Transplantation for Lymphoma What is New? Siddhartha Ganguly, MD, FACP

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1 Transplantation for Lymphoma What is New? Siddhartha Ganguly, MD, FACP Professor of Medicine Director, Lymphoma/Myeloma Program Division of Hematologic Malignancies and Cellular Therapeutics University of Kansas Cancer Center Kansas City, Kansas, USA

2 Transplantation for Lymphoma Hodgkin Lymphoma Post Transplant Consolidation by Brentuximab Allogeneic Transplantation for HL Mantle Cell Lymphoma- Rituximab Maintenance Post Auto SCT Refractory DLBCL New trials at KU Beyond CAR T T cell therapy for Tumor Associate Antigens Dinner Bell Antibody- Eat me or Do not eat me Pathways 2

3 Hodgkin Lymphoma (HL) Lymphoid neoplasm defined by the presence of Reed-Sternberg (RS) cells in a reactive infiltrate 3

4 1. Adapted from Stathis A, Younes A. Ann Oncol. 2015;26: Younes A, Ansell S. Semin Hematol. 2016;53:

5 Autologous Stem Cell Transplantation for Relapsed Hodgkin s Lymphoma 5

6 Why not Prevent a Post ASCT Relapse? Consolidation post-auto for High Risk Hodgkin s Lymphoma Moskowitz CH et al. Lancet May 9;385(9980):

7 Study Design and Key Eligibility Criteria 329 patients were randomized at 78 sites in North America and Europe 7

8 Progression-Free Survival PFS per IRF PFS per Investigator Hazard Ratio (95% CI) BV (N=165) Placebo (N=164) 0.57 ( , P=0.001) Events Median PFS (months) year PFS rate 63% 51% BV (N=165) Placebo (N=164) Hazard Ratio (95% CI) 0.50 ( ) Events Median PFS (months) year PFS rate 65% 45% * Regularly scheduled CT scans Includes information from both radiographic assessments and clinical lymphoma assessments 8

9 Overall Survival 9

10 Conclusions BV consolidation therapy is an important therapeutic option for High Risk HL patients undergoing ASCT to reduce the risk of relapse or progression 10

11 Relapse After Auto Transplant: What Next? 1. Treatment decision is based on goals of care 2. Localized low burden relapse- May consider IFXRT 3. Palliative care for patients with co-morbidities 4. Allogeneic transplantation for transplant eligible patients 5. Combination chemotherapy as a bridge to allogeneic transplantation 6. Immunotherapy/Immunomodulation 7. Clinical trials 11

12 Relapse After Auto Transplant: What Next? 1. Treatment decision is based on goals of care 2. Localized low burden relapse- May consider IFXRT 3. Palliative care for patients with co-morbidities 4. Allogeneic transplantation for transplant eligible patients 5. Combination chemotherapy as a bridge to allogeneic transplantation 6. Immunotherapy/Immunomodulation 7. Clinical trials 12

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14 Outcomes in Hodgkin Lymphoma Patients Following Allogeneic Transplant after Post- Autologous Transplant Consolidation Therapy with Brentuximab Vedotin: Results of an Exploratory Analysis in the AETHERA Trial Amanda Cashen 1, Edward Agura 2, Jeffrey Matous 3, Sally Arai 4, Andy Chen 5, Auayporn Nadamanee 6, Ramon Garcia-Sanz 7, Angelo Carella 8, Dirk Huebner 9, Emily Larsen 10, Juan Pinelli 10, Veronika Bachanova 11 1 Washington University School of Medicine, St. Louis, MO USA; 2 Baylor University Medical Center, Dallas, TX, USA; 3 Colorado Blood Cancer Institute, Presbyterian/St. Luke s Medical Center, Denver, CO USA; 4 Stanford University Medical Center, Stanford, CA USA; 5 Oregon Health and Science University, Portland, OR, USA; 6 City of Hope National Medical Center, Duarte, CA, USA; 7 Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain; 8 Universitaria San Martino- Ist, Genova, Italy; 9 Takeda Pharmaceuticals International Company, Cambridge, MA, USA; 10 Seattle Genetics, Inc., Bothell, WA, USA; 11 University of Minnesota Medical Center, Minneapolis, MN, USA BMT Tandem Meetings 2017, Orlando, FL, February 2017, Abstract No

15 Percent of Subjects Free of PD or Death N Placebo+BSC BV+BSC Stratified Median Hazard Events (Months) Ratio Time (Months) N at Risk (Events) Pla+BSC 164 (0) 113 (48) 92 (67) 83 (76) 77 (81) 72 (85) 66 (88) 64 (90) 62 (90) 61 (90) 59 (90) 56 (91) 52 (91) 39 (92) 21 (93) 19 (93) 10 (93) 0 (93) 0 (93) 0 (93) BV+BSC 165 (0) 149 (12)133 (27)122 (36)112 (45)104 (52)100 (55) 97 (58) 96 (59) 92 (61) 88 (64) 77 (64) 69 (65) 51 (65) 37 (65) 23 (65) 10 (65) 3 (65) 1 (65) 0 (65) Outcomes of patients who relapsed during long-term follow up (LTFU) and received allohct (10.3% [17/165] on BV arm and 16.5% [27/164] on PBO arm) 15

16 Conclusions Allogeneic Transplantation salvages substantial number of patients who relapsed after autologous Transplantation Post BV Consolidation The incidence of acute GVHD in patients who received BV consolidation or salvage prior to allohct was not elevated compared with historical rates. HL patients received primarily non-myeloablative conditioning for allohct with a wide variety of regimens. OS rates after allohct were similar for patients on both treatment arms. 3-year OS rates following allohct after BV consolidation or post-autohct salvage compares favorably to historical controls. 16

17 Hodgkin Lymphoma : Treatment Summary & Role of Novel Therapy B-cell lymphoid malignancy 9,050 new patients annually; 11.2% of all lymphomas in US CD30 expression Advanced HL: CT-based treatment Relapsed/refractory: HDCT followed by ASCT BV consolidation PD-1 blockade (nivolumab) Clinical trial CT ± XRT High-dose CT NCT Before 2011 Brentuximab vedotin (BV) (postasct or post two lines CT)2 BV (post-asct consolidation at high risk of relapse) through 2017 Nivolumab (relapsed HL postasct, post-bv)4 1. Ansell SM. Am J Hematol ;91: Younes A et al. J Clin Oncol.2012;30: Moskowitz CH et al. Lancet. 2015;385: Younes A et al. Lancet Oncol. 2016;17:

18 Hodgkin Lymphoma High Risk Hodgkin patients may receive BV consolidation post transplantation (PFS benefit only) Consider allogeneic Transplantation for patients who relapse after auto SCT. BV or PD-1 inhibitor can be used as a bridge to allo SCT 18

19 Mantle Cell Lymphoma Clinical Features M:F ratio 4:1 Median age 64 Advanced stage Leukemic phase 30% B symptoms 30% extranodal sites common GI tract 80% lymphomatous polyposis Elevated LDH 25% Elevated B2M 60% Variable clinical course (indolent to aggressive) Fisher RI, et al. Hematology. 2004; Available at: Accessed May

20 Chan Yoon Cheah et al. JCO

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22 LyMa Trial Randomization N=240 Inclusion N=299 OBSERVATION W1 R-DHAP W4 R-DHAP W7 R-DHAP W10 R-DHAP If < VGPR RBEAM If > VGPR RITUXIMAB MAINTENANCE every 2 months during 3 years R-DHAP: Rituximab 375mg/m2; aracytine 2g/m2 x2 IV 3 hours injection 12hours interval; dexamethasone 40mg d1-4; Cisplatin 100mg/m2 d1 (or oxaliplatin or carboplatin) R-BEAM: Rituximab 500mg/m2 d-8; BCNU 300mg/m2 d-7; Etoposide 400mg/m2/d d-6 to -3; aracytine 400mg/m2/d d-6 to d-3; melphalan 140mg/m2 d-2 22

23 PFS from Randomization mfu: 50.2m ( ) Obs 24m: 36m: 48m: (95%CI) 79.8 % ( ) 72.8 % ( ) 64.6 % ( ) PFS vs Rituximab (95%CI) 93.3 % ( ) 89.1 % ( ) 82.2 % ( ) PFS (months) from randomization 23

24 OS from Randomization mfu: 50.2m ( ) Obs 24m: 36m: 48m: OS (95%CI) vs 93.3 % ( ) 85.4 % ( ) 81.4 % ( ) Rituximab (95%CI) 93.3 % ( ) 93.3 % ( ) 88.7 % ( ) OS (months) from randomization 24

25 Conclusions The LyMa design (R-DHAP/R-BEAM) provides: Long-term disease control (PFS and EFS) Prolonged OS The final analysis demonstrates that Rituximab maintenance after ASCT prolongs: EFS: 78.9% vs 61.4% at 4 years (HR=0.457; ; p= ) PFS: 82.2% vs 64.6 % at 4 years (HR=0.4; ; p= ) OS : 88.7% vs 81.4 % at 4 years (HR=0.502; ; p= ) Rituximab maintenance (375mg/m2 every 2 months for 3 years) should be recommended to transplanted MCL patients 25

26 How about maintenance for Diffuse Large B Cell Lymphoma? 26

27 Maintenance in DLBCL Rituximab 3 studies No benefit Enzastaurin 2 studies No benefit Everolimus 1 study No benefit 27

28 EFS PFS Female RTX Male Obs p=.74 p=.04 Female pts benefited from RTX maintenance 28

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30 UNMC/KUMC Collaborative Trial on Lenalidomide Maintenance after Autologous Stem Cell Transplantation for High Risk Lymphoma Will be presented soon. PI: Julie Vose, UNMC; S. Ganguly, KUMC 30

31 Personalized Lymphoma Medicine 31

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33 Proposed Study Schema Alliance/BMT-CTN: Soon at KU-HMCT Relapsed/Refractory DLBCL-ABC Salvage PR, stem cells collected Randomization Stratify by response, TTR, regimen Arm A Arm B ASCT: CBV or BEAM ASCT: CBV or BEAM <60 d Ibrutinib Maintenance Placebo Maintenance Follow Up Follow Up 33

34 Refractory DLBCL Outcomes in refractory aggressive diffuse large b-cell lymphoma (DLBCL): Results from the international SCHOLAR-1 study. Michael Crump, et al ASCO Annual Meeting Presenter: Michael Crump Poster Board Number: Board #72 Median Overall Survival 6.6 months; ORR 20%; CR 8% 34

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37 MUD without ATG Probability, % Probability, % Progression-free Survival MUD with ATG 20 0 Haploidentical Overall Survival MUD without ATG 60 MUD with ATG Haploidentical year (95% CI) PFS OS 58 (51-65) 76 (69-81) URD w/o ATG 65 (61-70) 78 (74-81) 3 Years Years Haplo 2 3-years (95% CI) URD w/ ATG 53 (47-60) 65 (58-71) Haplo 47 (40-55) 60 (52-67) Kanate et al. Blood : URD w/o ATG 49 (44-54) 62 (57-67) URD w/ ATG 38 (31-45) 50 (42-57) 37

38 Beyond CAR-T Therapy 38

39 Courtesy: Ann M. Leen, PhD: CAGT, Houston 39

40 Challenge: Tumor Heterogeneity Courtesy: Ann M. Leen, PhD: CAGT, Houston 40

41 MultiTAA T Cell Therapy Courtesy: Ann M. Leen, PhD: CAGT, Houston 41

42 MultiTAA Manufacture Courtesy: Ann M. Leen, PhD: CAGT, Houston 42

43 T Cell Therapy for Cancer Courtesy: Ann M. Leen, PhD: CAGT, Houston 43

44 Clinical Trial- Eligibility Courtesy: Ann M. Leen, PhD: CAGT, Houston 44

45 Clinical Trial: Current Status Courtesy: Ann M. Leen, PhD: CAGT, Houston 45

46 Clinical Response: DLBCL Courtesy: Ann M. Leen, PhD: CAGT, Houston 46

47 Clinical Response: DLBCL Courtesy: Ann M. Leen, PhD: CAGT, Houston 47

48 Clinical Response: DLBCL Courtesy: Ann M. Leen, PhD: CAGT, Houston 48

49 Clinical Outcomes- Active Disease Courtesy: Ann M. Leen, PhD: CAGT, Houston 49

50 Clinical Outcomes- Adjuvant Courtesy: Ann M. Leen, PhD: CAGT, Houston 50

51 T Cell Therapy for Cancer Courtesy: Ann M. Leen, PhD: CAGT, Houston 51

52 Dinner Bell Antibody 52

53 Young Cells overexpress CD47 to evade phagocytosis 53

54 Increased CD47 Expression is Associated with Worse Survival in Normal Karyotype (NK) AML Patients 54

55 Anti-CD47 Mab Synergizes with Other Anti-Cancer Antibodies Macrophage Anti-CD47 antibody Anti-CD47 antibody SIRPα CD47 Phagocytosis + lymphoma cell CD20 Phagocytosis +++ Anti-CD20 antibody Monoclonal cancer antibodies such as rituximab provides a substantial eat me signal through the Fc receptor (ADCC, ADCP) Hu5F9-G4 blocks the don t eat me signal Synergistic activity occurs through releasing the brakes (don t eat me blockade) and stepping on the gas (eat me signal) FcR 55

56 Come and let us eat folks! 56

57 Combination antibodies eliminate a primary human lymphoma for immune deficient mice 57

58 Phase I trial with Anti CD47 antibody with Rituximab in DLBCL Coming near you! 58

59 1950 s 1960 s 1980 s to Today The Future? 59

60 Acknowledgements Ann leen, PhD- Baylor College of Medicine Amanda Kashen, MD-Wash U Med Center Helen Heslop, MD- Cell and Gene Therapy, Houston, TX Catherine Thieblemont, MD- LYSA, France HMCT Of KUMC Staff, and Patients and their family 60

61 Thank You 61