1. WEILL.CORNELL.EDU Should All Eligible Patients with Mantle Cell Lymphoma Be Transplanted? Answer: No Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Assistant Professor of Medicine

2. WEILL.CORNELL.EDU Let’s define “eligible” N=1066 Abrahamsson A et al. Blood 2014;124:1288-1295

3. WEILL.CORNELL.EDU Let’s define “eligible” Abrahamsson A et al. Blood 2014;124:1288-1295

4. WEILL.CORNELL.EDU Let’s define “eligible” Abrahamsson A et al. Blood 2014;124:1288-1295

5. WEILL.CORNELL.EDU Let’s define “eligible” Abrahamsson A et al. Blood 2014;124:1288-1295

6. WEILL.CORNELL.EDU Let’s define “eligible” Abrahamsson A et al. Blood 2014;124:1288-1295

7. WEILL.CORNELL.EDU Should 24% of All Patients with Mantle Cell Lymphoma Be Transplanted? Answer: No Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Assistant Professor of Medicine

8. WEILL.CORNELL.EDU Overall Survival Is Better in Real-World Patients That Undergo ASCT Abrahamsson A et al. Blood 2014;124:1288-1295

9. WEILL.CORNELL.EDU But Overall Survival Is Even Better in Patients That Don’t Undergo Any Treatment Abrahamsson A et al. Blood 2014;124:1288-1295

10. WEILL.CORNELL.EDU Interpretation: Observational data is not particularly helpful here.

11. WEILL.CORNELL.EDU Autologous Stem Cell Transplantation Provides Durable Remissions!! Damon L E et al. JCO 2009;27:6101-6108

12. WEILL.CORNELL.EDU Autologous Stem Cell Transplantation Provides Durable Remissions Damon L E et al. JCO 2009;27:6101-6108 British Journal of Haematology Volume 158, Issue 3, pages 355-362Volume 158, Issue 3,

13. WEILL.CORNELL.EDU Autologous Stem Cell Transplantation Provides Durable Remissions Damon L E et al. JCO 2009;27:6101-6108 British Journal of Haematology Volume 158, Issue 3, pages 355-362Volume 158, Issue 3, Fenske T S et al. JCO 2014;32:273-281

14. WEILL.CORNELL.EDU Autologous Stem Cell Transplantation Provides Durable Remissions Damon L E et al. JCO 2009;27:6101-6108 British Journal of Haematology Volume 158, Issue 3, pages 355-362Volume 158, Issue 3, Fenske T S et al. JCO 2014;32:273-281 Dreyling. Blood 2005; 105:2677-2684

15. WEILL.CORNELL.EDU Autologous Stem Cell Transplantation Does Not Result in Cure Damon L E et al. JCO 2009;27:6101-6108 British Journal of Haematology Volume 158, Issue 3, pages 355-362Volume 158, Issue 3, Fenske T S et al. JCO 2014;32:273-281 Dreyling. Blood 2005; 105:2677-2684

16. WEILL.CORNELL.EDU Autologous Stem Cell Transplantation Is Associated with a 5-10% Mortality Rate Dreyling. Blood 2005; 105:2677-2684 British Journal of Haematology Volume 158, Issue 3, pages 355-362Volume 158, Issue 3, Damon L E et al. JCO 2009;27:6101-6108 Fenske T S et al. JCO 2014;32:273-281

17. WEILL.CORNELL.EDU Who Does ASCT Benefit?

18. WEILL.CORNELL.EDU Hoster E et al. JCO 2014;32:1338-1346 European MCL Younger: MIPI Predicts Outcome Post-Transplant

19. WEILL.CORNELL.EDU MCL2: MIPI Predicts Outcome Post-Transplant British Journal of Haematology Volume 158, Issue 3, pages 355-362, 29 MAY 2012 Volume 158, Issue 3,

20. WEILL.CORNELL.EDU Response to Induction Pre-Transplant Predicts Outcome Post-Transplant Kolstad A et al. Blood 2014;123:2953-2959

21. WEILL.CORNELL.EDU MCL3: Pre-Transplant PET Predicts Outcome Post-ASCT Kolstad A et al. Blood 2014;123:2953-2959

22. WEILL.CORNELL.EDU Clinical Lymphoma Myeloma and Leukemia, Volume 14, Issue 2, 2014, 114 - 121 U Minn: Pre-Transplant PET Predicts Outcome Post-ASCT

23. WEILL.CORNELL.EDU European MCL Younger Trial: Pre-Transplant MRD Status Predicts Outcome Post-ASCT Williams M E Hematology 2013;2013:568-574

24. WEILL.CORNELL.EDU MCL3: Pre-Transplant MRD Status Predicts Outcome Post-ASCT Kolstad A et al. Blood 2014;123:2953-2959

25. WEILL.CORNELL.EDU Liu H et al. Haematologica 2012;97:579-585 CALGB59909: Pre-Transplant MRD Status Predicts Outcome Post-ASCT

26. WEILL.CORNELL.EDU Should 12% of All Patients with Low- Risk, PET-Negative, MRD-Negative Mantle Cell Lymphoma Be Transplanted? Answer: No Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Assistant Professor of Medicine

27. WEILL.CORNELL.EDU How Does ASCT Prolong Survival? Eliminate sub-clones before they accumulate new mutations that confer resistance to subsequent treatment

28. WEILL.CORNELL.EDU Chemotherapy works by inducing dsDNA damage

29. WEILL.CORNELL.EDU Frequent Somatic Mutations in The DNA Damage Response Pathway Beà S et al. PNAS 2013;110:18250-18255

30. WEILL.CORNELL.EDU Nordic MCL2/3: TP53 add prognostic information to MIPI British Journal of Haematology Volume 166, Issue 1, pages 98-108, 29 MAR 2014 DOI: 10.1111/bjh.12854 Volume 166, Issue 1,

31. WEILL.CORNELL.EDU Complex karyotype in mantle cell lymphoma is a prognostic factor Genes, Chromosomes and Cancer Volume 53, Issue 1, pages 106-116, 29 OCT 2013 DOI: 10.1002/gcc.22123 Volume 53, Issue 1,

32. WEILL.CORNELL.EDU Interpretation:~50% of MCL cases may be chemoresistant at diagnosis

33. WEILL.CORNELL.EDU Should X% of All Patients with Low- Risk, PET-Negative, MRD-Negative, TP53 WT, ATM WT Mantle Cell Lymphoma Be Transplanted? Answer: No Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Assistant Professor of Medicine

34. WEILL.CORNELL.EDU Can Chemotherapy Make Cancer Worse? Levine et al. Nature Medicine 2014;20(4)

35. WEILL.CORNELL.EDU Chemotherapy Increases Clonal Heterogeneity in CLL Landau, D.A. et al. Cell 152, 714–726 (2013).

36. WEILL.CORNELL.EDU L Ding et al. Nature 000, 1-5 (2012) Clonal Evolution in AML

37. WEILL.CORNELL.EDU Should X% of All Patients with Low- Risk, PET-Negative, MRD-Negative, TP53 WT, ATM WT Mantle Cell Lymphoma Be Transplanted? Answer: No Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Assistant Professor of Medicine

38. WEILL.CORNELL.EDU Conclusions The minority of patients with MCL are eligible to receive aggressive transplant. – Is this question even relevant to real-world practice? Conventional chemotherapy does not cure MCL, regardless of the dose. But it dose induce real toxicity. – Do the ends justify the means? Aggressive approaches appear to be most active in patients with the best prognosis. – There is a clear selection bias in data.

39. WEILL.CORNELL.EDU Conclusions MCL is inherently chemoresistant – More chemotherapy doesn’t make it better Chemotherapy can induce clonal heterogeneity – May be worse in the long run Aggressive therapies should be undertaken in the context of a clinical trial. Honest and open discussions with patients should guide management decisions.