bethge W, Hegenbart U, Stuart M, et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood 103:790-795, 2004.

6. Marks D, Lush R, Cavenagh J, et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 100:3108-3114, 2002.

7. Peggs K, Thomson K, Hart D, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood 103:1548-1556, 2004.

8. Dey B, McAfee S, Colby C, et al. Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 9:320-329, 2003.

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Characteristic of patients who received an NST/RIC allogeneic HCT for CLL reported to the CIBMTR between 1995 and 2008


10-19 1 (<1)20-29 5 (<1)30-39 24 ( 4)40-49 122 (19)50-59 309 (47)>=60 191 (29)



CLL disease status at transplant CR/PR/nPR 123 (19)Stable/progressive 105 (16)Unknown/untreated/not evaluable 424 (65)

Type of donor HLA-identical sibling 232 (36)Twin 2 (<1)Other relative 10 ( 2)URD well-matched 213 (33)URD partially matched 72 (11)URD mismatched 22 ( 3)URD matching to be classified 101 (15)


D-R CMV status +/+ 174 (27)+/- 69 (11)-/+ 176 (27)-/- 147 (23)Missing 86 (13)

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Continued. Characteristics of patients N (%)Graft type

Bone marrow 92 (14)Peripheral blood 540 (83)Cord blood 20 ( 3)

Year of HCT 1995-1996 4 (<1)1997-1998 8 ( 1)1999-2000 43 ( 7)2001-2002 88 (13)2003-2004 149 (23)2005-2006 179 (27)2007-2008 181 (28)

GVHD prophylaxis T-cell depletion 6 (<1)FK506+MTX+-other 216 (33)FK506+-other 141 (22)CsA+MTX+-other 82 (13)CsA+-other 187 (29)Other 17 ( 3)Missing 3 (<1)

Median follow-up of survivors, range, months 39 (<1 - 113)

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Study Title: Development of a prognostic scoring system to predict relapse of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) after allogeneic hematopoietic stem cell transplantation. Brian C. Shaffer, MD, National Institutes of Health, Bethesda, MD Jose F. Leis, MD, PhD, Mayo Clinic, Phoenix, AZ Steven Z. Pavletic, MD, National Institutes of Health, Bethesda, MD Specific Aims: The primary aim is to develop a prognostic scoring system based on patient, disease, and transplant-specific factors that is predictive of relapse after allogeneic hematopoietic stem cell transplantation in patients with CLL. The secondary aims are to assess the association of the variables identified within this scoring system with transplantation outcomes and outcomes after relapse.

Scientific Justification: Chronic lymphocytic leukemia is incurable with traditional therapy; however, allogeneic hematopoietic stem cell transplantation (HSCT) is a source of durable disease control, likely due to its recognized graft versus tumor effect. Despite this, relapse after transplantation remains a major problem in the therapy of CLL, occurring in 30-40% of patients after allogeneic HSCTs. Relapse related mortality, typically 20-30%, has become the leading cause of death post allogeneic HSCT in selected populations.[1] Thus, strategies to define which patients are at high risk for relapse after allogeneic transplantation are warranted.

A number of factors are predictive of poor outcomes in patients with newly diagnosed CLL, including deletion or loss of function of the p53 loci on chromosome 17p, expression of the T-cell antigen ZAP-70, or absence of somatic hypermutation of the IgVH region. [2-3] These factors are independent of outcomes after allogeneic transplantation. For example, in a report of 90 patients who underwent RIC and allogeneic transplantation, only chemotherapy refractory disease prior to transplant and the use of T-cell depletion with alemtuzumab were identified as prognostic for event-free survival after transplantation. [4] In separate analyses, the use of T-cell depleted allografts, delayed donor engraftment, or presence of minimal residual disease were associated with higher rates of relapse after allogeneic HSCT. [1, 5]

The currently proposed study will use patient, disease, and transplant-specific factors acquired in the

CIBMTR dataset to develop a prognostic scoring system to identify patients with CLL who are at high risk for relapse after allogeneic HSCT. The proposed study is most appropriately performed on a large dataset as single center studies do not have sufficient patient numbers to adequately examine this issue with the necessary statistical power. Strategies to prevent relapse after transplantation are needed in patients with CLL. If validated, a prognostic scoring system to predict relapse in this population would allow for identification of individuals who are most likely to benefit from investigational approaches designed to prevent relapse. Patient Eligibility Population: All CLL/SLL patients reported to the CIBMTR who underwent HLA-identical sibling or unrelated donor myeloablative or RIC/NST transplantation for relapsed/refractory CLL/SLL between 1995 and 2008. Data Requirements: The proposed study does not require the collection of supplemental data outside of the current data collection forms. The proposed study will incorporate data currently compiled in the CK06-03 dataset. Additionally, the following data collection forms may be required to supplement some outcome or variable data not included in the above dataset: Recipient Baseline Data (2000), Hematopoietic Stem Cell

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Transplant Infusion (2006), Chronic Lymphocytic Leukemia Pre-HSCT Data (2013), 100 Day Post-HSCT Data (2100), Chronic Lymphocytic Leukemia Post-HSCT Data (2113), Six Months to Two Years Post-HSCT Data (2200), Yearly Follow-Up for Greater than Two Years Post-HSCT Data (2300), Pre-Transplant Essential Data (2400), Post-Transplant Essential Data (2450), Chimerism (2451), Selective Post-Transplant Essential Data (2455), Recipient Death Data (2900). Sample Requirements: None. Study Design: Initial analysis: Variables related to patient, disease, and transplant characteristics (Table 1) will be summarized using descriptive statistics. The primary analysis will be actuarial (Kaplan-Meier) curve of time to progression or relapse (in which non-relapse deaths will be censored). Cumulative incidence curves will also be calculated for (1) relapse competing with non-relapse mortality (NRM) and (2) NRM. Variables found to be significant in univariate (log-rank) analyses will subsequently be evaluated in a Cox proportional hazards model. Secondary analyses will explore associations between the variables identified within this scoring system and transplantation outcomes, including late relapse (>12 months after transplant), survival after relapse, and NRM. Three patient cohorts will be evaluated for the primary outcome (relapse): a) Patients at transplant baseline prior to starting conditioning; b) Patient survivors at day 100 post transplant in which case the impact of post-transplant variables and acute GVHD will be included; c) Patient survivors at 12 months post transplant in which case the impact of post-transplant variables and acute and chronic GVHD will be included. Relapse risk score development: Our primary objective is to develop a risk score for relapse in patients at transplant baseline using the predictive variables identified above. Each individual factor that is significantly associated with a given outcome in a univariate analysis and is then found to be jointly prognostic in a Cox model will be included in the final risk score. For simplicity of implementation, each factor will contribute a single point to a patient’s final risk score. References:

1. Pavletic, S.Z., et al., NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biology of Blood and Marrow Transplantation, 2010. 16(7): p. 871-890.

2. Dohner, Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia. New England Journal of Medicine, 2000. 343(26): p. 1910-1916.

3. Rassenti, L.Z., et al., ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia. New England Journal of Medicine, 2004. 351(9): p. 893-901.

4. Dreger, P., et al., Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood, 2010. 116(14): p. 2438-2447.

5. Kröger, N., et al., NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic Stem Cell Transplantation. Part II: Chronic Leukemias, Myeloproliferative Neoplasms, and Lymphoid Malignancies. Biology of Blood and Marrow Transplantation, 2010. 16(10): p. 1325-1346.

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Variables to be Analyzed Patient-Specific Patient age at transplant

Patient gender Karnofsky performance status at transplant

Disease-Specific Disease stage at transplant (Rai or Binet) Disease status at transplant: CR/PR versus not CR/PR Elevated LDH at transplant B-symptoms at transplant Bulky (≥ 5 cm) lymphadenopathy Splenomegaly Extent of bone marrow involvement at transplant Absolute lymphocyte count

Prior Therapy Number of prior chemotherapy regimens received Prior antibody therapy Response to last therapy

Transplant- Specific

Time from diagnosis to transplant Conditioning regimen CD34+ cell dose infused ATG given for any reason Alemtuzumab given for any reason CD3+ cell dose infused Donor-recipient gender match: M/M versus M/F versus F/M versus F/F Source of stem cells: bone marrow versus peripheral blood Type of GVHD prophylaxis Donor-recipient HLA disparity Days to neutrophil recovery Days to lymphocyte recovery Time to full donor T-lymphocyte chimerism Engraftment syndrome Donor cell infusion for any reason Time of donor cell infusion post transplant Development of acute graft versus host disease Development of chronic graft versus host disease Achievement of remission and minimal residual disease negativity

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Characteristic of patients who underwent an allogeneic transplant for CLL reported to the CIBMTR between 1995 and 2008


<10 yrs 1 (<1)10-19 yrs 2 (<1)20-29 yrs 16 ( 1)30-39 yrs 83 ( 7)40-49 yrs 316 (28)50-59 yrs 486 (43)>=60 yrs 224 (20)

Sex Male 823 (73)Female 304 (27)Missing 1 (<1)


Conditioning regimen Myeloablative 431 (38)Non-myeloablative 640 (57)TBD 57 ( 5)

Disease status at transplant CR/PR/nPR 253 (22)Stable/progressive 230 (20)Unknown/untreated/not evaluable 645 (57)



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Continued. Characteristics of patients N (%)D-R CMV status

+/+ 330 (29)+/- 117 (10)-/+ 292 (26)-/- 276 (24)Missing 113 (10)

Graft type Bone marrow 315 (28)Peripheral blood 784 (70)Cord blood 29 ( 3)

Year of HCT 1995-1996 107 ( 9)1997-1998 85 ( 8)1999-2000 115 (10)2001-2002 131 (12)2003-2004 205 (18)2005-2006 249 (22)2007-2008 236 (21)

GVHD prophylaxis T-cell depletion 61 ( 5)FK506+MTX+-other 328 (29)FK506+-other 191 (17)CsA+MTX+-other 275 (24)CsA+-other 238 (21)Other 32 ( 3)Missing 3 (<1)

Median follow-up of survivors, range, months 48 (<1 - 181)

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Study Proposal 0510-01 Study Title: Trends in allogeneic stem cell transplantation for myelodysplastic syndromes over the last decade: Impact of novel agents, predictive models, and reduced conditioning intensity. Erica Warlick, MD, University of Minnesota, Minneapolis, MN Paulette Mehta, MD, MPH, University of Arkansas for Medical Sciences/CAVHS, Little Rock, AR Girindra Raval, MD, University of Arkansas for Medical Sciences/CAVHS, Little Rock, AR Daniel Weisdorf, MD, University of Minnesota, Minneapolis, MN Specific Aims:

– Analyze trends and outcomes in transplantation of myelodysplastic syndrome from 1995-2006 with respect to conditioning intensity, donor type (sibling, MUD, cord), cell source (bone marrow or peripheral blood), disease status at transplant.

– Determine the impact of novel agents (lenalidomide, azacitidine, decitabine) on outcomes after HCT in terms of engraftment, toxicity, GVHD, overall and DFS, and relapse incidence.

– Develop a predictive model for MDS patients undergoing HCT based on specific variables such as diagnostic cytogenetics, disease burden at transplant, transfusion dependence, exposure to chemotherapy vs. novel agents prior to transplant, donor type, conditioning intensity that may help predict who will benefit most from HCT.

Scientific Justification: Myelodysplastic syndromes are a complex and heterogeneous group of stem cell disorders. While a number of newly FDA approved agents (azacitidine, decitabine, lenalidomide1-3) have impacted the treatment paradigm for MDS, transplant remains the only curative therapy4, 5. Many questions remain regarding transplantation in MDS: 1) What is the optimal timing of transplantation and what impact does age, IPSS, transfusion dependence have on this decision?6-8 ; 2) What impact does conditioning intensity have on outcome: Does myeloablative conditioning improve outcomes enough to compensate for the potential increased TRM?; 5, 9-113) What impact does pre-transplant therapy (induction type chemotherapy vs. novel agents) have on post-transplant outcomes?; 4) What predictive tools help predict outcome post transplant?12, 13 5) How have transplant trends in MDS changed over the last decade and how can that inform future decision making regarding transplantation? Numerous CIBMTR analyses and development of randomized prospective trials are underway to further inform our decision-making regarding timing of transplantation and to answer the question definitively regarding conditioning intensity given the contradictory findings in the current data available. 5, 9-11, 14-16. However, the answers generated by these larger randomized Phase III studies will take years to mature. While these studies are in progress at varying stages of development, data from large scale studies evaluating the impact of pre-transplant chemotherapy on post-transplant outcomes and development of predictive models specifically for MDS patients undergoing HCT are lacking. In the interim, the CIBMTR provides a wealth of currently available data to help evaluate trends in transplantation for MDS that may help to inform clinical decision-making. In this analysis we propose to evaluate the overall trends in transplantation for MDS based on time period transplanted (1995-1998, 1999-2002, 2003-2006) with respect to impact of various factors on outcomes. Factors to include:1) exposure to pre-transplant chemotherapy (AML-type induction versus novel agents), 2) Disease burden at time of transplant (CR, untreated <5% blasts, treated <5% blasts with ongoing dysplasia, > 5% blasts, untreated), 3) Conditioning intensity (MA vs. RIC), 4) Donor type (sibling, MUD, cord), 5) Stem cell source (bone marrow and PB).

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If adequate data is available, we will focus a portion of the analysis on the impact of pre-transplant therapy on the post transplant outcomes of overall survival, relapse, and TRM. We hypothesize that more recent use of novel therapies prior to transplant (hypomethylating agents and lenalidomide) may have a positive impact on post-transplant outcomes. Lastly, we will attempt to develop a predictive model for MDS patients undergoing transplant utilizing variable such as transfusion dependence, diagnostic cytogenetics, exposure to novel therapeutics, or any other disease criteria that is shown in multivariate analysis to be significant. Patient Eligibility Population:

– 1st Allogeneic HSCT: 1995–1998; 1999-2002; 2003-2006 ( to permit 2 year follow-up) – Myelodysplastic Syndromes (MDS) including the following subtypes (FAB):

– RA – RARS – RAEB1/2 – RAEB t – We will exclude CMML and Myelofibrosis as the disease biology is different

– De novo and Treatment related MDS will both be included – Age 18-40; 41-50; 51-65; 65+ – Donor: Related or Unrelated – Stem Cell source: BM, PB, or UCB

Data to be Collected/ Variables to Examine:

– Patient-related: – Age – Gender – KPS and HCT-CI prior to transplant

– Disease-related: – FAB subtype of MDS at diagnosis (RA/RARS/RAEB 1 or 2/RAEBt) – IPSS Score at Diagnosis – Percentage blasts at diagnosis – Blood counts at diagnosis: Hgb, WBC, platelet, ANC – Cytogenetics at diagnosis – Transfusion dependence:

– PRBC: yes or no – Platelets: yes or no

– Therapy Prior to transplant – Conventional Induction Type chemotherapy: yes or no – Hypomethylating Agents (azacitidine or decitabine): yes or no – Immunomodulatory Medications (thalidomide/lenalidomide/ATG+CSA): yes or no – Prior Erythropoietin Use: Yes or No – No Therapy: yes or no

– Time from Diagnosis to Transplant – Disease Status at the time of transplant

– % Blasts: 0-4%;< 5% – Advanced Disease (RAEB1/2) vs. Less Advanced Disease (RA/RARS) – CR vs. untreated vs. treated with <5% blasts vs. treated with > 5% blasts

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– Transplant-related: – Donor Type (related vs. unrelated) and HLA matching – Graft Source ( BM. PB, cord blood)

– GVHD Prophylaxis – Conditioning Intensity (Myeloablative vs. RIC) – Year of transplant (1995-1998, 1999-2003, 2003-2006)

Outcomes:

– N cases of MDS per year group of transplant (1995–1998; 1999-2002; 2003-2006) – Each time period to be compared with respect to the above patient variable, disease specific

variable, and transplant variables to assess changing trends in practice and effect on outcome – Assess Overall and DFS, relapse incidence, and TRM per time period

Cumulative incidence calculations should be used for time to relapse; TRM; GVHD and Kaplan-Meier projections for survival and DFS with Cox multivariate modeling to evaluate the independence of factors. We will specifically evaluate these endpoints across time periods to evaluate improvements over time and uncover specific etiologies for improvements in outcome. Additionally, we will attempt to develop a predictive model from the above variables to determine who will best benefit from transplant. References:

1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223-232.

2. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52-57.

3. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.

4. Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;100:1997-2004.

5. Warlick ED, Cioc A, Defor T, Dolan M, Weisdorf D. Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplant disease burden. Biol Blood Marrow Transplant. 2009;15:30-38.

6. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579-585.

7. Kuendgen A, Strupp C, Aivado M, et al. Myelodysplastic syndromes in patients younger than age 50. J Clin Oncol. 2006;24:5358-5365.

8. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002;20:4420-4427.

9. Martino R, Iacobelli S, Brand R, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006;108:836-846.

10. Martino R, Valcarcel D, Brunet S, Sureda A, Sierra J. Comparable non-relapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission. Bone Marrow Transplant. 2008;41:33-38.

11. Alyea EP, Kim HT, Ho V, et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2006;12:1047-1055.

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12. Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503-3510.

13. Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood. 2008;112:895-902.

14. Storb R. Reduced-intensity conditioning transplantation in myeloid malignancies. Curr Opin Oncol. 2009;21 Suppl 1:S3-5.

15. Oliansky DM, Antin JH, Bennett JM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant. 2009;15:137-172.

16. Kindwall-Keller T and Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant. 2009;43:597-609.

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Characteristic of recipients >=18 years of age who underwent an allogeneic transplant for MDS (RA, RAEB, RARS, RAEB1/2) reported to the CIBMTR between 1995 and 2008, by year of

transplant

Characteristics of patients 1995-1998 1999-2002 2003-2008Number of patients 331 426 858Number of centers 125 125 152Age, median (range), years 42 (18 - 68) 48 (18 - 70) 52 (18 - 74)

18-40 152 (46) 144 (34) 191 (22)41-50 111 (34) 110 (26) 194 (23)51-65 67 (20) 167 (39) 430 (50)>65 1 (<1) 5 ( 1) 43 ( 5)

Sex Male 184 (56) 229 (54) 505 (59)Female 147 (44) 196 (46) 352 (41)Missing 0 1 (<1) 1 (<1)

Karnofsky score <90% 136 (41) 135 (32) 246 (29)>=90% 190 (57) 267 (63) 540 (63)Missing 5 ( 2) 24 ( 6) 72 ( 8)

FAB subtype of MDS at diagnosis ** RA 186 (56) 200 (47) 309 (36)RAEB 128 (39) 199 (47) 414 (48)RARS 17 ( 5) 27 ( 6) 58 ( 7)RAEB-1 0 0 38 ( 4)RAEB-2 0 0 39 ( 5)

Conditioning regimen Myeloablative 315 (95) 278 (65) 438 (51)Non-myeloablative 14 ( 4) 138 (32) 396 (46)TBD 2 (<1) 10 ( 2) 24 ( 3)

Disease status at HCT Early 161 (49) 185 (43) 334 (39)Advanced 168 (51) 241 (57) 509 (59)Missing 2 (<1) 0 15 ( 2)

Type of donor HLA-id sibling 153 (46) 177 (42) 234 (27)Twin 1 (<1) 2 (<1) 2 (<1)Other relative 21 ( 6) 20 ( 5) 13 ( 2)URD well-matched 43 (13) 88 (21) 364 (42)URD partially matched 51 (15) 53 (12) 86 (10)URD mismatched 30 ( 9) 27 ( 6) 29 ( 3)URD matching TBD 32 (10) 59 (14) 130 (15)

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Continued. Characteristics of patients 1995-1998 1999-2002 2003-2008D-R sex match

M-M 111 (34) 140 (33) 298 (35)M-F 79 (24) 95 (22) 185 (22)F-M 73 (22) 89 (21) 164 (19)F-F 68 (21) 101 (24) 145 (17)Missing 0 1 (<1) 66 ( 8)

D-R CMV match +/+ 100 (30) 150 (35) 253 (29)+/- 38 (11) 54 (13) 75 ( 9)-/+ 88 (27) 94 (22) 227 (26)-/- 94 (28) 108 (25) 206 (24)Missing 11 ( 3) 20 ( 5) 97 (11)

Graft type Bone marrow 267 (81) 201 (47) 184 (21)Peripheral blood 62 (19) 219 (51) 644 (75)Cord blood 2 (<1) 6 ( 1) 30 ( 3)

Year of transplant 1995 70 (21) 0 01996 91 (27) 0 01997 87 (26) 0 01998 83 (25) 0 01999 0 86 (20) 02000 0 105 (25) 02001 0 125 (29) 02002 0 110 (26) 02003 0 0 126 (15)2004 0 0 159 (19)2005 0 0 176 (21)2006 0 0 173 (20)2007 0 0 132 (15)2008 0 0 92 (11)

GVHD prophylaxis None 6 ( 2) 7 ( 2) 7 (<1)T-cell depletion 43 (13) 25 ( 6) 37 ( 4)FK506+MTX+-other 26 ( 8) 52 (12) 303 (35)FK506+-other 11 ( 3) 26 ( 6) 119 (14)CsA+MTX+-other 213 (64) 213 (50) 219 (26)CsA+-other 26 ( 8) 99 (23) 147 (17)Other 5 ( 2) 2 (<1) 19 ( 2)Missing 1 (<1) 2 (<1) 7 (<1)

Median follow-up of survivors, range, months 112 (3 - 180) 80 (3 - 133) 40 (<1 - 85)** RAEB-t not included (AML based on new WHO classification).

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Study Proposal 1210-25 Study Title: Development of a prognostic scoring system to predict relapse of myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation. Brian C. Shaffer, MD, National Institutes of Health, Bethesda, MD Martin S. Tallman, MD, Memorial Sloan-Kettering Cancer Center, New York, NY Steven Z. Pavletic, MD, National Institutes of Health, Bethesda, MD Specific Aims: The primary aim is to develop a prognostic scoring system based on patient, disease, and transplant-specific factors that is predictive of relapse after allogeneic hematopoietic stem cell transplantation in patients with MDS. The secondary aims are to assess the association of the variables identified within this scoring system with transplantation outcomes and outcomes after relapse.

Scientific Justification: MDS is incurable with traditional therapy; however, allogeneic hematopoietic stem cell transplantation (HSCT) is a source of durable disease control, possibly due to its recognized graft versus tumor effect. Relapse after transplantation is a major source of morbidity and mortality in the therapy of MDS, occurring in 10-40% of patients after allogeneic HSCT.[1] In an analysis of 461 patients with therapy-related MDS (tMDS) or MDS/AML included in the EBMT database, risk factors for relapse included not being in a complete remission prior to transplant, older age, abnormal cytogenetics, and tMDS.[2] Similar findings were noted in an analysis of 868 patients undergoing HSCT for tMDS or tAML.[3] Other factors contributing to relapse of MDS after allogeneic transplant include delayed time to transplant and donor stem cell source. [1, 4-5] With respect to the latter, both unrelated and related donors have been found to positively associate with disease-free survival.[3-4] These analyses are complicated by poor representation of patients with advanced IPSS score and older age in studies of allogeneic HSCT for MDS. Furthermore, the optimal timing of transplantation for MDS, as well as which patients with early stage disease that would benefit from early HSCT, is not well understood. Thus, strategies to define which patients are at high risk for relapse after allogeneic transplantation are warranted.

In our proposed study we aim to develop a prognostic scoring system to define which patients with MDS are at high risk for relapse after allogeneic HSCT. The proposed study is most appropriately performed on a large dataset as single center studies do not have sufficient patient numbers to adequately examine this issue with the necessary statistical power. Using data from multiple sites will also increase the degree to which the patients are representative of patients with MDS. Strategies to prevent relapse after transplantation are needed in patients with MDS. If validated, a prognostic scoring system to predict relapse in this population would allow for identification of individuals who are most likely to benefit from investigational approaches designed to prevent relapse. Patient Eligibility Population: Patients greater than 18 years in age with MDS reported to the CIBMTR who received a myeloablative, nonmyeloablative or reduced intensity peripheral blood stem cell, or bone marrow transplant while in complete remission or with relapsed disease from a matched related, or unrelated donor between 1995 and 2008.

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Data Requirements: The proposed study does not require the collection of supplemental data outside of the current data collection forms. The proposed study will incorporate data currently compiled in the LK-08-02, LK-09-02, LK07-01, and LK-07-03b datasets. Additionally, the following data collection forms may be required to supplement outcome or variable data not included in the above dataset: Recipient Baseline Data (2000), Hematopoietic Stem Cell Transplant Infusion (2006), MDS/MPD Pre-HSCT Data (2014), 100 Day Post-HSCT Data (2100), MDS/MPD Post-HSCT Data (2114), Six Months to Two Years Post-HSCT Data (2200), Yearly Follow-Up for Greater than Two Years Post-HSCT Data (2300), Pre-Transplant Essential Data (2400), Post-Transplant Essential Data (2450), Chimerism (2451), Selective Post-Transplant Essential Data (2455), Recipient Death Data (2900).

Variables from the existing CIBMTR data collection forms that need to be analyzed Patient-Specific Patient age

Patient gender Karnofsky performance status

Disease-Specific Disease status at transplant: CR versus not CR IPSS karyotype category: Good, intermediate, poor Monosomal karyotype [6]: Yes or No ≥4 chromosomal abnormalities without t(8;21) or t(15;17): Yes or No Percentage bone marrow blasts at transplant Percentage peripheral blasts at transplant Patient hemoglobin, platelet, and WBC count at time of transplant Elevated LDH at transplant Splenomegaly IPSS score at transplant

Prior Therapy Number of prior chemotherapy regimens received Primary refractory disease: Y or N Response to last therapy Prior use of hypomethylating agent (5-azacitidine or decitabine)

Transplant- Specific

Time from diagnosis to transplant Conditioning regimen CD34+ cell dose infused CD3+ cell dose infused Donor-recipient gender match: M/M versus M/F versus F/M versus F/F Source of stem cells: bone marrow versus peripheral blood versus cord Type of GVHD prophylaxis Donor-recipient HLA disparity Days to neutrophil recovery Days to lymphocyte recovery Recovery of normal Immunoglobulin levels Time to full donor chimerism Donor cell infusion for any reason Time of donor cell infusion post transplant Development of acute graft versus host disease Development of chronic graft versus host disease

128


Sample Requirements: None

Study Design: Initial analysis: Variables related to patient, disease, and transplant characteristics (Table 1) will be summarized using descriptive statistics. The primary analysis will be actuarial (Kaplan-Meier) curve of time to progression or relapse (in which non-relapse deaths will be censored). Cumulative incidence curves will also be calculated for (1) relapse competing with non-relapse mortality (NRM) and (2) NRM. Variables found to be significant in univariate (log-rank) analyses will subsequently be evaluated in a Cox proportional hazards model. Secondary analyses will explore associations between the variables identified within this scoring system and transplantation outcomes, including late relapse (>12 months after transplant), survival after relapse, and NRM. Three patient cohorts will be evaluated for the primary outcome (relapse): a) Patients at transplant baseline prior to starting conditioning; b) Patient survivors at day 100 post transplant in which case the impact of post-transplant variables and acute GVHD will be included; c) Patient survivors at 12 months post transplant in which case the impact of post-transplant variables and acute and chronic GVHD will be included. Relapse risk score development: Our primary objective is to develop a risk score for relapse in patients at transplant baseline using the predictive variables identified above. Each individual factor that is significantly associated with a given outcome in a univariate analysis and is then found to be jointly prognostic in a Cox model will be included in the final risk score. For simplicity of implementation, each factor will contribute a single point to a patient’s final risk score. References:

1. Pavletic, S.Z., et al., NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biology of Blood and Marrow Transplantation, 2010. 16(7): p. 871-890.

2. Kroger, N., et al., Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation. Haematologica, 2009. 94(4): p. 542-549.

3. Litzow, M.R., et al., Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood, 2010. 115(9): p. 1850-1857.

4. Chang, C., et al., Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood, 2007. 110(4): p. 1379-1387.

5. McClune, B.L., et al., Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome. Journal of Clinical Oncology, 2010. 28(11): p. 1878-1887.

6. Breems, D.A., et al., Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype. Journal of Clinical Oncology, 2008. 26(29): p. 4791-4797.

129


Characteristic of patients >=18 years of age who underwent an allogeneic transplant for MDS reported to the CIBMTR between 1995 and 2008

Characteristics of patients N (%)Number of patients 2094Number of centers 230Age, median (range), year 50 (18 - 78)

18-30 273 (13)31-40 317 (15)41-50 540 (26)51-60 672 (32)>=61 292 (14)


Karnofsky score, % <90% 708 (34)90-100% 1253 (60)Missing 133 ( 6)

FAB prior transplant MDS, NOS 40 ( 2)RA 578 (28)RAEB 835 (40)CMML 209 (10)RARS 80 ( 4)RAEB-1 35 ( 2)RAEB-2 39 ( 2)Other MFS/MPS specify 278 (13)


Disease status pre transplant Early 645 (31)Advanced 1106 (53)TBD 343 (16)

Type of donor HLA-id sibling 759 (36)URD well-matched 646 (31)URD partially matched 254 (12)URD mismatched 93 ( 4)URD matching unknown 2 (<1)URD matching to be classified 340 (16)

130


Continued. Characteristics of patients N (%)D-R sex match

M-M 750 (36)M-F 449 (21)F-M 431 (21)F-F 370 (18)Missing 94 ( 4)

D-R CMV status +/+ 638 (30)+/- 214 (10)-/+ 533 (25)-/- 565 (27)Missing 144 ( 7)

Graft type Bone marrow 836 (40)Peripheral blood 1258 (60)

Year of HCT 1995-1996 180 ( 9)1997-1998 201 (10)1999-2000 235 (11)2001-2002 309 (15)2003-2004 374 (18)2005-2006 470 (22)2007-2008 325 (16)


Median follow-up of survivors, range, months 56 (<1 - 180)Twin (n=7), other relative (n=66) and cord blood (n=54) were excluded.

131

Not for publication or presentation Attachment 19-1


Study Title: Allogeneic hematopoietic stem cell transplant for chronic myelomonocytic leukemia. Hien K. Duong, MD, Cleveland Clinic Foundation, Cleveland, OH Specific Aims:

– To determine the rates of treatment-related mortality (TRM), relapse/progression, disease-free survival (DFS) and overall survival (OS) for adults with chronic myelomonocytic leukemia (CMML) who underwent allogeneic hematopoietic cell transplant for CMML between1999-2009.

– To determine the prognostic effect of age, disease status, disease stage, presence of circulating blasts, treatment prior to transplant, donor type, and preparative regimen on transplant outcomes.

Scientific Justification: CMML is a clonal hematopoietic stem cell disorder with both myeloproliferative and myelodysplastic properties. Given these concomitant properties, it was difficult to classify, prompting a new category of myeloproliferative/myelodysplastic disorders (MPD/MDS) that was formed in the WHO classification of myeloid disorders in 2001. The diagnosis of CMML is characterized by a peripheral blood monocytosis, absence of Philadelphia chromosome, presence of <20% blasts in the bone marrow (<5% blasts in the peripheral blood), and evidence of dysplasia in at least one precursor cell lineage. CMML is further divided into two subcategories with prognostic significance: CMML-1 (presence of <5% blasts in the peripheral blood and <10% blasts in the bone marrow) and CMML-2 (presence of 5-19% blasts in the peripheral blood and 10-19% in the bone marrow).1,2 Prognosis for CMML is unfavorable and overall outcomes remain poor. The median reported survival is 12-24 months.3,4 There are no specific therapies for CMML and optimal treatment is not yet defined. Recent studies in patients with myelodysplastic syndrome (MDS) with azacitidine and decitabine have included CMML patients, however the number of CMML patients included is small and results are difficult to interpret for this population.5,6 Allogeneic hematopoietic cell transplant (HCT) remains the only curative treatment. Although allogeneic HCT is the only curative treatment, the outcomes data are limited. The largest study reported is a retrospective report from the European Group for Blood and Marrow Transplantation (EBMT), which included 50 patients who underwent allogeneic HCT between 1988 and 2000. The median age was 44 years old. They reported 5-year estimated OS and DFS of 21% and 18%, respectively. Poor outcomes were due to high rates of TRM (52%) and relapse (49%).7 Zang, et al reported on 21 patients with CMML who underwent transplant at the Fred Hutchinson Cancer Research Center from 1990 to1998. The median age was 47 years. The Kaplan-Meier estimates for 3-year OS and DFS were 39% and 25%. However, TRM and relapse rates were 34% and 23%, respectively.8 Kerbauy, et al reported their updated experience indicating a 4-year OS and DFS of 41%. This series also included infants and children.9 Mittal, et al reported on the role of allogeneic HCT in myelofibrosis, CMML, and BCR-ABL-negative CML. Twenty patients who underwent HSCT between 1991 to 2001, with a median age of 51 years, were included in the study; only 8 patients with CMML. Of those patients, at the time of report, 3 (38%) were alive and 5 (72%) had died (1 patient from pneumonia, 4 patients from disease relapse).10 Elliot, et al reported on the use of allogeneic HCT and donor lymphocyte infusions in patients with CMML. This retrospective study included 17 patients who underwent HCT from 1992 to 2004, with a median age of 50 years. 3-year OS and DFS were 18%. TRM and relapse rate were both 41%.11

132


Laport, et al reported on the use of reduced-intensity conditioning regimens prior to allogeneic HSCT in patients with myelodysplastic syndrome and myeloproliferative disorders. This analysis included 148 patients, undergoing allogeneic HCT at multiple institutions between 1998 and 2004. The median age was 59 years. Of these patients, only 7 patients had CMML. For the CMML patients, the 3-year OS and relapse-free survival were both 43%. The 3-year NRM for all patients was 32%.12

More recently, Krishnamurthy, et al reported on 18 patients with CMML who underwent allogeneic HCT from 1998 to 2007. The median age was 54 years. Seven of these patients had acute myeloid leukemia (AML), transformed from CMML. Fifteen of these patients underwent reduced-intensity conditioning prior to HCT. The actuarial 3-year OS, NRM, and relapse incidence was 31%, 31%, and 47% respectively.13 These studies are limited by their small numbers and are mostly single-institution reports. Some suggest that the percentage of blasts present in the peripheral blood, cytogenetic abnormalities, and transplant type may have prognostic importance following transplant, however the studies are limited and no definitive conclusions have been made. Also, aside from the studies mentioned, there is a paucity of data on the effectiveness of reduced-intensity conditioning transplantation and donor lymphocyte infusions in this population of patients. These may offer more treatment options for older adults with CMML who would not be able to tolerate myeloablative conditioning regimens. We propose a study to evaluate the overall outcomes following allogeneic HCT in adult patients with CMML. Patient Eligibility Criteria: Any adult patient (>18 years of age) with the diagnosis of CMML who underwent hematopoietic stem cell transplantation between 1999 and 2009 in a CIBMTR research institution with 2-year post-transplant follow-up information. Study Design: Data Collection: Eligible patients will be identified and the following information will be collected: – Patient characteristics: age, sex, performance status age – Disease specific characteristics: time from diagnosis to transplant, disease stage at presentation,

presence of immature circulating myeloid cells, treatment prior to transplant, disease stage at transplant, cytogenetic abnormalities

– Donor characteristics: donor/recipient sex match, donor type (HLA-identical sibling, related other, unrelated, cord-blood), donor–recipient HLA match

– Conditioning regimen and GVHD prophylaxis: myeloablative vs. non-myeloablative, total body radiation (TBI) vs. non-TBI, graft type (bone marrow, peripheral blood, cord blood), GVHD prophylaxis

– Transplant outcome: time to neutrophil and platelet engraftment, TRM, acute and chronic GVHD incidence, relapse/progression, progression-free survival, and overall survival.

Data Analyses: – Descriptive analyses of characteristics described above 1 -4. – Compare outcome measures (DFS, OS, GVHD, TRM, engraftment) according to baseline patient

characteristics, time from diagnosis to transplant, disease stage at presentation, presence of immature circulating myeloid cells, treatment prior to transplant.

133


References: 1. Emanuel PD. Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia.

Leukemia 2008; 22: 1335-1342. 2. Vardiman JW, Harris NL, Brunning RD, et al. The World Health Organization (WHO)

classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302. 3. Onida F, Kantarjian HM, Smith TL, et al. Prognostic factors and scoring systems in chronic

myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 2002; 99: 840-849. 4. Germing U, Kundgen A, Gattermann N. Risk assessment in chronic myelomonocytic leukemia

(CMML). Leukemia Lymphoma 2004; 45: 1311–1318. 5. Kantarjian HM, Yasuhiro O, Garcia-Manero G, et al. Results of a randomized study of 3

schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109 (1): 52-7.

6. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol 2009; 10 (3): 223-32.

7. Kroger N, Zabelina T, Guardiola P, et al. Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2002; 118: 67–73.

8. Zang DY, Deeg HJ, Gooley T, et al. Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation. Br J Haematol 2000; 110: 217-222.

9. Kerbauy DM, Chyou F, Gooley T, et al. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia. Biol Blood Marrow Transplant 2005; 11: 713–720.

10. Mittal P, Saliba RM, Giralt SA, et al. Allogeneic transplantation: a therapeutic option for myelofibrosis, chronic myelomonocytic leukemia and Philadephia-negative/BCR-ABL-negative chronic myelogenous leukemia. Bone Marrow Transplant 2004; 33: 1005-1009.

11. Elliott MA, Tefferi A, Hogan WJ, et al. Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia. Bone Marrow Transplant 2006; 37: 1003-1008.

12. Laport GG, Sandmaier BM, Storer BE, et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant 2008; 14:246-255.

13. Krishnamurthy P, Lim ZY, Nagi W, et al. Allogeneic haematopoietic SCT for chronic myelomonocytic leukaemia: a single-centre experience. Bone Marrow Transplant 2010; Jan ePub.

134


Characteristic of patients who received an allogeneic HCT for CMML reported to the CIBMTR between 1995 and 2008


18-30 16 ( 7)31-40 21 ( 9)41-50 56 (24)51-60 99 (42)>=61 43 (18)




Type of donor HLA-id sibling 74 (31)Twin 2 (<1)Other relative 2 (<1)URD well-matched 72 (31)URD partially matched 33 (14)URD mismatched 16 ( 7)URD matching to be classified 36 (15)


135



+/+ 67 (29)+/- 22 ( 9)-/+ 61 (26)-/- 60 (26)Missing 25 (11)


Year of HCT 1995-1996 20 ( 9)1997-1998 18 ( 8)1999-2000 25 (11)2001-2002 40 (17)2003-2004 41 (17)2005-2006 52 (22)2007-2008 39 (17)

GVHD prophylaxis T-cell depletion 14 ( 6)FK506+MTX+-other 58 (25)FK506+-other 31 (13)CsA+MTX+-other 90 (38)CsA+-other 36 (15)Other 6 ( 3)

Median follow-up of survivors, range, months 60 (2 - 147)** Patients in 2009 are not included because they do not have sufficient follow-up.

136


Study Proposal 1210-42 Study Title: Outcomes of allogeneic hematopoietic stem cell transplantation for adult chronic myelomonocytic leukemia. Mojtaba Akhtari, MD, University of Nebraska Medical Center, Omaha, NE Fausto Loberiza, MD, MS, University of Nebraska Medical Center, Omaha, NE H. Jean Khoury, MD, Emory University School of Medicine, Atlanta, GA Steven Devine, MD, The Ohio State University Comprehensive Cancer Center, Columbus, OH

Specific Aims: – To compare the patient-, disease-, and transplant-related characteristics of patients with CMML

who underwent HLA-identical sibling HCT or matched unrelated HCT. – To compare the following outcomes between HLA-identical sibling HCT and matched unrelated

HCT: – neutrophil and platelet engraftment – acute and chronic GVHD – relapse – treatment-related mortality – leukemia free survival – overall survival

Scientific Justification: Chronic myelomonocytic leukemia (CMML) is a rare and heterogeneous clonal myeloid neoplasm with an annual incidence of 13:100,000 occurring mostly older age groups (>65 years of age), and is characterized by increased numbers of monocytes in the peripheral blood and bone marrow, bone marrow (BM) dysplasia and fewer than 20% blasts in the BM. CMML has an unfavorable prognosis, with reported median survivals of 12-40 months with transformation to acute myeloid leukemia (AML) in up to 1/3 of patients.1, 2, 3 The optimal therapeutic modality remains uncertain. Hematopoietic cell transplantation (HCT) offers the only potentially curative treatment option. However, there is a paucity of clinical trial data specific for CMML; and the HCT data available are limited and restricted to small retrospective series, with the largest study comprising only of 50 patients.4, 5 Myeloablative conditioning regimens have been used in this setting, with results indicating high non-relapse mortality (NRM).4, 6, 7 A report from the European Group for Blood and Marrow Transplantation (EBMT) registry with analysis of 50 adult patients who underwent allogeneic HCT for CMML, 38 patients received matched sibling allografts, and approximately half of the patients were in complete remission (CR) at the time of transplantation; and they reported that 26 patients (52%) died because of non-relapse causes (mainly GVHD) and the 2-year estimated relapse incidence was 42%.4 Many patients are not eligible for a standard conditioning regimen, and there are centers which have started suing reduce-conditioning (RIC) regimens to treat patients with CMML.5 In one report a high rate of relapse (47% at 3 years) was observed.5 There are reports of high day 100-TRM after SCT in CMML: 25% in a German study8, 35% in the EBMT report4 and 41% in another report.6 Severe GVHD grades II–IV and III–IV occurred in 46 and 23% of transplantations, which was comparable to 35–75% and 23–37% in earlier analyses. Severe acute GVHD was a major cause of TRM in this and the other studies.4, 6

There is existing evidence that allogeneic HSCT is a feasible therapeutic modality for selected patients with CMML; however, the overall outcomes remain less optimal and unpredictable. It is very important to continue examining the role of either standard conditioning regimens or RIC in the management of CMML in order to be able have better strategies to improve patient selection and increase transplantation options for older CMML patients.

137


Patient Eligibility Population: This study will include adult patients (≥18 years old) with CMML who underwent related or unrelated HCT, regardless of level matching and type of conditioning, from 1984 to 2009 in any United States center and were reported to CIBMTR. Data Requirements:

– Acute and Chronic graft-versus-host disease: incidence of grades II-IV acute GVHD and limited and extensive chronic GVHD.

– Treatment-related mortality: time to death without evidence of leukemia recurrence. This event is summarized by the cumulative incidence estimate with relapse/progression as the competing risk.

– Relapse: time to onset of leukemia recurrence. Events will be summarized by the cumulative incidence estimate with treatment-related mortality as the competing risk.

– Leukemia-free survival: time to treatment failure (death or relapse). Patients are censored at time of last follow-up.

– Overall mortality: time to death from any cause. Patients are censored at time of last follow-up. – Disease related: Disease status at transplant: early vs intermediate vs advanced – Transplant related:

− Graft source: bone marrow vs PBSC − Interval from diagnosis to transplant: continuous − HLA match status: well-matched vs partially matched vs mismatched − Donor-recipient sex-match: F-M vs M-F vs M-M vs F-F − Donor-recipient CMV match: -/- vs -/+ vs +/- vs +/+ vs unknown − Conditioning regimen: Bu+Cy vs Cy+TBI vs TBI ± others vs Fludara ± others vs other (can

also include Myeloablative vs Non-myeloablative) − GVHD prophylaxis: T-cell depletion vs Csa+MTX vs Csa ± others vs FK506+MTX vs

FK506 ± others vs Other vs None − Infused cell dose

− BM: ≤ 2 x 108 vs > 2 x 108 nucleated cells − PBSC: ≤ 5 x 108 vs > 5 x 108 mononucleated cells

Study Design: The probabilities of leukemia-free and overall survival will be estimated by the method of Kaplan–Meier. Cumulative incidence will be used to estimate the probability of neutrophil and platelet engraftment, acute and chronic GVHD, treatment-related mortality, and relapse. Multivariate Cox proportional hazards regression analysis will be performed to compare the outcomes by type of transplant while controlling for patient, disease and transplant-related variables.8 Interaction between type of transplant and conditioning regimen (myeloablative vs non-myeloablative) will be tested. References:

1. Jaffe EHN, Stein H, Vardiman JW. World Health Organisation classification of tumors, pathology and genetics of tumors of hematopoietic and lymphoid tissues. In: Jaffe EHN, Stein H, Vardiman JW (eds). IARC Press: Lyon, France, 2001.

2. Aul C, Giagounidis A, Germing U, Ganser A. Evaluating the prognosis of patients with myelodysplastic syndromes. Ann Hematol 2002; 81: 485–497.

3. Onida F, Kantarjian HM, Smith TL, Ball G, Keating MJ, Estey EH, et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 2002; 99: 840–849.

138


4. Krӧger N, Zabelina T, Guardiola P, Runde V, Sierra J, Van Biezen A, et al. Allogeneic stem cell transplantation of adult chronic myelomonocytic leukemia. A report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2002; 118: 67–73.

5. Krishnamurthy P, Lim ZY, Nagi W, Kenyon M, Mijovic A, Ireland R, et al. Allogeneic hematopoietic SCT for chronic myelomonocytic leukemia: a single-centre experience. Bone Marrow Transplant. 2010; 45: 1502-1507.

6. Elliott MA, Tefferi A, Hogan WJ, Letendre L, Gastineau DA, Ansell SM, et al. Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia. Bone Marrow Transplant 2006; 37: 1003–1008.

7. Zang DY, Deeg HJ, Gooley T, Anderson JE, Anasetti C, Sanders J, et al. Treatment of chronic myelomonocytic leukemia by allogeneic marrow transplantation. Br J Haematol. 2000; 110:217-222.

8. Cox D. Regression models and life-tables. J Roy Statist Soc 1972; 34: 187–220.

139


Characteristic of patients who received an allogeneic HCT for CMML reported to the CIBMTR between 1995 and 2008


18-30 16 ( 7)31-40 21 ( 9)41-50 56 (24)51-60 99 (42)>=61 43 (18)




Type of donor HLA-id sibling 74 (31)Twin 2 (<1)Other relative 2 (<1)URD well-matched 72 (31)URD partially matched 33 (14)URD mismatched 16 ( 7)URD matching to be classified 36 (15)


140



+/+ 67 (29)+/- 22 ( 9)-/+ 61 (26)-/- 60 (26)Missing 25 (11)


Year of HCT 1995-1996 20 ( 9)1997-1998 18 ( 8)1999-2000 25 (11)2001-2002 40 (17)2003-2004 41 (17)2005-2006 52 (22)2007-2008 39 (17)

GVHD prophylaxis T-cell depletion 14 ( 6)FK506+MTX+-other 58 (25)FK506+-other 31 (13)CsA+MTX+-other 90 (38)CsA+-other 36 (15)Other 6 ( 3)

Median follow-up of survivors, range, months 60 (2 - 147)

141


Study Proposal 1210-18 Study Title: The role of EBMT score in predicting outcome of second allogeneic hematopoietic stem cell transplantation for relapse of hematological malignancies after first allogeneic or autologous transplantation. Katy Rezvani, MD, and Richard Szydlo, PhD, Hammersmith Hospital, Imperial College, London, United Kingdom Specific Aims: We propose to investigate whether the European Group for Blood and Marrow Transplantation (EBMT) risk score, previously established for chronic myeloid leukemia,(1), but now of general applicability (2), could be used to predict outcome after second allogeneic hematopoietic stem cell transplantation (allo-SCT). Scientific Justification: Relapse is the most frequent cause of treatment failure after allogeneic or autologous hematopoietic stem-cell transplantation. Several studies have shown that second allo-SCT may be an effective salvage intervention with a probability of disease-free survival (DFS) ranging from 11% to 44%, with a relapse rate of 25% to 75% (3-7). A recent evidence-based guideline published by the American Society of Hematology has given the use of second allogeneic transplant after relapse a recommendation score of 1B (8). Given that relapse after transplant has a dismal prognosis and that select patients can remain alive and disease-free after second allogeneic transplant, identification of prognostic factors to determine more reliably the patient group that best responds to the procedure is highly important. We analyzed prognostic factors in 124 consecutive patients who underwent second transplants between 10/1985 and 02/2010 (selected for oral presentation, Abstract No 14, 2011 BMT Tandem Meetings). Patients with either a first autologous (N=64) or first allogeneic (N=60) SCT were included. Age of patient, disease stage, time interval from diagnosis to transplant, donor type, and donor-recipient gender combination were used to establish a score from 0 to 7 points, from which 3 groups were identified. The survival probability at 5 years decreased from 51.7% (95% confidence interval [CI] 33-70%) for risk scores 0-3 (low, n=25), to 29.3% (95% CI, 17%-47%) for risk score 4 (medium, n=40), and only 10.4% (95%CI, 4%-24%) for risk scores 5-7 (high, n=57). Other factors investigated in univariate analysis included previous transplant type, myeloablative conditioning (Y/N), and interval between first and second SCT (median 20 months). In multivariate analysis, two factors were found to be important. An increased risk of death was associated with: a high risk score (Relative Risk 2.89, p=0.001) when compared with the low risk group and with a shorter interval between 1st and 2nd SCT (< 20 months), RR 1.55, p=0.05. We propose that taking into account both the interval between first and second SCT's and the five well-defined pre-transplant patient and donor characteristics that make up the EBMT risk can provide an accurate estimate of outcome and help in the selection of patient who are most likely to benefit from a second transplant. Data Requirements: To perform this study, the following CIBMTR data collection forms will be required:

- 2000 Recipient Baseline Data - 2100 100 Day Post-HSCT Data - 2200 Six Months to Two Years Post-HSCT Data - 2300 Yearly Follow-Up for Greater than Two Years Post-HSCT Data

142


We wish to study the following variables: The 5 pre-transplant EBMT risk factors as defined in Table 1 (1;2):

1) age of the patient 2) disease stage at time of 2nd transplant 3) time from diagnosis to 2nd transplant 4) donor type 5) donor-recipient sex combination

Each factor will be given 0, 1 or 2 points as outlined in Table 1. Table 1- European Group for Blood and Marrow Transplantation Risk Score Definition: Age of the patient, y<20 020-40 1>40 2Disease stage*Early 0Intermediate 1Late 2Time interval from diagnosis to transplant, months<12 0>12 1Donor typeHLA-identical sibling donor 0Unrelated donor 1Donor-recipient sex combinationAll other 0Donor female, male recipient 1 The EBMT risk score for disease stage was originally defined for each main disease category, as follows: Early disease stage (0): acute leukemia transplanted in first complete remission, myelodysplastic syndrome transplanted either untreated or in first complete remission, chronic myeloid leukemia in first chronic phase, and non-Hodgkin lymphoma and multiple myeloma transplanted untreated or in first complete remission. Intermediate disease stage (1): acute leukemia in second complete remission; chronic myeloid leukemia in all other stages than chronic phase or blast crisis; myelodysplastic syndrome in second complete remission or in partial remission; and non-Hodgkin lymphoma and multiple myeloma in second complete remission, in partial remission, or stable disease. Late stage disease (2): acute leukemia in all other disease stages, chronic myeloid leukemia in blast crisis, myelodysplastic syndromes in all other disease stages, and multiple myeloma and lymphoma in all other disease stages than those defined as early or intermediate. We would also like to look at the impact of cytomegalovirus (CMV) donor/recipient, serostatus, the impact of Karnofsky score, previous transplant type (autologous vs. allogeneic), myeloablative conditioning (Y/N), and interval between first and second SCT. Study Design: The primary study outcome is survival. Univariate survival analyses of the outlined potential prognostic factors will be undertaken and factors significant P<0.2 will be included in a multivariate analysis together with the EBMT risk score.

143


This will be a retrospective study, and so the use of regimens and technologies that are not necessarily current best practise will necessitate a certain degree of caution to its results. However, if the point of principle of the usefulness of the scoring system in the 2nd allograft setting can be established, its prospective utility could then be tested in an appropriate trial. Richard Szydlo will be able to carry out all statistical analyses once a dataset has been identified. References:

1. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 1998 October 3;352(9134):1087-92.

2. Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de WT et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer 2009 October 15;115(20):4715-26.

3. Bosi A, Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E et al. Second Allogeneic Bone Marrow Transplantation in Acute Leukemia: Results of a Survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2001 August 15;19(16):3675-84.

4. Michallet, Tanguy, Soci+®, Thi+®baut, Belhabri, Milpied et al. Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Soci+®t+® Fran+ºaise de Greffe de Moelle (SFGM). British Journal of Haematology 2000;108(2):400-7.

5. Pawson R, Potter MN, Theocharous P, Lawler M, Garg M, Yin JAL et al. Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG -¦GÇèIda) and second allogeneic stem cell transplant. British Journal of Haematology 2001;115(3):622-9.

6. Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE et al. Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant 2008 August 25;42(12):783-9.

7. Venepalli N, Rezvani K, Mielke S, Savani BN. Role of allo-SCT for CML in 2010. Bone Marrow Transplant 2010 November;45(11):1579-86.

8. Thakar MS, Forman SJ. ASH evidence-based guidelines: is there a role for second allogeneic transplant after relapse? Hematology 2009 January 1;2009(1):414-8.

144


Characteristic of patients who underwent a 2nd allogeneic transplant for relapsed AML, ALL, CML, non-Hodgkin lymphoma and multiple myeloma reported to the CIBMTR between 1995

and 2008


<10 yrs 110 ( 4)10-19 yrs 206 ( 8)20-29 yrs 383 (15)30-39 yrs 468 (19)40-49 yrs 568 (23)50-59 yrs 542 (22)>=60 yrs 229 ( 9)




Disease AML 725 (29)ALL 235 ( 9)CML 152 ( 6)MDS 44 ( 2)Lymphoma 1059 (42)Multiple Myeloma 291 (12)



145



+/+ 615 (25)+/- 306 (12)-/+ 690 (28)-/- 726 (29)Missing 169 ( 7)

Graft type Bone marrow 828 (33)Peripheral blood 1678 (67)

Year of HCT 1995-1996 213 ( 8)1997-1998 253 (10)1999-2000 323 (13)2001-2002 418 (17)2003-2004 482 (19)2005-2006 498 (20)2007-2008 319 (13)


Median follow-up of survivors, range, months 61 (<1 - 181)** Twin (n=12) and other relative (n=134) were excluded.

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Not for publication or presentation€¦ · Not for publication or presentation d. CK06-01 Ballen K, Arora M, Woolfrey A, Agovi M, Zhu X, Kalaycio M, Maziarz RT, Cortes J, Horowitz