The Role of Allogeneic Transplantation for High-Risk CLL

(in the age of targeted therapy)

David G. Maloney, MD, PhD

Member, Fred Hutchinson Cancer Research Center

Professor of Medicine, University of Washington, Seattle, WA

Allogeneic HCT has been Considered Standard Rx for Patients with High-Risk CLL

• Patients refractory to purine analogues• Short response to aggressive chemoimmunotherapy (FCR)

< 24 mo• Presence of 17p-/TP53 mutations

• Early trials with myeloablative regimens have given way to reduced intensity regimens with decreased NRM

• Is this still the case in the era of ibrutinib, idelalisib and ABT-199?

EBMT position paper: Dreger et al, Leukemia;21; 2007, Blood, 2014 on line

Survival for Fludarabine-Refractory CLL

• 147 pts

• Treated by different salvage therapies

• Overall response rate (RR) 22%

• CR 1%

Keating MJ; Leu & Lym; 2002

Myeloablative Allogeneic Transplantation for CLL

N AgeMed(range)

NRM Survival PFS Reference

54 41 (21-28) 46% @ 3y 46% @ 3y na EBMT, Michallet 1996

38 45 (26-57) 38% @ 5y 33% @ 5y 30% @ 5y CIBMTR, Pavletic 2005

25 47 (29-55) 24% @ 6y 55% @ 6y 24% @ 6y DFIC, Gribben 2005

30 48 (32-59) 47% @ 5y 39% @ 5y 39% @ 5y Canada, Toze 2005

12 39 (29-53) 25% 65% 65% Spain, Esteve 2001

28 43 (26-58) 32% @ 6y 45% @ 5y 42% @ 5y MDACC, Khouri 2002

Adapted from Delgado, Blood 2009

0

5

10

15

20

25

30

<1

1-4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

4

85+

AMLNHLMyelomaCLLALLCML

Age

Ad

just

ed I

nci

den

ce R

ate

Aging and Hematopoietic Malignancies

Myelosuppression

Imm

uno

sup

pre

ssio

n

Reduced Intensity Myeloablative

TBI 2 Gy

F/TBI 2 Gy

F/Cy

F/M 140

Flag-Ida

F/M 180

Bu8/F/ATG

Cy120/TBI 5.5 Gy

Cy120/TBI 12 Gy

Bu16/Cy120

TT-Cy

F/Cy/TBI 2 Gy

F/Bu16

Cy200/ATG

Ale/F/M 140

TLI ATG

Conditioning Regimens

Aggressiveness of Malignancy

Gen

etic

Dis

parit

y

HLA-haploid.-related/T-cell depleted/Cord blood

HLA-matched unrelated

HLA-identical sibling

(Adapted from R. Champlin)

McSweeney et al., Blood 97: 3390, 2001. Maris et al., Blood 102: 2021, 2003.Niederwieser et al., Blood 101: 1620, 2003. Sandmaier et al., ASH 2005, 2009.

Seattle Protocol: Nonmyeloablative Conditioning

MMF BID

2 Gy TBIHCT

Chimerism Analyses

-3 560 28 35 84-4 -2

FLU30 mg/m2/d

-1 180

CSP/TAC BID

MR

D

MMF BID / TID

CSP/TAC BID

100

UR

D

40Days

Observations using 2 Gy TBI +/- Flu

• G-CSF mobilized peripheral blood source– Two days PBSC harvest– No restriction on CD34 or CD3 numbers

• Out-patient treatment.– Minimal hematologic toxicity using MRD, greater with MURD

• Reliable engraftment with full donor chimerism in >95% patients

• Graft makes it’s own space and replaces marrow function• Anti-tumor activity due to immunologic graft-vs-tumor activity

Experience with Flu/TBI for Fludarabine Refractory, Advanced CLL

• 128 patients with CLL, SLL, or PLL

• Transplanted between 12/1997-12/2009

• Median follow up of survivors: 64 (12-138) months

Overall responses and outcomes at 5-years

Years after HCT

CR: 52%

Per

cent

Relapse: 34%

NRM: 31%

OS: 43%

PFS: 36%

n = 128

Years after HCT

Alive and on ISOverall survival

URDMRD

Outcomes by donor type (at 5-years)P

erce

nt

Risk factors: Disease status at HCT

Progression = 8Responsive = 51Refractory = 69

Years after HCT

Per

cent

NRMProgression/relapse

P = 0.3

Risk factors: Chromosomal abnormalities

Years after HCT

Per

cent

P = 0.22 del 11qNormal

del17q

Othersdel 13q

Tri12PFS

Risk factors: lymph node size

<5 cm = 95≥5 cm = 33

Years after HCT

Per

cent

NRMProgression/relapse

PFS

P = 0.003

P = 0.01 43%

14%

54%

27%

Risk factors: OS by lymph node size < 5 cm vs > 5 cm

Risk factors: Prior Alemtuzumab within 12 ms

No = 98Yes = 30

Years after HCT

Per

cent

NRMProgression/relapse

PFS

P = 0.01

Relapse/ Progression

PFS

HR p HR p

Cytogenetics Normal/13q 1.0 1.0

Trisomy 12 0.93 0.91 0.86 0.76

Del17q/11q/Other 1.47 0.25 1.40 0.16

LN size < 5 cm 1.0 1.0

≥ 5 cm 2.26 0.02 1.86 0.02

Disease status at HCT

Responsive 1.0 1.0

Refractory 1.12 0.74 1.11 0.69

Progression 0.98 0.97 1.08 0.88

Prior Campath within 12 ms

No 1.0 1.0

Yes 1.78 0.02 2.54 0.005

Multivariate analyses

Sorror JCO 2008

CLL: Risk-Stratification Model

Group 1: No HCT-CI/ LN <5 cm Group 2: HCT-CI > 0 Group 3: LN > 5 cm Group 4: HCT-CI >0 and LN >5 cm

3 year OS 78% (n=28) 60% (n=34) 43% (n=7) 27% (n=13)

Selected Trials of Reduced Intensity Conditioning Allogeneic HCT for CLL

NAge Years

(range)

RegimenDonor NRM

aGVHD 2-4

cGVHD Extensive

OS/PFS%

Reference

82 56 (42-72)

Flu/TBI 63% RD37% URD

25% 5y 55% 49% RD53% URD

50/455 yr

Sorror et al 2008

90 53 (27-65)

Fly/Cy +/- ATG

40% RD 23% 6y 45% 55% 58/38 6 yr

Dreger et al 2010, 2013

76 55 (36-73)

Flu/Mel 33% RD67% URD

16% 30% 62% 63/435 yr

Brown et al 2006, 2013

40 54 (35-65)

Flu/TBI/R 100% RD 27% 3y 44% 29% 55/463 yr

Michallet et al2013

86 58 (36-70)

Flu/Cy/R 50% RD 17% 4y 37% 56% 51/36*5 yr

Khouri et al 2011

30 50(12-63)

Flu/Bu + ATG

50% RD 16% 2y 56% 21% 72/672 yr

Schetelig et al2003

Allogeneic Transplantation for CLL

• Major risks are GVHD and infection– Low day 100 NRM < 5%, but 15-30% NRM at 1 year– ~25% risk of cGVHD effecting QOL

• Graft vs CLL effect is active in CLL– Lower risk of relapse in the setting of cGVHD– Higher risk of relapse with T cell depletion– Clearance of MRD

• May provide curative potential• Effective in high-risk disease

– Fludarabine refractory– Adverse cytogenetics– unmutated Ig genes

• May provides a better functioning hematopoietic and immune system post HCT

Nonmyeloablative Allogeneic Transplantation for CLL

• Effective therapy for fludarabine refractory CLL• Appears superior to available treatment options• Risk factors for poor outcome include

– Lymph node size > 5 cm– The presence of comorbidities– Alemtuzumab within 12 months

• Other factors (cytogenetics, age, CD38) did not have a significant effect on outcome

• The challenge is to determine the optimal time to consider transplant– Prior to the development of bulky disease– Earlier for patients with high risk disease?

B-Cell Receptor Signaling and Inhibition in B-Cell Malignancies.

Stevenson F K et al. Blood 2011;118:4313-4320

Ibrutinib for Relapsed Refractory CLL

Byrd J NEJM 369(1):32, 2013

Ibrutinib vs Ofatumumab for relapsed CLL (n=391)

Byrd JC et al. N Engl J Med 2014;371:213-223

PFS

OS

Median age: 67Bulky disease: 50-60%17p del: 33%Median prior Rx: 2-3FLU refractory: 45%

PFS (6 Mo) 17p- patients

Ibrutinib: 83%Ofatumumab: 49%

Treatment of Refractory CLL: Idelalisib

• Rituximab and Idelalisib active in relapsed/ref CLL

• Improved PFS and OS compared with rituximab alone

• Use in relapsed/refractory CLL warranted

Furman RR et al NEJM 370(11):997, 2014

Dreger, P et al Blood Online 10/9/2014

Points to Discuss With Patients

• HCT has been considered as the treatment of choice for high-risk CLL

• Only documented curative potential for CLL• B cell TKI/BCL-2 inhibitors are major advances

– Best option available to date– responders have 2 yr OS 70-90% (60-80% HCT)– long term uncertain, resistance possible, cure unlikely

• Outcome of HCT post novel agents uncertain• HCT has early NRM (15-30%) in first 2 years with risk

of cGVHD (25%)Dreger, P et al Blood Pre pub 10/2014

Conclusions: Role of Allogeneic HCT for High-Risk CLL

• BCR inhibitors best available treatment– cure (or CR) seems unlikely– resistance can arise (uncertain timing)

• Allogeneic HCT is still the ONLY curative option• Timing remains controversial (and patient specific)

– prior to bulky disease• Randomized trials unlikely, requires close contact with

HCT team• At minimum discuss options, HLA type, determine options• Targeted therapy with CAR-T cells will also impact HCT

•

•

Colleagues at FHCRC / UW

Mohamed Sorror

Postdoctoral Fellows

Transplant + Research Nurses

Clinical Support Staff

Collaborating Investigators