Trapianto allogenico einfezioni fungine

Attilio Olivieri

Head of SCT program

Clinica di Ematologia-Ancona

amp Elena Inglese Laura Maracci Giorgia Mancini

1 We all have a donor

2 News in GVHD

(nuovi attori e nuovi

approcci)

3 Infezioni fungine

fattori di rischio e

outcome del trapianto

Oral Abst 732

Survival after T-Cell Replete Haploidentical Related Donor Transplant Using

Post-Transplant Cyclophosphamide Compared with Matched Unrelated

Donor (MUD) Transplant for Lymphoid Malignancies

Alberto Mussetti MD Abraham Sebastian Kanate MD Mohamed A Kharfan-Dabaja MD Kwang Woo Ahn PhD Alyssa DiGilio MS Stefan

O Ciurea MD Philippe Armand MD PhD Rachel B Salit MD Timothy S Fenske MD MS Sonali M Smith MD Anna Sureda MD PhD

Javier Bolanos-Meade MD and Mehdi Hamadani MD

Alberto Mussetti et al Blood 2015126194

copy2015 by American Society of Hematology

HAPLO

()

MUD

wo ATG

()

MUD

w

ATG

()

Pvalue

aGVHD 27 40 49 007

cGVHD 13 51 33 lt0001

NRM 17 22 26 008

PFS 47 49 38 nd

OS 60 62 50 nd

Oral Abstr 732

Stem-Cell Transplantation in Adults with Philadelphia-Negative High-Risk

Acute Lymphoblastic Leukemia in First Complete Remission A Prospective

Multicenter Trial Comparing Haploidentical Donors with Identical Sibling

Donors

Yu Wang Wu Depei Qifa Liu MD Lan-Ping Xu Xiao-Hui Zhang and Xiao-Jun Huang MDPhD

HAPLO () SIB () Pvalue

NRM 13 11 084

DFS 68 64 056

OS 75 69 084

Poster Abst 732 ndash Poster II

Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid

Leukemia Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising

from MDS The MD Anderson Experience

Reshma Ramlal MD Sameh Gaballa MD Julianne Chen Gabriela Rondon MD Betul Oran MD Sairah Ahmed MD Qaiser Bashir MD

Katayoun Rezvani MD PhD David Marin MD Amin M Alousi MD Partow Kebriaei MD Muzaffar Qazilbash MD Chitra Hosing MD Uday R

Popat MD Elizabeth J Shpall MD Richard Champlin MD and Stefan O Ciurea MD

80 patients

-60 de novo AML

38 adverse cytogenetics 64 in CR at the time of trasplant

-20 MDS or MDSAML

Conditioning regimen FLUDA+MELPH+- TH or TBI200

77 evaluable aGVHD II-IV 30 III-IV 3

cGVHD 13

NRM 1y 274

OS 2y 475

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

1 We all have a donor

2 News in GVHD

(nuovi attori e nuovi

approcci)

3 Infezioni fungine

fattori di rischio e

outcome del trapianto

Oral Abst 732

Survival after T-Cell Replete Haploidentical Related Donor Transplant Using

Post-Transplant Cyclophosphamide Compared with Matched Unrelated

Donor (MUD) Transplant for Lymphoid Malignancies

Alberto Mussetti MD Abraham Sebastian Kanate MD Mohamed A Kharfan-Dabaja MD Kwang Woo Ahn PhD Alyssa DiGilio MS Stefan

O Ciurea MD Philippe Armand MD PhD Rachel B Salit MD Timothy S Fenske MD MS Sonali M Smith MD Anna Sureda MD PhD

Javier Bolanos-Meade MD and Mehdi Hamadani MD

Alberto Mussetti et al Blood 2015126194

copy2015 by American Society of Hematology

HAPLO

()

MUD

wo ATG

()

MUD

w

ATG

()

Pvalue

aGVHD 27 40 49 007

cGVHD 13 51 33 lt0001

NRM 17 22 26 008

PFS 47 49 38 nd

OS 60 62 50 nd

Oral Abstr 732

Stem-Cell Transplantation in Adults with Philadelphia-Negative High-Risk

Acute Lymphoblastic Leukemia in First Complete Remission A Prospective

Multicenter Trial Comparing Haploidentical Donors with Identical Sibling

Donors

Yu Wang Wu Depei Qifa Liu MD Lan-Ping Xu Xiao-Hui Zhang and Xiao-Jun Huang MDPhD

HAPLO () SIB () Pvalue

NRM 13 11 084

DFS 68 64 056

OS 75 69 084

Poster Abst 732 ndash Poster II

Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid

Leukemia Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising

from MDS The MD Anderson Experience

Reshma Ramlal MD Sameh Gaballa MD Julianne Chen Gabriela Rondon MD Betul Oran MD Sairah Ahmed MD Qaiser Bashir MD

Katayoun Rezvani MD PhD David Marin MD Amin M Alousi MD Partow Kebriaei MD Muzaffar Qazilbash MD Chitra Hosing MD Uday R

Popat MD Elizabeth J Shpall MD Richard Champlin MD and Stefan O Ciurea MD

80 patients

-60 de novo AML

38 adverse cytogenetics 64 in CR at the time of trasplant

-20 MDS or MDSAML

Conditioning regimen FLUDA+MELPH+- TH or TBI200

77 evaluable aGVHD II-IV 30 III-IV 3

cGVHD 13

NRM 1y 274

OS 2y 475

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Oral Abst 732

Survival after T-Cell Replete Haploidentical Related Donor Transplant Using

Post-Transplant Cyclophosphamide Compared with Matched Unrelated

Donor (MUD) Transplant for Lymphoid Malignancies

Alberto Mussetti MD Abraham Sebastian Kanate MD Mohamed A Kharfan-Dabaja MD Kwang Woo Ahn PhD Alyssa DiGilio MS Stefan

O Ciurea MD Philippe Armand MD PhD Rachel B Salit MD Timothy S Fenske MD MS Sonali M Smith MD Anna Sureda MD PhD

Javier Bolanos-Meade MD and Mehdi Hamadani MD

Alberto Mussetti et al Blood 2015126194

copy2015 by American Society of Hematology

HAPLO

()

MUD

wo ATG

()

MUD

w

ATG

()

Pvalue

aGVHD 27 40 49 007

cGVHD 13 51 33 lt0001

NRM 17 22 26 008

PFS 47 49 38 nd

OS 60 62 50 nd

Oral Abstr 732

Stem-Cell Transplantation in Adults with Philadelphia-Negative High-Risk

Acute Lymphoblastic Leukemia in First Complete Remission A Prospective

Multicenter Trial Comparing Haploidentical Donors with Identical Sibling

Donors

Yu Wang Wu Depei Qifa Liu MD Lan-Ping Xu Xiao-Hui Zhang and Xiao-Jun Huang MDPhD

HAPLO () SIB () Pvalue

NRM 13 11 084

DFS 68 64 056

OS 75 69 084

Poster Abst 732 ndash Poster II

Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid

Leukemia Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising

from MDS The MD Anderson Experience

Reshma Ramlal MD Sameh Gaballa MD Julianne Chen Gabriela Rondon MD Betul Oran MD Sairah Ahmed MD Qaiser Bashir MD

Katayoun Rezvani MD PhD David Marin MD Amin M Alousi MD Partow Kebriaei MD Muzaffar Qazilbash MD Chitra Hosing MD Uday R

Popat MD Elizabeth J Shpall MD Richard Champlin MD and Stefan O Ciurea MD

80 patients

-60 de novo AML

38 adverse cytogenetics 64 in CR at the time of trasplant

-20 MDS or MDSAML

Conditioning regimen FLUDA+MELPH+- TH or TBI200

77 evaluable aGVHD II-IV 30 III-IV 3

cGVHD 13

NRM 1y 274

OS 2y 475

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Alberto Mussetti et al Blood 2015126194

copy2015 by American Society of Hematology

HAPLO

()

MUD

wo ATG

()

MUD

w

ATG

()

Pvalue

aGVHD 27 40 49 007

cGVHD 13 51 33 lt0001

NRM 17 22 26 008

PFS 47 49 38 nd

OS 60 62 50 nd

Oral Abstr 732

Stem-Cell Transplantation in Adults with Philadelphia-Negative High-Risk

Acute Lymphoblastic Leukemia in First Complete Remission A Prospective

Multicenter Trial Comparing Haploidentical Donors with Identical Sibling

Donors

Yu Wang Wu Depei Qifa Liu MD Lan-Ping Xu Xiao-Hui Zhang and Xiao-Jun Huang MDPhD

HAPLO () SIB () Pvalue

NRM 13 11 084

DFS 68 64 056

OS 75 69 084

Poster Abst 732 ndash Poster II

Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid

Leukemia Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising

from MDS The MD Anderson Experience

Reshma Ramlal MD Sameh Gaballa MD Julianne Chen Gabriela Rondon MD Betul Oran MD Sairah Ahmed MD Qaiser Bashir MD

Katayoun Rezvani MD PhD David Marin MD Amin M Alousi MD Partow Kebriaei MD Muzaffar Qazilbash MD Chitra Hosing MD Uday R

Popat MD Elizabeth J Shpall MD Richard Champlin MD and Stefan O Ciurea MD

80 patients

-60 de novo AML

38 adverse cytogenetics 64 in CR at the time of trasplant

-20 MDS or MDSAML

Conditioning regimen FLUDA+MELPH+- TH or TBI200

77 evaluable aGVHD II-IV 30 III-IV 3

cGVHD 13

NRM 1y 274

OS 2y 475

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Oral Abstr 732

Stem-Cell Transplantation in Adults with Philadelphia-Negative High-Risk

Acute Lymphoblastic Leukemia in First Complete Remission A Prospective

Multicenter Trial Comparing Haploidentical Donors with Identical Sibling

Donors

Yu Wang Wu Depei Qifa Liu MD Lan-Ping Xu Xiao-Hui Zhang and Xiao-Jun Huang MDPhD

HAPLO () SIB () Pvalue

NRM 13 11 084

DFS 68 64 056

OS 75 69 084

Poster Abst 732 ndash Poster II

Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid

Leukemia Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising

from MDS The MD Anderson Experience

Reshma Ramlal MD Sameh Gaballa MD Julianne Chen Gabriela Rondon MD Betul Oran MD Sairah Ahmed MD Qaiser Bashir MD

Katayoun Rezvani MD PhD David Marin MD Amin M Alousi MD Partow Kebriaei MD Muzaffar Qazilbash MD Chitra Hosing MD Uday R

Popat MD Elizabeth J Shpall MD Richard Champlin MD and Stefan O Ciurea MD

80 patients

-60 de novo AML

38 adverse cytogenetics 64 in CR at the time of trasplant

-20 MDS or MDSAML

Conditioning regimen FLUDA+MELPH+- TH or TBI200

77 evaluable aGVHD II-IV 30 III-IV 3

cGVHD 13

NRM 1y 274

OS 2y 475

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Poster Abst 732 ndash Poster II

Outcomes of Haploidenitical Stem Cell Transplants for De Novo Acute Myeloid

Leukemia Myelodysplastic Syndrome and Acute Myeloid Leukemia Arising

from MDS The MD Anderson Experience

Reshma Ramlal MD Sameh Gaballa MD Julianne Chen Gabriela Rondon MD Betul Oran MD Sairah Ahmed MD Qaiser Bashir MD

Katayoun Rezvani MD PhD David Marin MD Amin M Alousi MD Partow Kebriaei MD Muzaffar Qazilbash MD Chitra Hosing MD Uday R

Popat MD Elizabeth J Shpall MD Richard Champlin MD and Stefan O Ciurea MD

80 patients

-60 de novo AML

38 adverse cytogenetics 64 in CR at the time of trasplant

-20 MDS or MDSAML

Conditioning regimen FLUDA+MELPH+- TH or TBI200

77 evaluable aGVHD II-IV 30 III-IV 3

cGVHD 13

NRM 1y 274

OS 2y 475

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Reshma Ramlal et al Blood 20151263225

copy2015 by American Society of Hematology

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

Poster Abst 721 ndash Poster I

Unmanipulated G-CSF Mobilized Peripheral Blood Stem Cells As Graft Source

for Non-Myeloablative Haploidentical Transplantation Fast Engraftment No

Evidence of Graft Rejection and Low Incidence of Graft-Versus-Host Disease

Rocco Pastano MD Giovanna Andreola MD Federica Gigli MD Simona Sammassimo MD Mara Negri Liptrott Jayne Sarah and Corrado

Tarella MD

31 patients (3 AML 6 ALL9 NHL 5 MM 2 MDS 6 HL)

Median follow up 366 days

27 evaluable aGVHD I-II 21

cGVHD 11

NRM 18

OS 55

(a) conventional GVHD group (n=71) in-vivo T-cell depletion with ATG tacrolimus and methotrexate

(b) PTCy group (n=41) that received PTCy (50 mgkgday IV on days 3 and 4) with tacrolimus and MMF

After exclusion of 29 patients with isolated HLA-DQ mismatches a separate analysis was performed in 84 patients with 78 HLA-MUD HSCT 38 patients received PTCy while 46 patients received conventionalprophylaxis

bull PB was used more frequently as a graft source in the conventional group (38 vs 17 p=002) PTCygroup included more patients with HLA class-I mismatches (878) compared to conventional group(569)

Results

bullSimilar incidence of grade II-IV (37 vs 36 p=08) or grade III-IV (17 vs 12 p=05) acute GVHD at

day +100

bullIncidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0 vs 15 p lt0001) Similar incidence of cGVHD at 6 months (20 vs 15) 1-year (30 vs 31) or 2-years (30 vs 42)

bullPTCy was the sole independent predictor of lower risk of grade II-IV acute GVHD at day 30 (p=001)

bullTwo-year cumulative incidences of NRM (35 vs 25) disease progression (20 vs 31) DFS (42 vs 38) and OS (52 vs 40) were similar in the PTCy and the conventional groups respectively

bull Comparing patients with 78-HLA-MUD HSCT no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0005)

bull no differences in incidence of grade II-IV (HR 1) or grade III-IV (HR 11) acute GVHD at day 100 chronic GVHD at 6 months (HR 08 95 CI 02-29 p=07) 1-year (HR 08p=06) or 2-years (HR p=05) between the groups

bull Median times to neutrophil (18 vs 12 days plt0001) and platelet (255 vs 18 days p=005) engraftment were prolonged in PTCy group

bull Disease recurrencepersistence was the leading cause of death in both groups accounting for about 46 of all deaths

bull In patients with HLA class-I mismatch PTCy was associated with significantly reduced risk of grade II-IV but not grade III-IV acute GVHD at day 30 (p=001)

bull However there were no differences in acute grade II-IV GVHD (HR 11 p=07) or acute grade

III-IV GVHD (HR 15 p=05) by day 100 between the groups

Poster Abst 732 ndash Poster I

Using Haploidentical (haplo) Donors and High-Dose Post-Transplant

Cyclophosphamide (PTCy) for Refractory Severe Aplastic Anemia (SAA)

Amy E DeZern MD MH Donna Dorr RN MSN AOCN Leo Luznik MD Javier Bolanos-Meade MD Christopher Gamper MD PhD Heather J

Symons MD MHS Kenneth R Cooke MD Richard J Jones Sr MD and Robert A Brodsky MD

bull 9 pz (34 aa mediana 50 maschi)

bull F-U 175 mesimdashgttutti vivi

bull chimerismo completo

bull 2 aGVHD I-II e mild cGVHD

News in GVHD

biomarkerspathphisiology

TX

bull 14 patients with TMA enrolled into the study in a single medical center 71 pts recruited as control including 11 cases of VOD 20 cases of severe infections 20 cases of severe II-IVdeg aGVHD and 20 cases without complications

bull plasma ADAMTS13 activity decreased and the ratio of VWF antigenactivity increased significantly in patients with VOD (p lt 005)

bull Plasma VWF multimer distribution was similar in patients with infection GVHD or without complication but ultralarge multimers of VWF were present in patients with TMA and VOD

bull Plasma levels of complement C3b was increased after HSCT (19846 ngml plusmn1478 ngml) compared with healthy subjects (8502 ngmlplusmn850ngml) (p lt 005)

bull Plasma C3b increased significantly in patients with TMA and GVHD (plt005) -

Results

bull Plasma levels of C5b in patients with TMA were significantly increased (105949 ngml plusmn8557 ngml) as compared with those before transplantation (65319ngml plusmn4491ngml) and other groups (p lt 005)

A New Multiple Single-Nucleotide Polymorphisms Based Predictive Model for Grades III to IV and Extensive Graft Versus Host Disease

after Identical HLA-Allogeneic Stem-CellElena Buces12 Carolina Martiacutenez-Laperche13 M Carmen Aguilera4 Antoni Picornell13 Rosa Lillo4 Milagros Gonzaacutelez-Rivera35 Anna Bosch-Vizcaya6 Beatriz Martiacuten-Antonio7 Jose B Nieto8 Vicent Guillem9 Marcos Gonzaacutelez MD PhD10 Rafael De la Caacutemara11 Salut Brunet MD PhD12 Antonio Jimenez-Velasco13 Ildefonso Espigado MD PhD14 Carlos Vallejo15 Antonia Sampol MD PhD16 David Serrano13 Mi Kwon MD12 Jorge Gayoso13 Pascual Balsalobre PhD13 Aacutelvaro Urbano-Izpizua7 Carlos Solano MD17 David Gallardo6 Joseacute Luis Diacuteez Martiacuten1819 Juan Romo4 and Ismael Buno13

1Instituto de Investigacioacuten Sanitaria Gregorio Marantildeoacuten Madrid Spain2Hematology Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain3Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain4Department of Statistics Universidad Carlos III de Madrid Madrid Spain5Instituto de Investigacioacuten Sanitaria Madrid Spain6ICO Hospital Josep Trueta Girona Spain7Hospital Cliacutenic IDIBAPS Barcelona Spain8Hospital Universitario Morales Meseguer Murcia Spain9Hospital Cliacutenico de Valencia Valencia Spain10Hospital Cliacutenico Universitario de Salamanca Salamanca Spain11Hospital Universitario de La Princesa Madrid Spain12Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain13Hospital Regional de Maacutelaga Maacutelaga Spain14Hospital Universitario Virgen del Rociacuteo Sevilla Sevilla Spain15Hospital central de Asturias Oviedo Spain16Hospital Son Espases Palma de Mallorca Spain17Hospital Clinico de Valenci Valencia Spain

bull Comparing patients with 78-HLA-MUD HSCT no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0005)

bull no differences in incidence of grade II-IV (HR 1) or grade III-IV (HR 11) acute GVHD at day 100 chronic GVHD at 6 months (HR 08 95 CI 02-29 p=07) 1-year (HR 08p=06) or 2-years (HR p=05) between the groups

bull Median times to neutrophil (18 vs 12 days plt0001) and platelet (255 vs 18 days p=005) engraftment were prolonged in PTCy group

bull Disease recurrencepersistence was the leading cause of death in both groups accounting for about 46 of all deaths

bull In patients with HLA class-I mismatch PTCy was associated with significantly reduced risk of grade II-IV but not grade III-IV acute GVHD at day 30 (p=001)

bull However there were no differences in acute grade II-IV GVHD (HR 11 p=07) or acute grade

III-IV GVHD (HR 15 p=05) by day 100 between the groups

Poster Abst 732 ndash Poster I

Using Haploidentical (haplo) Donors and High-Dose Post-Transplant

Cyclophosphamide (PTCy) for Refractory Severe Aplastic Anemia (SAA)

Amy E DeZern MD MH Donna Dorr RN MSN AOCN Leo Luznik MD Javier Bolanos-Meade MD Christopher Gamper MD PhD Heather J

Symons MD MHS Kenneth R Cooke MD Richard J Jones Sr MD and Robert A Brodsky MD

bull 9 pz (34 aa mediana 50 maschi)

bull F-U 175 mesimdashgttutti vivi

bull chimerismo completo

bull 2 aGVHD I-II e mild cGVHD

News in GVHD

biomarkerspathphisiology

TX

bull 14 patients with TMA enrolled into the study in a single medical center 71 pts recruited as control including 11 cases of VOD 20 cases of severe infections 20 cases of severe II-IVdeg aGVHD and 20 cases without complications

bull plasma ADAMTS13 activity decreased and the ratio of VWF antigenactivity increased significantly in patients with VOD (p lt 005)

bull Plasma VWF multimer distribution was similar in patients with infection GVHD or without complication but ultralarge multimers of VWF were present in patients with TMA and VOD

bull Plasma levels of complement C3b was increased after HSCT (19846 ngml plusmn1478 ngml) compared with healthy subjects (8502 ngmlplusmn850ngml) (p lt 005)

bull Plasma C3b increased significantly in patients with TMA and GVHD (plt005) -

Results

bull Plasma levels of C5b in patients with TMA were significantly increased (105949 ngml plusmn8557 ngml) as compared with those before transplantation (65319ngml plusmn4491ngml) and other groups (p lt 005)

A New Multiple Single-Nucleotide Polymorphisms Based Predictive Model for Grades III to IV and Extensive Graft Versus Host Disease

after Identical HLA-Allogeneic Stem-CellElena Buces12 Carolina Martiacutenez-Laperche13 M Carmen Aguilera4 Antoni Picornell13 Rosa Lillo4 Milagros Gonzaacutelez-Rivera35 Anna Bosch-Vizcaya6 Beatriz Martiacuten-Antonio7 Jose B Nieto8 Vicent Guillem9 Marcos Gonzaacutelez MD PhD10 Rafael De la Caacutemara11 Salut Brunet MD PhD12 Antonio Jimenez-Velasco13 Ildefonso Espigado MD PhD14 Carlos Vallejo15 Antonia Sampol MD PhD16 David Serrano13 Mi Kwon MD12 Jorge Gayoso13 Pascual Balsalobre PhD13 Aacutelvaro Urbano-Izpizua7 Carlos Solano MD17 David Gallardo6 Joseacute Luis Diacuteez Martiacuten1819 Juan Romo4 and Ismael Buno13

1Instituto de Investigacioacuten Sanitaria Gregorio Marantildeoacuten Madrid Spain2Hematology Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain3Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain4Department of Statistics Universidad Carlos III de Madrid Madrid Spain5Instituto de Investigacioacuten Sanitaria Madrid Spain6ICO Hospital Josep Trueta Girona Spain7Hospital Cliacutenic IDIBAPS Barcelona Spain8Hospital Universitario Morales Meseguer Murcia Spain9Hospital Cliacutenico de Valencia Valencia Spain10Hospital Cliacutenico Universitario de Salamanca Salamanca Spain11Hospital Universitario de La Princesa Madrid Spain12Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain13Hospital Regional de Maacutelaga Maacutelaga Spain14Hospital Universitario Virgen del Rociacuteo Sevilla Sevilla Spain15Hospital central de Asturias Oviedo Spain16Hospital Son Espases Palma de Mallorca Spain17Hospital Clinico de Valenci Valencia Spain

Poster Abst 732 ndash Poster I

Using Haploidentical (haplo) Donors and High-Dose Post-Transplant

Cyclophosphamide (PTCy) for Refractory Severe Aplastic Anemia (SAA)

Amy E DeZern MD MH Donna Dorr RN MSN AOCN Leo Luznik MD Javier Bolanos-Meade MD Christopher Gamper MD PhD Heather J

Symons MD MHS Kenneth R Cooke MD Richard J Jones Sr MD and Robert A Brodsky MD

bull 9 pz (34 aa mediana 50 maschi)

bull F-U 175 mesimdashgttutti vivi

bull chimerismo completo

bull 2 aGVHD I-II e mild cGVHD

News in GVHD

biomarkerspathphisiology

TX

bull 14 patients with TMA enrolled into the study in a single medical center 71 pts recruited as control including 11 cases of VOD 20 cases of severe infections 20 cases of severe II-IVdeg aGVHD and 20 cases without complications

bull plasma ADAMTS13 activity decreased and the ratio of VWF antigenactivity increased significantly in patients with VOD (p lt 005)

bull Plasma VWF multimer distribution was similar in patients with infection GVHD or without complication but ultralarge multimers of VWF were present in patients with TMA and VOD

bull Plasma levels of complement C3b was increased after HSCT (19846 ngml plusmn1478 ngml) compared with healthy subjects (8502 ngmlplusmn850ngml) (p lt 005)

bull Plasma C3b increased significantly in patients with TMA and GVHD (plt005) -

Results

bull Plasma levels of C5b in patients with TMA were significantly increased (105949 ngml plusmn8557 ngml) as compared with those before transplantation (65319ngml plusmn4491ngml) and other groups (p lt 005)

A New Multiple Single-Nucleotide Polymorphisms Based Predictive Model for Grades III to IV and Extensive Graft Versus Host Disease

after Identical HLA-Allogeneic Stem-CellElena Buces12 Carolina Martiacutenez-Laperche13 M Carmen Aguilera4 Antoni Picornell13 Rosa Lillo4 Milagros Gonzaacutelez-Rivera35 Anna Bosch-Vizcaya6 Beatriz Martiacuten-Antonio7 Jose B Nieto8 Vicent Guillem9 Marcos Gonzaacutelez MD PhD10 Rafael De la Caacutemara11 Salut Brunet MD PhD12 Antonio Jimenez-Velasco13 Ildefonso Espigado MD PhD14 Carlos Vallejo15 Antonia Sampol MD PhD16 David Serrano13 Mi Kwon MD12 Jorge Gayoso13 Pascual Balsalobre PhD13 Aacutelvaro Urbano-Izpizua7 Carlos Solano MD17 David Gallardo6 Joseacute Luis Diacuteez Martiacuten1819 Juan Romo4 and Ismael Buno13

1Instituto de Investigacioacuten Sanitaria Gregorio Marantildeoacuten Madrid Spain2Hematology Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain3Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain4Department of Statistics Universidad Carlos III de Madrid Madrid Spain5Instituto de Investigacioacuten Sanitaria Madrid Spain6ICO Hospital Josep Trueta Girona Spain7Hospital Cliacutenic IDIBAPS Barcelona Spain8Hospital Universitario Morales Meseguer Murcia Spain9Hospital Cliacutenico de Valencia Valencia Spain10Hospital Cliacutenico Universitario de Salamanca Salamanca Spain11Hospital Universitario de La Princesa Madrid Spain12Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain13Hospital Regional de Maacutelaga Maacutelaga Spain14Hospital Universitario Virgen del Rociacuteo Sevilla Sevilla Spain15Hospital central de Asturias Oviedo Spain16Hospital Son Espases Palma de Mallorca Spain17Hospital Clinico de Valenci Valencia Spain

News in GVHD

biomarkerspathphisiology

TX

bull 14 patients with TMA enrolled into the study in a single medical center 71 pts recruited as control including 11 cases of VOD 20 cases of severe infections 20 cases of severe II-IVdeg aGVHD and 20 cases without complications

bull plasma ADAMTS13 activity decreased and the ratio of VWF antigenactivity increased significantly in patients with VOD (p lt 005)

bull Plasma VWF multimer distribution was similar in patients with infection GVHD or without complication but ultralarge multimers of VWF were present in patients with TMA and VOD

bull Plasma levels of complement C3b was increased after HSCT (19846 ngml plusmn1478 ngml) compared with healthy subjects (8502 ngmlplusmn850ngml) (p lt 005)

bull Plasma C3b increased significantly in patients with TMA and GVHD (plt005) -

Results

bull Plasma levels of C5b in patients with TMA were significantly increased (105949 ngml plusmn8557 ngml) as compared with those before transplantation (65319ngml plusmn4491ngml) and other groups (p lt 005)

A New Multiple Single-Nucleotide Polymorphisms Based Predictive Model for Grades III to IV and Extensive Graft Versus Host Disease

after Identical HLA-Allogeneic Stem-CellElena Buces12 Carolina Martiacutenez-Laperche13 M Carmen Aguilera4 Antoni Picornell13 Rosa Lillo4 Milagros Gonzaacutelez-Rivera35 Anna Bosch-Vizcaya6 Beatriz Martiacuten-Antonio7 Jose B Nieto8 Vicent Guillem9 Marcos Gonzaacutelez MD PhD10 Rafael De la Caacutemara11 Salut Brunet MD PhD12 Antonio Jimenez-Velasco13 Ildefonso Espigado MD PhD14 Carlos Vallejo15 Antonia Sampol MD PhD16 David Serrano13 Mi Kwon MD12 Jorge Gayoso13 Pascual Balsalobre PhD13 Aacutelvaro Urbano-Izpizua7 Carlos Solano MD17 David Gallardo6 Joseacute Luis Diacuteez Martiacuten1819 Juan Romo4 and Ismael Buno13

1Instituto de Investigacioacuten Sanitaria Gregorio Marantildeoacuten Madrid Spain2Hematology Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain3Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain4Department of Statistics Universidad Carlos III de Madrid Madrid Spain5Instituto de Investigacioacuten Sanitaria Madrid Spain6ICO Hospital Josep Trueta Girona Spain7Hospital Cliacutenic IDIBAPS Barcelona Spain8Hospital Universitario Morales Meseguer Murcia Spain9Hospital Cliacutenico de Valencia Valencia Spain10Hospital Cliacutenico Universitario de Salamanca Salamanca Spain11Hospital Universitario de La Princesa Madrid Spain12Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain13Hospital Regional de Maacutelaga Maacutelaga Spain14Hospital Universitario Virgen del Rociacuteo Sevilla Sevilla Spain15Hospital central de Asturias Oviedo Spain16Hospital Son Espases Palma de Mallorca Spain17Hospital Clinico de Valenci Valencia Spain

bull 14 patients with TMA enrolled into the study in a single medical center 71 pts recruited as control including 11 cases of VOD 20 cases of severe infections 20 cases of severe II-IVdeg aGVHD and 20 cases without complications

bull plasma ADAMTS13 activity decreased and the ratio of VWF antigenactivity increased significantly in patients with VOD (p lt 005)

bull Plasma VWF multimer distribution was similar in patients with infection GVHD or without complication but ultralarge multimers of VWF were present in patients with TMA and VOD

bull Plasma levels of complement C3b was increased after HSCT (19846 ngml plusmn1478 ngml) compared with healthy subjects (8502 ngmlplusmn850ngml) (p lt 005)

bull Plasma C3b increased significantly in patients with TMA and GVHD (plt005) -

Results

bull Plasma levels of C5b in patients with TMA were significantly increased (105949 ngml plusmn8557 ngml) as compared with those before transplantation (65319ngml plusmn4491ngml) and other groups (p lt 005)

A New Multiple Single-Nucleotide Polymorphisms Based Predictive Model for Grades III to IV and Extensive Graft Versus Host Disease

after Identical HLA-Allogeneic Stem-CellElena Buces12 Carolina Martiacutenez-Laperche13 M Carmen Aguilera4 Antoni Picornell13 Rosa Lillo4 Milagros Gonzaacutelez-Rivera35 Anna Bosch-Vizcaya6 Beatriz Martiacuten-Antonio7 Jose B Nieto8 Vicent Guillem9 Marcos Gonzaacutelez MD PhD10 Rafael De la Caacutemara11 Salut Brunet MD PhD12 Antonio Jimenez-Velasco13 Ildefonso Espigado MD PhD14 Carlos Vallejo15 Antonia Sampol MD PhD16 David Serrano13 Mi Kwon MD12 Jorge Gayoso13 Pascual Balsalobre PhD13 Aacutelvaro Urbano-Izpizua7 Carlos Solano MD17 David Gallardo6 Joseacute Luis Diacuteez Martiacuten1819 Juan Romo4 and Ismael Buno13

1Instituto de Investigacioacuten Sanitaria Gregorio Marantildeoacuten Madrid Spain2Hematology Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain3Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain4Department of Statistics Universidad Carlos III de Madrid Madrid Spain5Instituto de Investigacioacuten Sanitaria Madrid Spain6ICO Hospital Josep Trueta Girona Spain7Hospital Cliacutenic IDIBAPS Barcelona Spain8Hospital Universitario Morales Meseguer Murcia Spain9Hospital Cliacutenico de Valencia Valencia Spain10Hospital Cliacutenico Universitario de Salamanca Salamanca Spain11Hospital Universitario de La Princesa Madrid Spain12Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain13Hospital Regional de Maacutelaga Maacutelaga Spain14Hospital Universitario Virgen del Rociacuteo Sevilla Sevilla Spain15Hospital central de Asturias Oviedo Spain16Hospital Son Espases Palma de Mallorca Spain17Hospital Clinico de Valenci Valencia Spain

A New Multiple Single-Nucleotide Polymorphisms Based Predictive Model for Grades III to IV and Extensive Graft Versus Host Disease

after Identical HLA-Allogeneic Stem-CellElena Buces12 Carolina Martiacutenez-Laperche13 M Carmen Aguilera4 Antoni Picornell13 Rosa Lillo4 Milagros Gonzaacutelez-Rivera35 Anna Bosch-Vizcaya6 Beatriz Martiacuten-Antonio7 Jose B Nieto8 Vicent Guillem9 Marcos Gonzaacutelez MD PhD10 Rafael De la Caacutemara11 Salut Brunet MD PhD12 Antonio Jimenez-Velasco13 Ildefonso Espigado MD PhD14 Carlos Vallejo15 Antonia Sampol MD PhD16 David Serrano13 Mi Kwon MD12 Jorge Gayoso13 Pascual Balsalobre PhD13 Aacutelvaro Urbano-Izpizua7 Carlos Solano MD17 David Gallardo6 Joseacute Luis Diacuteez Martiacuten1819 Juan Romo4 and Ismael Buno13

1Instituto de Investigacioacuten Sanitaria Gregorio Marantildeoacuten Madrid Spain2Hematology Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain3Hospital General Universitario Gregorio Marantildeoacuten Madrid Spain4Department of Statistics Universidad Carlos III de Madrid Madrid Spain5Instituto de Investigacioacuten Sanitaria Madrid Spain6ICO Hospital Josep Trueta Girona Spain7Hospital Cliacutenic IDIBAPS Barcelona Spain8Hospital Universitario Morales Meseguer Murcia Spain9Hospital Cliacutenico de Valencia Valencia Spain10Hospital Cliacutenico Universitario de Salamanca Salamanca Spain11Hospital Universitario de La Princesa Madrid Spain12Hematology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain13Hospital Regional de Maacutelaga Maacutelaga Spain14Hospital Universitario Virgen del Rociacuteo Sevilla Sevilla Spain15Hospital central de Asturias Oviedo Spain16Hospital Son Espases Palma de Mallorca Spain17Hospital Clinico de Valenci Valencia Spain

bull 273 patients with available acute GVHD data

bull and 213 patients with chronic GVHD

bull evaluated 25 SNPs in 12 genes in genomic DNA obtained from 273 patients with available acute GVHD data and 213 patients with chronic GVHD data included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation and their HLA-identical sibling donors

bull Each SNP was assessed for different models of transmission (recessive dominant co-dominant and additive) producing 25 SNPs x 4 models = 100 variables

Multivariant analysis was made with LASSO an innovative estimation method for linear regression models able to select a set of optimal predictors from a

large set of potential predictor variables

bull The best model to predict aGVHD II-IV included 11 genetic variables and no clinical variables with a CCR for patients who developed (CCR1) aGVHD II-IV of 636

bull The best model to predict aGVHD III-IV included 20 genetic and 7 clinical variables with a CCR1 for aGVHD III-IV of 100

bull The best model to predict extensive chronic GVHD included 10 genetic and 3 clinical variables with a CCR1 for extensive cGVHD of 80

The novel predictive model proposed based on clinical and genetic factors

allows significantly improved anticipation of aGVHD III-IV (100 accuracy) and extensive cGVHD (80)

after HLA-identical sibling donor allo-SCT

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Frances T Hakim PhD1 Sarfraz Memon MD1 Ping Jin PhD2 Matin M Imanguli DDS MD1 Najibah Rehman MD1 Xiao-Yi Yan MS1 Jeremy J Rose BA1 Jacqueline W Mays DDS PhD3 Susan Dhamala BA1 Veena Kapoor1 William Telford PhD1 David C Halverson MD1 Kristin Baird MD45 Daniel H Fowler MD1 David Stroncek MD6 Edward W Cowen MD MHSc7 Steven Z Pavletic MD1 and Ronald E Gress MD11Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD2Department of Transfusion Medicine National Institutes of Health Clinical Center Bethesda MD3Clinical Research Core National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD4Pediatric Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD5Center For Biologics Evaluation and Research FDA Rockville MD6Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD7Dermatology Branch Nation

bull To identify the systemic cytokine pathways supporting the development and persistence of CGVHD we chose to profile gene expression in circulating monocytes monocytes up-regulate distinct patterns of gene expression in response to different cytokines acting as in situ reporters

bull Two interrelated pathways were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis

bull (1) IFN-inducible genes including those involved in signaling lymphocyte homeostasis and trafficking apoptosis and antigen uptake and presentation (STAT1 CXCL10 TNFSF13B TNFSF10 TAP1

bull (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2 TLR4 TLR7 AIM2 DDX58 CLEC4E)

bull evaluated 25 SNPs in 12 genes in genomic DNA obtained from 273 patients with available acute GVHD data and 213 patients with chronic GVHD data included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation and their HLA-identical sibling donors

bull Each SNP was assessed for different models of transmission (recessive dominant co-dominant and additive) producing 25 SNPs x 4 models = 100 variables

Multivariant analysis was made with LASSO an innovative estimation method for linear regression models able to select a set of optimal predictors from a

large set of potential predictor variables

bull The best model to predict aGVHD II-IV included 11 genetic variables and no clinical variables with a CCR for patients who developed (CCR1) aGVHD II-IV of 636

bull The best model to predict aGVHD III-IV included 20 genetic and 7 clinical variables with a CCR1 for aGVHD III-IV of 100

bull The best model to predict extensive chronic GVHD included 10 genetic and 3 clinical variables with a CCR1 for extensive cGVHD of 80

The novel predictive model proposed based on clinical and genetic factors

allows significantly improved anticipation of aGVHD III-IV (100 accuracy) and extensive cGVHD (80)

after HLA-identical sibling donor allo-SCT

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Frances T Hakim PhD1 Sarfraz Memon MD1 Ping Jin PhD2 Matin M Imanguli DDS MD1 Najibah Rehman MD1 Xiao-Yi Yan MS1 Jeremy J Rose BA1 Jacqueline W Mays DDS PhD3 Susan Dhamala BA1 Veena Kapoor1 William Telford PhD1 David C Halverson MD1 Kristin Baird MD45 Daniel H Fowler MD1 David Stroncek MD6 Edward W Cowen MD MHSc7 Steven Z Pavletic MD1 and Ronald E Gress MD11Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD2Department of Transfusion Medicine National Institutes of Health Clinical Center Bethesda MD3Clinical Research Core National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD4Pediatric Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD5Center For Biologics Evaluation and Research FDA Rockville MD6Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD7Dermatology Branch Nation

bull To identify the systemic cytokine pathways supporting the development and persistence of CGVHD we chose to profile gene expression in circulating monocytes monocytes up-regulate distinct patterns of gene expression in response to different cytokines acting as in situ reporters

bull Two interrelated pathways were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis

bull (1) IFN-inducible genes including those involved in signaling lymphocyte homeostasis and trafficking apoptosis and antigen uptake and presentation (STAT1 CXCL10 TNFSF13B TNFSF10 TAP1

bull (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2 TLR4 TLR7 AIM2 DDX58 CLEC4E)

The novel predictive model proposed based on clinical and genetic factors

allows significantly improved anticipation of aGVHD III-IV (100 accuracy) and extensive cGVHD (80)

after HLA-identical sibling donor allo-SCT

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Frances T Hakim PhD1 Sarfraz Memon MD1 Ping Jin PhD2 Matin M Imanguli DDS MD1 Najibah Rehman MD1 Xiao-Yi Yan MS1 Jeremy J Rose BA1 Jacqueline W Mays DDS PhD3 Susan Dhamala BA1 Veena Kapoor1 William Telford PhD1 David C Halverson MD1 Kristin Baird MD45 Daniel H Fowler MD1 David Stroncek MD6 Edward W Cowen MD MHSc7 Steven Z Pavletic MD1 and Ronald E Gress MD11Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD2Department of Transfusion Medicine National Institutes of Health Clinical Center Bethesda MD3Clinical Research Core National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD4Pediatric Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD5Center For Biologics Evaluation and Research FDA Rockville MD6Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD7Dermatology Branch Nation

bull To identify the systemic cytokine pathways supporting the development and persistence of CGVHD we chose to profile gene expression in circulating monocytes monocytes up-regulate distinct patterns of gene expression in response to different cytokines acting as in situ reporters

bull Two interrelated pathways were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis

bull (1) IFN-inducible genes including those involved in signaling lymphocyte homeostasis and trafficking apoptosis and antigen uptake and presentation (STAT1 CXCL10 TNFSF13B TNFSF10 TAP1

bull (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2 TLR4 TLR7 AIM2 DDX58 CLEC4E)

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Frances T Hakim PhD1 Sarfraz Memon MD1 Ping Jin PhD2 Matin M Imanguli DDS MD1 Najibah Rehman MD1 Xiao-Yi Yan MS1 Jeremy J Rose BA1 Jacqueline W Mays DDS PhD3 Susan Dhamala BA1 Veena Kapoor1 William Telford PhD1 David C Halverson MD1 Kristin Baird MD45 Daniel H Fowler MD1 David Stroncek MD6 Edward W Cowen MD MHSc7 Steven Z Pavletic MD1 and Ronald E Gress MD11Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD2Department of Transfusion Medicine National Institutes of Health Clinical Center Bethesda MD3Clinical Research Core National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda MD4Pediatric Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD5Center For Biologics Evaluation and Research FDA Rockville MD6Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD7Dermatology Branch Nation

bull To identify the systemic cytokine pathways supporting the development and persistence of CGVHD we chose to profile gene expression in circulating monocytes monocytes up-regulate distinct patterns of gene expression in response to different cytokines acting as in situ reporters

bull Two interrelated pathways were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis

bull (1) IFN-inducible genes including those involved in signaling lymphocyte homeostasis and trafficking apoptosis and antigen uptake and presentation (STAT1 CXCL10 TNFSF13B TNFSF10 TAP1

bull (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2 TLR4 TLR7 AIM2 DDX58 CLEC4E)

bull significant up-regulation of IFN-inducible and damage-response genes in 69 cGVHD patients with a broad range of organ involvement as compared with 14 allo-HSCT patients never developing cGVHD or with 19 normal controls

bull plasma ELISA assays showed elevated levels of IFN-induced chemokines (CXCL9 CXCL10) in both lichenoid and severe sclerotic patients

bull Immunohistochemistry substantiated expression of Type I IFN-induced factors in inflammatory infiltrates in cGVHD-targeted organs lichenoid and sclerotic skin oral mucosa and salivary gland

Upregulation of Interferon-Inducible and Damage Response Receptors in cGVHD

Acute Gvhd Induce Critical Depletion of Naiumlve Pool in Regulatory T Cells Implication for Linked Pathogenesis into Chronic Gvhd

Takanori Yoshioka MD1 Yusuke Meguri MD1 Takeru Asano MD1 Yuriko Kishi1 Miki Iwamoto1 YoshinobuMaeda MD PhD1 Mitsune Tanimoto MD PhD1 and Ken-Ichi Matsuoka MD PhD21Department of Hematology and Oncology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

2Hematology and Oncology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

bull Long-term severe lymphopenia could result in the collapse of Treg homeostasis leading to the onset of chronic GVHD (Matsuoka et al JCI 2010)

bull In the acute phase the homeostasis of Treg is more susceptible to the post-transplant environment as compared to other lymphocyte subsets (Yoshioka et al ASH 2014)

18 patients with aGVHD studied before and after the onset of GVHD bull Before the onset of acute GVHD Ki-67+ cells in Treg and Tcon were in the

equivalent levels in these patients bull After the onset of acute GVHD Ki-67+ cells in Treg was dramatically increased

from 191 to 612

bull As a consequence naiumlve Treg pool including CD45RA+CD31+ recent thymic emigrant Treg were critically decreased during acute GVHD (CD45RA+ cells 127 into 65 Plt0004 CD45RA+CD31+ cells 36 into 21 Plt0003)

Acute Gvhd Induce Critical Depletion of Naiumlve Pool in Regulatory T Cells Implication for Linked Pathogenesis into Chronic Gvhd

Takanori Yoshioka MD1 Yusuke Meguri MD1 Takeru Asano MD1 Yuriko Kishi1 Miki Iwamoto1 YoshinobuMaeda MD PhD1 Mitsune Tanimoto MD PhD1 and Ken-Ichi Matsuoka MD PhD21Department of Hematology and Oncology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

2Hematology and Oncology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

bull Long-term severe lymphopenia could result in the collapse of Treg homeostasis leading to the onset of chronic GVHD (Matsuoka et al JCI 2010)

bull In the acute phase the homeostasis of Treg is more susceptible to the post-transplant environment as compared to other lymphocyte subsets (Yoshioka et al ASH 2014)

18 patients with aGVHD studied before and after the onset of GVHD bull Before the onset of acute GVHD Ki-67+ cells in Treg and Tcon were in the

equivalent levels in these patients bull After the onset of acute GVHD Ki-67+ cells in Treg was dramatically increased

from 191 to 612

bull As a consequence naiumlve Treg pool including CD45RA+CD31+ recent thymic emigrant Treg were critically decreased during acute GVHD (CD45RA+ cells 127 into 65 Plt0004 CD45RA+CD31+ cells 36 into 21 Plt0003)

Activated Circulating T Follicular Helper Cells with Increased Function during Chronic Graft Versus Host Disease after Allogeneic Stem Cell Transplantation

Edouard Forcade MD12 Haesook T Kim PhD34 Corey S Cutler MD MPH12 Kathy S Wang PhD12 Vincent T Ho MD25 John Koreth MBBS DPhil12 Philippe Armand MD PhD12 Edwin P Alyea MD26 Bruce R Blazar MD7 Robert J Soiffer MD25 Joseph H Antin MD12 and Jerome Ritz MD28

1Division of Hematologic Malignancies and Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School Boston MA2Harvard Medical School Boston MA3Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute Boston MA4Harvard School of Public Health Boston5Dana-Farber Cancer Institute Boston MA6Department of Medical Oncology Dana-Farber Cancer Institute Boston MA7Division of Pediatrics Department of Medicine University of Minnesota Cancer Center Minneapolis MN8Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston MA

bull T follicular helper cells (TFH) interact with B cells in the germinal center to support B cell proliferation differentiation and immunoglobulin class switch

bull Previous studies have demonstrated that donor B cells contribute to the immune pathology of cGVHD and studies in murine models of cGVHD have suggested that TFH play a central role in this process

bull TFH can also be found in the peripheral blood (cTFH) and are identified as a subset of memory CD4 T cells expressing CXCR5

bull In cGVHD cTFH show high levels of activation proliferation and switch toward Th2 and Th17 phenotype These changes enhance cTFH function promoting GC reactions and B cell differentiation

bullThese data support the involvement of cTFH in cGVHDhelliphelliphelliphelliphellip

Phenotypic and functional analysis of cTFH was undertaken in 66 adult pts (gt9 months post-HSCT) 16 no cGVHD 12 resolved cGVHD and 38 had active cGVHD

(mild = 15 moderate = 14 severe = 9) Results were compared to 22 healthy donors

bull Frequency of cTFH was significantly reduced in HSCT patients compared to HD (median 987 vs 1365 of CD4+ T-cells respectively p =00003)

bull cTFH frequency was lower in active cGVHD compared to no cGVHD patients (median 944 vs 1165 of CD4+ T-cells p = 0029)

bull cTFH in patients with resolved cGVHD was similar to patients without cGVHD

CXCL13 chemokine facilitates T-B interaction thus

promoting the GC reaction

CXCL13 levels were increased in active cGVHD compared to no cGVHD (1377 pgmL vs

3374 pgmL p lt 10-4) suggesting

that trafficking of cTFH to lymphoid organs was promoted in cGVHD

MAIN TARGETS OF ANTI-GVHD TX

bull Blockade of GVHD with anti-T and anti-B cellAbs

bull Targeting the mediators and amplifiers of the tissue damage anti-cytokine Abs

bull Targeting T-cell homing (anti-selectinintegrinAbs)

Anti ndashcytokine MoAbs

Anti-BcellMoAbs

Anti-TcellMoAbs

Anti-homing MoAb

New targets

Effectorphase

Homing

bull CD4 cells express CD30 following activationbull blockade of the CD30CD153 pathway impairs localization of CD4 cells in

GUT and prevents GVHD in mice

Brentuximab Vedotin for Steroid Refractory aGVHD

COP 81513 ASH 2015Blazar B JImmun 2004

Phase 1 study to establish the MTD of BV for the treatment of SR aGVHD

Results 24 patients enrolled MTD was defined at 08 mgkg with one DLT (neutropenia)Other adverse events thrombocytopenia (grade 3 n=1) fatigue (grade 3 n=1) and ileus (grade 3 n=1)

At day 28 ORR was 375 (9 of 24 pts) with 3 CR 125+ 6 VGPR 4 patients had stable disease

924 patients are currently alive with a median follow-up of 129 months (range 47-315 months)

Salvage Therapy for Steroid-Refractory Grades III-IV Acute GvHD with Basiliximab and Etanercept a Multicenter Prospective Study

41 pts with SR grades IIIndashIV aGVHD15 (366) had grade ll-III aGVHD and 634 grade IV Median number of infusions of Basiliximab was 4 (range 2ndash7)

median number of Etanercept infusions was 8 (range 1-11)

At day 28 ORR (CR+PR) was 927 with 78 of CR

CI of lung IFI at 12 months post-HSCT was 424 28 pts (693) had CMV reactivation without CMV disease

5 yrs OS 552

17 patients died due to bullLung fungal infection (n=8 471)bullrelapse (n=4 235)bull aGVHD (n=4 235)bullarrhythmia (n=1 59)

COP 84900 ASH 2015

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

CXCL13 chemokine facilitates T-B interaction thus

promoting the GC reaction

CXCL13 levels were increased in active cGVHD compared to no cGVHD (1377 pgmL vs

3374 pgmL p lt 10-4) suggesting

that trafficking of cTFH to lymphoid organs was promoted in cGVHD

MAIN TARGETS OF ANTI-GVHD TX

bull Blockade of GVHD with anti-T and anti-B cellAbs

bull Targeting the mediators and amplifiers of the tissue damage anti-cytokine Abs

bull Targeting T-cell homing (anti-selectinintegrinAbs)

Anti ndashcytokine MoAbs

Anti-BcellMoAbs

Anti-TcellMoAbs

Anti-homing MoAb

New targets

Effectorphase

Homing

bull CD4 cells express CD30 following activationbull blockade of the CD30CD153 pathway impairs localization of CD4 cells in

GUT and prevents GVHD in mice

Brentuximab Vedotin for Steroid Refractory aGVHD

COP 81513 ASH 2015Blazar B JImmun 2004

Phase 1 study to establish the MTD of BV for the treatment of SR aGVHD

Results 24 patients enrolled MTD was defined at 08 mgkg with one DLT (neutropenia)Other adverse events thrombocytopenia (grade 3 n=1) fatigue (grade 3 n=1) and ileus (grade 3 n=1)

At day 28 ORR was 375 (9 of 24 pts) with 3 CR 125+ 6 VGPR 4 patients had stable disease

924 patients are currently alive with a median follow-up of 129 months (range 47-315 months)

Salvage Therapy for Steroid-Refractory Grades III-IV Acute GvHD with Basiliximab and Etanercept a Multicenter Prospective Study

41 pts with SR grades IIIndashIV aGVHD15 (366) had grade ll-III aGVHD and 634 grade IV Median number of infusions of Basiliximab was 4 (range 2ndash7)

median number of Etanercept infusions was 8 (range 1-11)

At day 28 ORR (CR+PR) was 927 with 78 of CR

CI of lung IFI at 12 months post-HSCT was 424 28 pts (693) had CMV reactivation without CMV disease

5 yrs OS 552

17 patients died due to bullLung fungal infection (n=8 471)bullrelapse (n=4 235)bull aGVHD (n=4 235)bullarrhythmia (n=1 59)

COP 84900 ASH 2015

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

MAIN TARGETS OF ANTI-GVHD TX

bull Blockade of GVHD with anti-T and anti-B cellAbs

bull Targeting the mediators and amplifiers of the tissue damage anti-cytokine Abs

bull Targeting T-cell homing (anti-selectinintegrinAbs)

Anti ndashcytokine MoAbs

Anti-BcellMoAbs

Anti-TcellMoAbs

Anti-homing MoAb

New targets

Effectorphase

Homing

bull CD4 cells express CD30 following activationbull blockade of the CD30CD153 pathway impairs localization of CD4 cells in

GUT and prevents GVHD in mice

Brentuximab Vedotin for Steroid Refractory aGVHD

COP 81513 ASH 2015Blazar B JImmun 2004

Phase 1 study to establish the MTD of BV for the treatment of SR aGVHD

Results 24 patients enrolled MTD was defined at 08 mgkg with one DLT (neutropenia)Other adverse events thrombocytopenia (grade 3 n=1) fatigue (grade 3 n=1) and ileus (grade 3 n=1)

At day 28 ORR was 375 (9 of 24 pts) with 3 CR 125+ 6 VGPR 4 patients had stable disease

924 patients are currently alive with a median follow-up of 129 months (range 47-315 months)

Salvage Therapy for Steroid-Refractory Grades III-IV Acute GvHD with Basiliximab and Etanercept a Multicenter Prospective Study

41 pts with SR grades IIIndashIV aGVHD15 (366) had grade ll-III aGVHD and 634 grade IV Median number of infusions of Basiliximab was 4 (range 2ndash7)

median number of Etanercept infusions was 8 (range 1-11)

At day 28 ORR (CR+PR) was 927 with 78 of CR

CI of lung IFI at 12 months post-HSCT was 424 28 pts (693) had CMV reactivation without CMV disease

5 yrs OS 552

17 patients died due to bullLung fungal infection (n=8 471)bullrelapse (n=4 235)bull aGVHD (n=4 235)bullarrhythmia (n=1 59)

COP 84900 ASH 2015

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Anti ndashcytokine MoAbs

Anti-BcellMoAbs

Anti-TcellMoAbs

Anti-homing MoAb

New targets

Effectorphase

Homing

bull CD4 cells express CD30 following activationbull blockade of the CD30CD153 pathway impairs localization of CD4 cells in

GUT and prevents GVHD in mice

Brentuximab Vedotin for Steroid Refractory aGVHD

COP 81513 ASH 2015Blazar B JImmun 2004

Phase 1 study to establish the MTD of BV for the treatment of SR aGVHD

Results 24 patients enrolled MTD was defined at 08 mgkg with one DLT (neutropenia)Other adverse events thrombocytopenia (grade 3 n=1) fatigue (grade 3 n=1) and ileus (grade 3 n=1)

At day 28 ORR was 375 (9 of 24 pts) with 3 CR 125+ 6 VGPR 4 patients had stable disease

924 patients are currently alive with a median follow-up of 129 months (range 47-315 months)

Salvage Therapy for Steroid-Refractory Grades III-IV Acute GvHD with Basiliximab and Etanercept a Multicenter Prospective Study

41 pts with SR grades IIIndashIV aGVHD15 (366) had grade ll-III aGVHD and 634 grade IV Median number of infusions of Basiliximab was 4 (range 2ndash7)

median number of Etanercept infusions was 8 (range 1-11)

At day 28 ORR (CR+PR) was 927 with 78 of CR

CI of lung IFI at 12 months post-HSCT was 424 28 pts (693) had CMV reactivation without CMV disease

5 yrs OS 552

17 patients died due to bullLung fungal infection (n=8 471)bullrelapse (n=4 235)bull aGVHD (n=4 235)bullarrhythmia (n=1 59)

COP 84900 ASH 2015

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

bull CD4 cells express CD30 following activationbull blockade of the CD30CD153 pathway impairs localization of CD4 cells in

GUT and prevents GVHD in mice

Brentuximab Vedotin for Steroid Refractory aGVHD

COP 81513 ASH 2015Blazar B JImmun 2004

Phase 1 study to establish the MTD of BV for the treatment of SR aGVHD

Results 24 patients enrolled MTD was defined at 08 mgkg with one DLT (neutropenia)Other adverse events thrombocytopenia (grade 3 n=1) fatigue (grade 3 n=1) and ileus (grade 3 n=1)

At day 28 ORR was 375 (9 of 24 pts) with 3 CR 125+ 6 VGPR 4 patients had stable disease

924 patients are currently alive with a median follow-up of 129 months (range 47-315 months)

Salvage Therapy for Steroid-Refractory Grades III-IV Acute GvHD with Basiliximab and Etanercept a Multicenter Prospective Study

41 pts with SR grades IIIndashIV aGVHD15 (366) had grade ll-III aGVHD and 634 grade IV Median number of infusions of Basiliximab was 4 (range 2ndash7)

median number of Etanercept infusions was 8 (range 1-11)

At day 28 ORR (CR+PR) was 927 with 78 of CR

CI of lung IFI at 12 months post-HSCT was 424 28 pts (693) had CMV reactivation without CMV disease

5 yrs OS 552

17 patients died due to bullLung fungal infection (n=8 471)bullrelapse (n=4 235)bull aGVHD (n=4 235)bullarrhythmia (n=1 59)

COP 84900 ASH 2015

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Salvage Therapy for Steroid-Refractory Grades III-IV Acute GvHD with Basiliximab and Etanercept a Multicenter Prospective Study

41 pts with SR grades IIIndashIV aGVHD15 (366) had grade ll-III aGVHD and 634 grade IV Median number of infusions of Basiliximab was 4 (range 2ndash7)

median number of Etanercept infusions was 8 (range 1-11)

At day 28 ORR (CR+PR) was 927 with 78 of CR

CI of lung IFI at 12 months post-HSCT was 424 28 pts (693) had CMV reactivation without CMV disease

5 yrs OS 552

17 patients died due to bullLung fungal infection (n=8 471)bullrelapse (n=4 235)bull aGVHD (n=4 235)bullarrhythmia (n=1 59)

COP 84900 ASH 2015

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Anti-IL-6 MoAb Tocilizumab

High IL-6 levels can be predictive of severe aGVHD and IL6 gene polymorphisms are

associated with aGVHD

Dose 8 mgkgtwo weeks Effective and safein several autoimmune diseases and Castleman Disease

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Targeting T-cell homing(selectins and their ligands)

bull P-selectin is expressed on vascular endothelium

bull mRNA encoding P-selectin ligand-1 is upregulated in aGVHD

bull P-selectin-deficient recipients exhibit diminished infiltration of alloactivated T-cells into the Peyerrsquos patches and small bowel

bull Blockade of selectinligand axis can be used for inhibition of alloreactive T-cells homing (anti-Integrin Abs)

bull precluding CD30CD153 interactions inhibits the homing of CD4 T cells to the GUT (anti-CD30 Abs)

Blazar 2004

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Antibody against α4-integrin

bull Natalizumab MoAb against α4-integrin approved for patients with MS but resulted in a progressive demyelinating disease in 02 of cases

bull The beta7 subunit of α4-integrin plays a pivotal role in intestinal homing of alloreactive T cells and its inhibition can significantly reduce gut aGVHD

Ghezzi A et al Safety and efficacy of natalizumab in children with multiple sclerosis Neurology 2010MacDonald JK et al Natalizumab for induction of remission in Crohns disease Cochrane Database Syst Rev 2007 Jan 24

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Vedolizumab targets T-cells homing to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM

77 patients exhibited clinical responses within 7 ndash 10 days after start of TX

Targeting Integrin α4b7-Expressing T-Cells in SR-gut-GvHD

Presenter has relevant financial relationship(s) to disclose No

ASH 2015

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Immunologic Effects of CCR5 Blockade in GVHD ProphylaxisRyan H Moy MD PhD12 Austin P Huffman BA23 Lee P Richman BA2 Lisa Crisalli BS2 James A Hoxie MD2 Robert H Vonderheide MD DPhil2 David L Porter MD2 and Ran Reshef MD341Department of Medicine NewYork-Presbyterian Hospital-Weill Cornell Medical College New York NY2Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia PA3Division of HematologyOncology and the Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York NY4Columbia Center for Translational Immunology Department of Medicine Columbia University Medical Center New York

bull previously reported a phase III study of 38 high-risk patients undergoing HSCT with standard GVHD prophylaxis (tacrolimus methotrexate) combined with brief (33-day) MVC treatment

bull We compared clinical and immunologic outcomes of these patients to a control cohort of 115 consecutive patients undergoing HSCT with standard GVHD prophylaxis

bull chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD

Adoptively-Transferred EBV-Specific T Cells to Prevent or Treat PTLD in AlloHSCT Recipients

a Single Center Experience Spanning 22 Years

bull 198209 patients infused with donor-derived virus-specific T cells at doses from 5x106 to 12x108 cellsm2

bull Infusions were well tolerated with aGvHD) grade I-II documented in just 10 pts Chronic GvHD occurred in

13 pts

bull Of 162 pts infused prophylactically only 1 developed EBV-PTLD

bull 31 of 36 (86) patients with elevated viral load (n=21) or biopsy-provenprobable LPD (n=15) achieved

durable CR and the infused cells persisted long term as demonstrated in 26 patients who received gene-

marked VSTs that were detectable for up to 9 years post-infusion

Based on the safety and efficacy profile of donor-derived EBV-specific VSTs we extended our approach to

provide an ldquooff the shelfrdquo product to third party recipients generating and banking T cell lines from 88

consenting normal donors

bull To date we have treated 11 patients all of whom had drug-refractory EBV infections Two patients were

treated for elevated viral loads while 9 had established PTLD

bull Patients received 1-5 doses (fixed dose - 2x107 cellsm2) with 3rd party VSTs matching at one to three of

six HLA alleles Despite the HLA disparity the cells have proven safe with a single case of grade I GvHD

reported

bull Of the 11 patients infused 8 responded to therapy with 5CR and 3 PR for an overall response rate of 73

INFEZIONI FUNGINE

Invasive Fungal Infections in Patients with High-Risk MDS and AML Treated with Azacitidine

Helena Pomares et al

bull MDSAML pts treated with AZA have a very low risk of IFI including those with concurrent severe prolonged neutropenia

bull Primary antifungal prophylaxis should not be recommended for this subset of patients

bull This very low risk (4121) of IFI is a potential additional benefit before and after SCT

Whole Genome Sequencing of Azole-Resistant Aspergillus Fumigatus Strains from Hematopoietic Stem Cell Recipients Identifies Candidate Molecular Targets Potentially Implicated in Novel Resistance

Mediating Mechanisms - First Results

Maximilian Mossner1 Birgit Spiess PhD2 Johann-Christoph Jann1 Verena Nowak1 Julia Oblaumlnder2 Oliver Bader3 Wolf-Karsten Hofmann MD1 Daniel Nowak MD1 Dieter Buchheidt MD2 and Tobias Boch MD1

bull Several studies recently reported azole resistant fungal strains detectable in patients at risk with rapidly increasing frequency

bull While mutations in the 14α-sterol demethylase (cyp51A) gene have been implicated in mediating azole resistance in approximately 50 of resistant patient isolates the underlying genetic cause is unknown

bull we performed whole genome sequencing (WGS) of azole-resistant cyp51A-wildtype Aspergillus fumigatus (Afu) specimen the main effector of IA with the aim to identify novel genetic alterations leading to azole resistance

bull Methods Afu clinical strains were isolated from six different patients with IA undergoing intensive chemotherapy for acute leukemia or after allo-HSCT Sanger sequencing revealed characteristic resistance associated cyp51A mutations (TR46Y121FT289A) in four of the six specimen while two samples harbored cyp51A wildtype sequences

bull High molecular weight genomic DNA (gDNA) was isolated using a modified DNeasy Plant Mini Kit protocol (Qiagen) WGS sequencing libraries were sequenced on a MiSeq next generation sequencing (NGS) system (Illumina)

bull Results we first identified all mutations that are exclusively present in the cyp51A wildtype samples and undetectable in the cyp51Amutated cohort Next we identified a core candidate cluster of 112 nucleotide variants in 62 genes that were exclusively found in the cyp51A wildtype group and predicted to have an impact on the amino acid sequence of the corresponding translational products

bull In particular exemplary identified mutations affected genes coding for glycosyl hydrolase family 31 proteinimplicated in carbohydrate metabolic processes and 3-oxo-5-alpha-steroid 4-dehydrogenase family protein which is similar to cyp51A involved in steroid metabolism

bull Conclusion The rapid increase in detection of triazole resistant fungal strains in clinical contexts represents a critical problem particularly for immunocompromised patients at high risk for IA and highlights the need to explore the underlying molecular causes

bull Pending further validation in a larger cohort our NGS-based approach for sequencing the genomes of azole resistant Afu strains identified several candidate genomic alterations that might pinpoint alternative pathways to acquisition of resistance independent of the previously described cyp51A mutations

bull Ultimately our approach for discovery of previously undescribed resistance pathways in fungal strains might aid in exploration of novel therapeutic targets and identify suitable biomarkers for effective clinical and epidemiological surveillance

NUOVI APPROCCI DI TXProf

Allo-HSCT conditioned with reduced BUCY2 and antifungal prophylaxis with low-dose of Amphotericin B (20 mgday) in the neutropenic phase lead to reduced

bowel mucosal damage lower incidence of IFI and lower transplant related mortality 58 pts treated IFI in 68

Canseco F M A et al

Efficacy and safety of Micafungin (150 mgday) as salvage treatment for IFD in patients with hematologic malignancies who were either

refractory or intolerant to first-line antifungal therapies 51pts treated 65 ORR 1SAE

Gao L et al

DIAGNOSIEPIDEMIOLOGIA

bull Epidemiology of fungemia in hematological malignancies inSEIFEM-2015 survey reduced incidence most episode caused by Candida non albicans frequently in onset or rr malignancies or during allo-SCT (AML ALL NHL and MM)

bull still high mortality related with advance stage of HM molds fungemia and rare yeast isolation (Candida non-A Geotrichum Trichosporon Rhodotorula) 100 pts with bloodstream infections 74 mortality rate Criscuolo M et al

bull Screening efectiveness with weekly serum GM assay in the post allo-HSCT in patientswith high risk (previous proven or probable IFI or suffering from GVHD) high riskpatients should receive anti-mold prophylaxis (Voriconazole or Posaconazole)

139 pts studied 2110 low risk were GM+2978 (including those developing GVHD) were GM+ HR (risk factors GVHD previous IFI to be monitored and eligible for proph) Gomez F A R Jr et al

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

INFEZIONI FUNGINE

Invasive Fungal Infections in Patients with High-Risk MDS and AML Treated with Azacitidine

Helena Pomares et al

bull MDSAML pts treated with AZA have a very low risk of IFI including those with concurrent severe prolonged neutropenia

bull Primary antifungal prophylaxis should not be recommended for this subset of patients

bull This very low risk (4121) of IFI is a potential additional benefit before and after SCT

Whole Genome Sequencing of Azole-Resistant Aspergillus Fumigatus Strains from Hematopoietic Stem Cell Recipients Identifies Candidate Molecular Targets Potentially Implicated in Novel Resistance

Mediating Mechanisms - First Results

Maximilian Mossner1 Birgit Spiess PhD2 Johann-Christoph Jann1 Verena Nowak1 Julia Oblaumlnder2 Oliver Bader3 Wolf-Karsten Hofmann MD1 Daniel Nowak MD1 Dieter Buchheidt MD2 and Tobias Boch MD1

bull Several studies recently reported azole resistant fungal strains detectable in patients at risk with rapidly increasing frequency

bull While mutations in the 14α-sterol demethylase (cyp51A) gene have been implicated in mediating azole resistance in approximately 50 of resistant patient isolates the underlying genetic cause is unknown

bull we performed whole genome sequencing (WGS) of azole-resistant cyp51A-wildtype Aspergillus fumigatus (Afu) specimen the main effector of IA with the aim to identify novel genetic alterations leading to azole resistance

bull Methods Afu clinical strains were isolated from six different patients with IA undergoing intensive chemotherapy for acute leukemia or after allo-HSCT Sanger sequencing revealed characteristic resistance associated cyp51A mutations (TR46Y121FT289A) in four of the six specimen while two samples harbored cyp51A wildtype sequences

bull High molecular weight genomic DNA (gDNA) was isolated using a modified DNeasy Plant Mini Kit protocol (Qiagen) WGS sequencing libraries were sequenced on a MiSeq next generation sequencing (NGS) system (Illumina)

bull Results we first identified all mutations that are exclusively present in the cyp51A wildtype samples and undetectable in the cyp51Amutated cohort Next we identified a core candidate cluster of 112 nucleotide variants in 62 genes that were exclusively found in the cyp51A wildtype group and predicted to have an impact on the amino acid sequence of the corresponding translational products

bull In particular exemplary identified mutations affected genes coding for glycosyl hydrolase family 31 proteinimplicated in carbohydrate metabolic processes and 3-oxo-5-alpha-steroid 4-dehydrogenase family protein which is similar to cyp51A involved in steroid metabolism

bull Conclusion The rapid increase in detection of triazole resistant fungal strains in clinical contexts represents a critical problem particularly for immunocompromised patients at high risk for IA and highlights the need to explore the underlying molecular causes

bull Pending further validation in a larger cohort our NGS-based approach for sequencing the genomes of azole resistant Afu strains identified several candidate genomic alterations that might pinpoint alternative pathways to acquisition of resistance independent of the previously described cyp51A mutations

bull Ultimately our approach for discovery of previously undescribed resistance pathways in fungal strains might aid in exploration of novel therapeutic targets and identify suitable biomarkers for effective clinical and epidemiological surveillance

NUOVI APPROCCI DI TXProf

Allo-HSCT conditioned with reduced BUCY2 and antifungal prophylaxis with low-dose of Amphotericin B (20 mgday) in the neutropenic phase lead to reduced

bowel mucosal damage lower incidence of IFI and lower transplant related mortality 58 pts treated IFI in 68

Canseco F M A et al

Efficacy and safety of Micafungin (150 mgday) as salvage treatment for IFD in patients with hematologic malignancies who were either

refractory or intolerant to first-line antifungal therapies 51pts treated 65 ORR 1SAE

Gao L et al

DIAGNOSIEPIDEMIOLOGIA

bull Epidemiology of fungemia in hematological malignancies inSEIFEM-2015 survey reduced incidence most episode caused by Candida non albicans frequently in onset or rr malignancies or during allo-SCT (AML ALL NHL and MM)

bull still high mortality related with advance stage of HM molds fungemia and rare yeast isolation (Candida non-A Geotrichum Trichosporon Rhodotorula) 100 pts with bloodstream infections 74 mortality rate Criscuolo M et al

bull Screening efectiveness with weekly serum GM assay in the post allo-HSCT in patientswith high risk (previous proven or probable IFI or suffering from GVHD) high riskpatients should receive anti-mold prophylaxis (Voriconazole or Posaconazole)

139 pts studied 2110 low risk were GM+2978 (including those developing GVHD) were GM+ HR (risk factors GVHD previous IFI to be monitored and eligible for proph) Gomez F A R Jr et al

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

Invasive Fungal Infections in Patients with High-Risk MDS and AML Treated with Azacitidine

Helena Pomares et al

bull MDSAML pts treated with AZA have a very low risk of IFI including those with concurrent severe prolonged neutropenia

bull Primary antifungal prophylaxis should not be recommended for this subset of patients

bull This very low risk (4121) of IFI is a potential additional benefit before and after SCT

Whole Genome Sequencing of Azole-Resistant Aspergillus Fumigatus Strains from Hematopoietic Stem Cell Recipients Identifies Candidate Molecular Targets Potentially Implicated in Novel Resistance

Mediating Mechanisms - First Results

Maximilian Mossner1 Birgit Spiess PhD2 Johann-Christoph Jann1 Verena Nowak1 Julia Oblaumlnder2 Oliver Bader3 Wolf-Karsten Hofmann MD1 Daniel Nowak MD1 Dieter Buchheidt MD2 and Tobias Boch MD1

bull Several studies recently reported azole resistant fungal strains detectable in patients at risk with rapidly increasing frequency

bull While mutations in the 14α-sterol demethylase (cyp51A) gene have been implicated in mediating azole resistance in approximately 50 of resistant patient isolates the underlying genetic cause is unknown

bull we performed whole genome sequencing (WGS) of azole-resistant cyp51A-wildtype Aspergillus fumigatus (Afu) specimen the main effector of IA with the aim to identify novel genetic alterations leading to azole resistance

bull Methods Afu clinical strains were isolated from six different patients with IA undergoing intensive chemotherapy for acute leukemia or after allo-HSCT Sanger sequencing revealed characteristic resistance associated cyp51A mutations (TR46Y121FT289A) in four of the six specimen while two samples harbored cyp51A wildtype sequences

bull High molecular weight genomic DNA (gDNA) was isolated using a modified DNeasy Plant Mini Kit protocol (Qiagen) WGS sequencing libraries were sequenced on a MiSeq next generation sequencing (NGS) system (Illumina)

bull Results we first identified all mutations that are exclusively present in the cyp51A wildtype samples and undetectable in the cyp51Amutated cohort Next we identified a core candidate cluster of 112 nucleotide variants in 62 genes that were exclusively found in the cyp51A wildtype group and predicted to have an impact on the amino acid sequence of the corresponding translational products

bull In particular exemplary identified mutations affected genes coding for glycosyl hydrolase family 31 proteinimplicated in carbohydrate metabolic processes and 3-oxo-5-alpha-steroid 4-dehydrogenase family protein which is similar to cyp51A involved in steroid metabolism

bull Conclusion The rapid increase in detection of triazole resistant fungal strains in clinical contexts represents a critical problem particularly for immunocompromised patients at high risk for IA and highlights the need to explore the underlying molecular causes

bull Pending further validation in a larger cohort our NGS-based approach for sequencing the genomes of azole resistant Afu strains identified several candidate genomic alterations that might pinpoint alternative pathways to acquisition of resistance independent of the previously described cyp51A mutations

bull Ultimately our approach for discovery of previously undescribed resistance pathways in fungal strains might aid in exploration of novel therapeutic targets and identify suitable biomarkers for effective clinical and epidemiological surveillance

NUOVI APPROCCI DI TXProf

Allo-HSCT conditioned with reduced BUCY2 and antifungal prophylaxis with low-dose of Amphotericin B (20 mgday) in the neutropenic phase lead to reduced

bowel mucosal damage lower incidence of IFI and lower transplant related mortality 58 pts treated IFI in 68

Canseco F M A et al

Efficacy and safety of Micafungin (150 mgday) as salvage treatment for IFD in patients with hematologic malignancies who were either

refractory or intolerant to first-line antifungal therapies 51pts treated 65 ORR 1SAE

Gao L et al

DIAGNOSIEPIDEMIOLOGIA

bull Epidemiology of fungemia in hematological malignancies inSEIFEM-2015 survey reduced incidence most episode caused by Candida non albicans frequently in onset or rr malignancies or during allo-SCT (AML ALL NHL and MM)

bull still high mortality related with advance stage of HM molds fungemia and rare yeast isolation (Candida non-A Geotrichum Trichosporon Rhodotorula) 100 pts with bloodstream infections 74 mortality rate Criscuolo M et al

bull Screening efectiveness with weekly serum GM assay in the post allo-HSCT in patientswith high risk (previous proven or probable IFI or suffering from GVHD) high riskpatients should receive anti-mold prophylaxis (Voriconazole or Posaconazole)

139 pts studied 2110 low risk were GM+2978 (including those developing GVHD) were GM+ HR (risk factors GVHD previous IFI to be monitored and eligible for proph) Gomez F A R Jr et al

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

Whole Genome Sequencing of Azole-Resistant Aspergillus Fumigatus Strains from Hematopoietic Stem Cell Recipients Identifies Candidate Molecular Targets Potentially Implicated in Novel Resistance

Mediating Mechanisms - First Results

Maximilian Mossner1 Birgit Spiess PhD2 Johann-Christoph Jann1 Verena Nowak1 Julia Oblaumlnder2 Oliver Bader3 Wolf-Karsten Hofmann MD1 Daniel Nowak MD1 Dieter Buchheidt MD2 and Tobias Boch MD1

bull Several studies recently reported azole resistant fungal strains detectable in patients at risk with rapidly increasing frequency

bull While mutations in the 14α-sterol demethylase (cyp51A) gene have been implicated in mediating azole resistance in approximately 50 of resistant patient isolates the underlying genetic cause is unknown

bull we performed whole genome sequencing (WGS) of azole-resistant cyp51A-wildtype Aspergillus fumigatus (Afu) specimen the main effector of IA with the aim to identify novel genetic alterations leading to azole resistance

bull Methods Afu clinical strains were isolated from six different patients with IA undergoing intensive chemotherapy for acute leukemia or after allo-HSCT Sanger sequencing revealed characteristic resistance associated cyp51A mutations (TR46Y121FT289A) in four of the six specimen while two samples harbored cyp51A wildtype sequences

bull High molecular weight genomic DNA (gDNA) was isolated using a modified DNeasy Plant Mini Kit protocol (Qiagen) WGS sequencing libraries were sequenced on a MiSeq next generation sequencing (NGS) system (Illumina)

bull Results we first identified all mutations that are exclusively present in the cyp51A wildtype samples and undetectable in the cyp51Amutated cohort Next we identified a core candidate cluster of 112 nucleotide variants in 62 genes that were exclusively found in the cyp51A wildtype group and predicted to have an impact on the amino acid sequence of the corresponding translational products

bull In particular exemplary identified mutations affected genes coding for glycosyl hydrolase family 31 proteinimplicated in carbohydrate metabolic processes and 3-oxo-5-alpha-steroid 4-dehydrogenase family protein which is similar to cyp51A involved in steroid metabolism

bull Conclusion The rapid increase in detection of triazole resistant fungal strains in clinical contexts represents a critical problem particularly for immunocompromised patients at high risk for IA and highlights the need to explore the underlying molecular causes

bull Pending further validation in a larger cohort our NGS-based approach for sequencing the genomes of azole resistant Afu strains identified several candidate genomic alterations that might pinpoint alternative pathways to acquisition of resistance independent of the previously described cyp51A mutations

bull Ultimately our approach for discovery of previously undescribed resistance pathways in fungal strains might aid in exploration of novel therapeutic targets and identify suitable biomarkers for effective clinical and epidemiological surveillance

NUOVI APPROCCI DI TXProf

Allo-HSCT conditioned with reduced BUCY2 and antifungal prophylaxis with low-dose of Amphotericin B (20 mgday) in the neutropenic phase lead to reduced

bowel mucosal damage lower incidence of IFI and lower transplant related mortality 58 pts treated IFI in 68

Canseco F M A et al

Efficacy and safety of Micafungin (150 mgday) as salvage treatment for IFD in patients with hematologic malignancies who were either

refractory or intolerant to first-line antifungal therapies 51pts treated 65 ORR 1SAE

Gao L et al

DIAGNOSIEPIDEMIOLOGIA

bull Epidemiology of fungemia in hematological malignancies inSEIFEM-2015 survey reduced incidence most episode caused by Candida non albicans frequently in onset or rr malignancies or during allo-SCT (AML ALL NHL and MM)

bull still high mortality related with advance stage of HM molds fungemia and rare yeast isolation (Candida non-A Geotrichum Trichosporon Rhodotorula) 100 pts with bloodstream infections 74 mortality rate Criscuolo M et al

bull Screening efectiveness with weekly serum GM assay in the post allo-HSCT in patientswith high risk (previous proven or probable IFI or suffering from GVHD) high riskpatients should receive anti-mold prophylaxis (Voriconazole or Posaconazole)

139 pts studied 2110 low risk were GM+2978 (including those developing GVHD) were GM+ HR (risk factors GVHD previous IFI to be monitored and eligible for proph) Gomez F A R Jr et al

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

NUOVI APPROCCI DI TXProf

Allo-HSCT conditioned with reduced BUCY2 and antifungal prophylaxis with low-dose of Amphotericin B (20 mgday) in the neutropenic phase lead to reduced

bowel mucosal damage lower incidence of IFI and lower transplant related mortality 58 pts treated IFI in 68

Canseco F M A et al

Efficacy and safety of Micafungin (150 mgday) as salvage treatment for IFD in patients with hematologic malignancies who were either

refractory or intolerant to first-line antifungal therapies 51pts treated 65 ORR 1SAE

Gao L et al

DIAGNOSIEPIDEMIOLOGIA

bull Epidemiology of fungemia in hematological malignancies inSEIFEM-2015 survey reduced incidence most episode caused by Candida non albicans frequently in onset or rr malignancies or during allo-SCT (AML ALL NHL and MM)

bull still high mortality related with advance stage of HM molds fungemia and rare yeast isolation (Candida non-A Geotrichum Trichosporon Rhodotorula) 100 pts with bloodstream infections 74 mortality rate Criscuolo M et al

bull Screening efectiveness with weekly serum GM assay in the post allo-HSCT in patientswith high risk (previous proven or probable IFI or suffering from GVHD) high riskpatients should receive anti-mold prophylaxis (Voriconazole or Posaconazole)

139 pts studied 2110 low risk were GM+2978 (including those developing GVHD) were GM+ HR (risk factors GVHD previous IFI to be monitored and eligible for proph) Gomez F A R Jr et al

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

DIAGNOSIEPIDEMIOLOGIA

bull Epidemiology of fungemia in hematological malignancies inSEIFEM-2015 survey reduced incidence most episode caused by Candida non albicans frequently in onset or rr malignancies or during allo-SCT (AML ALL NHL and MM)

bull still high mortality related with advance stage of HM molds fungemia and rare yeast isolation (Candida non-A Geotrichum Trichosporon Rhodotorula) 100 pts with bloodstream infections 74 mortality rate Criscuolo M et al

bull Screening efectiveness with weekly serum GM assay in the post allo-HSCT in patientswith high risk (previous proven or probable IFI or suffering from GVHD) high riskpatients should receive anti-mold prophylaxis (Voriconazole or Posaconazole)

139 pts studied 2110 low risk were GM+2978 (including those developing GVHD) were GM+ HR (risk factors GVHD previous IFI to be monitored and eligible for proph) Gomez F A R Jr et al

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

AGGIORNAMENTI FATTORI DI RISCHIO NEL HSCT

Hematopoietic cell transplantation comorbidity index as prognostic variable in patients with invasive fungal infections worse 2-years overall survival (in multivariate analysis) if use of alternative donor HCT-CI ge 3 and presence of IFI (multivariart an in

301 pts) Patients with high HCT-CI may be candidates for an intensive diagnostic work-up or a specific antifungal prophylaxis

Busca A et al

Clinical analysis of IFI after allo-HSCT patients with poor matching unrelated donor and II-IV degree of aGVHD are more likely to occur IFI and those who were used more

glucocorticoid are likely to die

Ni M et al

DISCUSSIONE

DISCUSSIONE