1. 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

2. 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

3. Survival for Fludarabine-Refractory CLL 147 pts Treated by different salvage therapies Overall response rate (RR) 22% CR 1% Keating MJ; Leu & Lym; 2002

4. Myeloablative Allogeneic Transplantation for CLL NAge Med(range) NRMSurvivalPFSReference 5441 (21-28)46% @ 3y naEBMT, Michallet 1996 3845 (26-57)38% @ 5y33% @ 5y30% @ 5yCIBMTR, Pavletic 2005 2547 (29-55)24% @ 6y55% @ 6y24% @ 6yDFIC, Gribben 2005 3048 (32-59)47% @ 5y39% @ 5y Canada, Toze 2005 1239 (29-53)25%65% Spain, Esteve 2001 2843 (26-58)32% @ 6y45% @ 5y42% @ 5yMDACC, Khouri 2002 Adapted from Delgado, Blood 2009

5. Age Adjusted Incidence Rate Aging and Hematopoietic Malignancies

6. Myelosuppression Immunosuppression Reduced IntensityMyeloablative 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 Genetic Disparity HLA-haploid.-related/ T-cell depleted/ Cord blood HLA-matched unrelated HLA-identical sibling (Adapted from R. Champlin)

7. 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 TBI HCT Chimerism Analyses -3560283584-4-2 FLU 30 mg/m 2 /d 180 CSP/TAC BID MRD MMF BID / TID CSP/TAC BID 100 URD 40 Days

8. 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

9. 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

10. Overall responses and outcomes at 5-years Years after HCT CR: 52% Percent Relapse: 34% NRM: 31% OS: 43% PFS: 36% n = 128

11. Years after HCT Alive and on IS Overall survival URDMRD Outcomes by donor type (at 5-years) Percent

12. Risk factors: Disease status at HCT Progression = 8 Responsive = 51 Refractory = 69 Years after HCT Percent NRM Progression/relapse P = 0.3

13. Risk factors: Chromosomal abnormalities Years after HCT Percent P = 0.22 del 11q Normal del17q Others del 13q Tri12 PFS

14. Risk factors: lymph node size <5 cm = 95 ≥5 cm = 33 Years after HCT Percent NRM Progression/relapse PFS P = 0.003 P = 0.01 43% 14% 54% 27%

15. Risk factors: OS by lymph node size 5 cm

16. Risk factors: Prior Alemtuzumab within 12 ms No = 98 Yes = 30 Years after HCT Percent NRM Progression/relapse PFS P = 0.01

17. Relapse/ Progression PFS HR p p CytogeneticsNormal/13q1.0 Trisomy 120.930.910.860.76 Del17q/11q/Other1.470.251.400.16 LN size< 5 cm1.0 ≥ 5 cm2.260.021.860.02 Disease status at HCT Responsive1.0 Refractory1.120.741.110.69 Progression0.980.971.080.88 Prior Campath within 12 ms No1.0 Yes1.780.022.540.005 Multivariate analyses

18. 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)

19. Selected Trials of Reduced Intensity Conditioning Allogeneic HCT for CLL N Age Years (range) Regimen DonorNRM aGVHD 2-4 cGVHD Extensive OS/PFS % Reference 8256 (42- 72) Flu/TBI63% RD 37% URD 25% 5y55%49% RD 53% URD 50/45 5 yr Sorror et al 2008 9053 (27- 65) Fly/Cy +/- ATG 40% RD23% 6y45%55%58/38 6 yr Dreger et al 2010, 2013 7655 (36- 73) Flu/Mel33% RD 67% URD 16%30%62%63/43 5 yr Brown et al 2006, 2013 4054 (35- 65) Flu/TBI/R100% RD27% 3y44%29%55/46 3 yr Michallet et al 2013 8658 (36- 70) Flu/Cy/R50% RD17% 4y37%56%51/36* 5 yr Khouri et al 2011 3050 (12-63) Flu/Bu + ATG 50% RD16% 2y56%21%72/67 2 yr Schetelig et al 2003

20. 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

21. 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?

22. B-Cell Receptor Signaling and Inhibition in B-Cell Malignancies. Stevenson F K et al. Blood 2011;118:4313-4320

23. Ibrutinib for Relapsed Refractory CLL Byrd J NEJM 369(1):32, 2013

24. Ibrutinib vs Ofatumumab for relapsed CLL (n=391) Byrd JC et al. N Engl J Med 2014;371:213-223 PFS OS Median age: 67 Bulky disease: 50-60% 17p del: 33% Median prior Rx: 2-3 FLU refractory: 45% PFS (6 Mo) 17p- patients Ibrutinib:83% Ofatumumab: 49%

25. 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

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

27. 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

28. 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

29. Colleagues at FHCRC / UW Mohamed Sorror Postdoctoral Fellows Transplant + Research Nurses Clinical Support Staff Collaborating Investigators