Miguel-Angel Perales MD Q. What is the optimal therapy for CLL patients failing to achieve PR with chemoimmunotherapy? A. Stem Cell Transplant Miguel-Angel Perales MD Adult Bone Marrow Transplantation Service Memorial Sloan Kettering Cancer Center #Debates_CLL14

Targeting of BCR signaling Hallek , Blood 2013; 122- 3723-3734 #Debates_CLL14

New drugs for CLL – so many choices … #Debates_CLL14

Byrd et al, N Engl J Med 2013;369:32-42 Goede et al, N Engl J Med 2014;370:1101-10. Furman et al, N Engl J Med 2014;370:997-1007 Cancer Discovery 2014;4:136 Souers et al, Nat Med 2013;19:202-210 #Debates_CLL14

Is there still a role for allogeneic HCT?

EBMT 2007 Transplant Consensus for CLL Patients with CLL who meet the following criteria should be considered for Allo-HCT: Non-response or early relapse (within 12 months) after purine analogue-containing therapy Relapse within 24 months after purine analogue combination therapy or autologous SCT Patients with p53 abnormalities requiring treatment Dreger et al, Leukemia (2007) 21, 12–17 #Debates_CLL14

Number of allo-HCT and auto-SCT for CLL in EBMT Registry Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369 #Debates_CLL14

Prospective trials of NMA/RIC Allo-HCT in CLL Dreger, 2010 Sorror, 2008 Brown, 2013 Khouri, 2011 Michallet, 2011 N 90 82 76 86 40 Regimen NMA RIC Alternative donors (%) 59 37 63 50 Relapse (%) 40 (4 y) 38 (5 y) 40 (5 y) n.r. 22 (3 y) PFS (%) 42 (4 y) 39 (5 y) 43 (5 y) 36 (5 y) 46 (3 y) OS (%) 70 (4 y) 50 (5 y) 63 (5 y) 51 (5 y) 55 (3 y) Follow-up (y) 3.8 (0.6 – 8.5) 5 (0.9 – 7.3) 5.1 3.1 (0.9 – 10.9) 2.3 (0.3 – 5.9) Adapted from Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369 Dreger, Blood 2010;116:2438–47; Sorror, JClin Oncol 2008;26:4912–20; Brown, Leukemia 2013;27:362-369; Khouri, Cancer 2011;117:4679–88; Michallet, Bone Marrow Transplant 2011;46(Suppl 1):S43–4. #Debates_CLL14

MRD kinetics in a patient with poor-risk CLL during RIC Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369 #Debates_CLL14

Patterns of response in CLL after allo-HCT Ritgen et al, Leukemia (2008) 22, 1377–1386 #Debates_CLL14

Analysis of MRD kinetics in 43 patients after RIC Allo-HCT 43 patients event-free 1 year after allo-HCT on GCLLSG CLL3X trial or pilot study MRD status 32 MRD negative at 1 year 11 did not reach MRD till 1 year Linked to tapering of immune suppression or donor leukocyte infusion (DLI) Absence of MRD detection associated with decreased risk of relapse (HR 0.037 (%CI 0.008-0.18, P<0.0001) Bottcher et al, Blood Reviews 2011;25:91-96 #Debates_CLL14

Studies on MRD kinetics after allo-HCT for CLL GCLLSG Milan Barcelona Spanish IG N 59 29 20 21 MRD assay RQ-PCR Flow NestPCR MRD pattern Sustained neg (>12 mo) 75% 31% 65% 94% Delayed clearance 46% 14% 50% 35% Always positive 17% 45% 30% n.a. Clinical relapse by MRD pattern Permanent neg 9% Always pos 70% 62% Clinical relapse in pts MRD- @ 12 mo 6% 11% MRD relapse in pts MRD- @ 12 mo 13% 40% Adapted from Bottcher, Blood Reviews 2011;25:91-96 Dreger, Blood 2010;116:2438–47; Ritgen, Leukemia 2008;22:1377–86; Farina, Haematologica 2009;94:654–62; Moreno, Blood 2006;107:4563–9; Caballero, Clin Cancer Res 2005;11:7757–63. #Debates_CLL14

Causes of Death after Transplants performed in 2008-2009 HLA-identical Sibling Infection (12%) Other (21%) Primary Disease (47%) GVHD (14%) Organ Failure (4%) New Malignancy (1%) Unrelated Donor Infection (16%) Other (29%) Organ Failure (6%) Primary Disease (33%) New Malignancy (1%) GVHD (15%) Autologous Infection (8%) Other (16%) Organ Failure (2%) New Malignancy (1%) Primary Disease (73%) #Debates_CLL14 Slide 18 SUM-WW11_17.ppt

Toxicity of NMA/RIC Allo-HCT in CLL Dreger, 2010 Sorror, 2008 Brown, 2013 Khouri, 2011 Michallet, 2011 N 90 82 76 86 40 Regimen NMA RIC Mucositis gr 3-4 (%) 6 12 n.r. < 5 Infection gr 3-4 (%) 55 60 48 Day 100 NRM (%) 2 < 10 < 3 3 NRM (%) 23 (4 y) 23 (5 y) 16 (5 y) 17 (1 y) 27 (3 y) aGVHD 2-4 (3-4) (%) 45 (14) n.r. (16-23) 30 (17) 37 (7) 44 (23) Extensive cGVHD (%) 49-53 56 29 Follow-up (y) 3.8 (0.6 – 8.5) 5 (0.9 – 7.3) 5.1 3.1 (0.9 – 10.9) 2.3 (0.3 – 5.9) Adapted from Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369 Dreger, Blood 2010;116:2438–47; Sorror, JClin Oncol 2008;26:4912–20; Brown, Leukemia 2013;27:362-369; Khouri, Cancer 2011;117:4679–88; Michallet, Bone Marrow Transplant 2011;46(Suppl 1):S43–4. #Debates_CLL14

NRM after allo-HCT for lymphoma (EBMT 2006 – 2010) Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369 #Debates_CLL14

Changing landscape in CLL Multiple new drugs recently approved or expected to be approved for CLL Changes in front-line and salvage therapy now and in the future with potential combinations of drugs + monoclonal antibodies and use of maintenance therapy Targeting of CD19 with ADC or CAR T cells #Debates_CLL14

New drugs for CLL – so many choices … #Debates_CLL14

Open questions in the new era of CLL Will new drugs or drug combinations redefine prognosis for “poor-risk” CLL? Will more patients achieve MRD-neg status with new drug combinations? Is a cure possible in CLL with new drug combinations? What about the emergence of resistance? What is long-term safety of novel agents? What will be the cost of long-term therapy with new drugs in patients with CLL? #Debates_CLL14

Results of ibrutinib in patients with 17p deletion Byrd et al, N Engl J Med 2013;369:32-42 #Debates_CLL14

Outcome after allo-HCT in patients with 17p–chronic CLL Schetelig et al, J Clin Oncol 2008; 26:5094-5100 #Debates_CLL14

Prognostic factors for PFS after NMA/RIC Allo-HCT in CLL Dreger, 2010 Sorror, 2008 Brown, 2013 Khouri, 2011 Michallet, 2011 N 90 82 76 86 40 Higher age ++ (>55) - ++ (>65) Comorbidity score n.r. ++ ++ (>0) Alternative donors Prior therapy Purine-analog Refract Unresponsonsive @ HCT 17p- Adapted from Dreger, Hematol Oncol Clin N Am 27 (2013) 355–369 Dreger, Blood 2010;116:2438–47; Sorror, JClin Oncol 2008;26:4912–20; Brown, Leukemia 2013;27:362-369; Khouri, Cancer 2011;117:4679–88; Michallet, Bone Marrow Transplant 2011;46(Suppl 1):S43–4. #Debates_CLL14

Integration of new approaches in allo-HCT for CLL Kochenderfer et al, Blood. 2013;122(25):4129-4139 Cruz et al , Blood 2013 122: 2965-2973 Burkhardt et al, J Clin Invest. 2013;123(9):3756–3765 #Debates_CLL14

How do we identify CLL patients who benefit from allo-HCT? Summary Allogeneic HCT remains a curative option for patients with CLL, with long-term PFS 40-45% and OS 50-70% The benefit is derived from clearly demonstrated graft-versus-leukemia effects and is associated with achieving MRD negative status How do we identify CLL patients who benefit from allo-HCT? Can we use novel agents after allo-HCT to further improve outcomes? #Debates_CLL14

Treatment algorithm for CLL patients in frontline indications Hallek M Blood 2013;122:3723-3734 #Debates_CLL14 ©2013 by American Society of Hematology

Treatment algorithm for CLL patients in second-line indications Hallek M Blood 2013;122:3723-3734 #Debates_CLL14 ©2013 by American Society of Hematology