1. 1 EBMT Lymphoma Working Party 11th Educational Course Treatment of Malignant Lymphoma: State of the Art and the Role of Stem Cell Transplantation 25-26 September 2015, Heidelberg, Germany GVHD & GVL in the lymphoma setting: The case of CLL Peter Dreger Dept Medicine V University of Heidelberg

2. 2 2 The EBMT database 2015 Trends in lymphoma transplants LWP activity report auto allo Absolute numbers 2013 CLLHLTCLDLC L FLMCL DLCLHLMCLTCLFLCLL Total lymphoma transplants 2013 (w/o CLL): allo 1652; auto 5992 CLLFL TCLHLDLCL HLFLCLL

3. -do GVL effects exist ? GVL vs GVHD in CLL: Key questions

4. -Plateau after RIC ? Evidence for GVL: Bullet points

5. Conditioning Regimens: Immunosuppressive vs anti-tumor activities (adopted from Champlin et al) Flu/Cy Bu/Cy TBI12/Cy BEAM TBI8/F TBI4/F TBI2/F MEL150/F Bu8/F „MAC“ „NMA“ „RIC“

6. Study GCLLSGSeattleBostonFCGCLLHoustonHeidelb.UK/IRL n90827640866650 Mucositis 3-4 6%12%na<5%na Infection 3-455%60%na48%na Early death (< d +100) <3%<10%<3%0%3% 2% NRM23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y) 24% (3y) 15% (4y) Ext. cGVHD55%49-53%48%42%56%53%48% Toxicity of RIC alloSCT for CLL Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn EBMT 2014; Richardson BJH 2013

7. Survival after RIC alloSCT for CLL StudyGCLLSGSeattleBostonFCGCLLHoustonHeidelb.UK/IRL n90827640867750 2-y PFS50%>50%n.a.57%40%*58%70% * 5-y PFS42%39%43%46%36%*52%55%* 2-y OS75%>60%n.a.63% 78%83% 5-y OS63%50%63%55%51%63%75% F/U mo72 (7-129) 11-876128 (3-71) 37 (11-131) 37 (12-101) 51 (11-143) Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn BMT 2015; Richardson BJH 2013 * Current PFS

8. -Plateau after RIC -Efficacy of donor lymphocyte infusions ? Evidence for GVL: Bullet points

9. Overall survival from relapse after HSCT (n = 25 of 87) MRD-neg after DLI + R 11.03.2015

10. -Plateau after RIC -Efficacy of donor lymphocyte infusions -Detrimental effect of T cell depletion ? Evidence for GVL: Bullet points

11. AlloBMT for CLL using ex-vivo CD6 TCD (Dana Farber results, n = 25) Gribben et al, Blood 106:4389 (2005)

12. -Plateau after RIC -Efficacy of donor lymphocyte infusions -Detrimental effect of T cell depletion -Protective effect of chronic GVHD ? Evidence for GVL: Bullet points

13. CLL: Relapse risk and chronic GVHD (EBMT survey, n = 77) Leukemia 17:841 (2005)

14. -Plateau after RIC -Efficacy of donor lymphocyte infusions -Detrimental effect of T cell depletion -Protective effect of chronic GVHD -Minimal residual disease (MRD) kinetics ? Evidence for GVL: Bullet points

15. CLL: Quantitative MRD assessment by 4 color flow cytometry (MRD-flow) a = CD19 + B cells b =exclude doublets c = CD5 - background d =CD5 + CD20 low e =CD43 + CD20 low f =CD43 + CD5 + 10E- 4 Böttcher et al, LEUKEMIA 2004; Rawstron et al, LEUKEMIA 2007 Sensitivity 1 in 10 4

16. alloSCT for CLL: MRD response patterns A: MRD- after CSA taper CSA taper GVHD Dreger et al, Blood 116:2438 (2010) MRD- immediately after SCT (16%) MRD- after CSA taper (42%) Other pattern (42%) Ritgen et al, Leukemia 22:1377 (2008) CLL3X (n=52)

17. -GVL effects do exist -Are GVL effects durable ? GVL vs GVHD in CLL: Key questions

18. Clinical impact of MRD negativity on disease control after alloHSCT (landmark studies) Farina et al, Haematologica 94:654 (2009)Richardson et al, Br J Haematol 160:640 (2013) UK (9-month landmark)Milan (6-month landmark)

19. CLL3X 6-year follow-up: Relapse by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12) Clinical Relapse MRD or clinical relapse Dreger et al, Blood 121:3284 (2013)

20. CLL3X 6-year follow-up: Relapse by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12) Blood 121:3284 (2013)

21. Clinical Relapse MRD relapse of 43 patients MRD- at 12months Hahn et al, BMT 2015 alloSCT in CLL: long-term disease control by GVL pattern (Heidelberg; patients with MRD monitoring and event-free at mo +12)

22. -GVL effects do exist -GVL effects are mostly durable -Can we have GVL w/o (chronic) GVHD ? GVL vs GVHD in CLL: Key questions

23. Can we separate GVL from GVHD by T cell depletion?

24. MRD- immediately after SCT (56%) MRD- after CSA taper (2%) Other pattern (25%) MRD- after DLI (12%) DLI: 31/50 (62%) (19 pre-emptive, 12 therapeutic) Ext. cGVHD 48%

25. -GVL effects do exist -GVL effects are mostly durable -Can we have GVL w/o GVHD: not yet -Does GVL help in real life GVL vs GVHD in CLL: Key questions ?

26. OS from 3-month landmark after start of search by compatible donor availability (high-risk CLL; donor vs no-donor comparison, n=97) Median follow-up 28 months Herth et al, Ann Oncol 25:200 (2014)

27. -GVL effects do exist -GVL effects are mostly durable -Can we have GVL w/o GVHD: not yet -Does GVL help in real life: it used to do -Indications GVL vs GVHD in CLL: Key questions ?

28. EBMT CLL transplant consensus Leukemia 21:12-17 (2007)

29. 29 The EBMT database 2015 Trends in lymphoma transplants LWP activity report auto allo Absolute numbers 2013% change 2011 -> 2013 CLLHLTCLDLC L FLMCL DLCLHLMCLTCLFLCLL Total lymphoma transplants 2013 (w/o CLL): allo 1652; auto 5992 CLLFL TCLHLDLCLMCL HLFLCLL MCL DLCL TCL

30. Along came…

31. → alloHSCT in HR-CLL: Better to be put… …into the museum?

32. Months 17p- R/R patients under Ibrutinib (PCYC 1102, n=28) versus R-Idelalisib (116, n=42) versus HR patients undergoing HSCT (Heidelberg; n=77) Overall survival until 30-month landmark

33. Months 17p- R/R patients under Ibrutinib (PCYC 1102, n=28) versus R-Idelalisib (116, n=42) versus HR patients undergoing HSCT (Heidelberg; n=77) Overall survival until 30-month landmark ? ?

34. Months 17p- R/R patients under Ibrutinib (PCYC 1102, n=28) versus R-Idelalisib (116, n=42) versus HR patients undergoing HSCT (Heidelberg; n=77) Overall survival until 30-month landmark ? ? Consumer health warning: This is not a fair comparison!

35. Refractory CLL and transplantation: What to do during the current phase of transition to the BCRi era?

36. Refractory CLL (FR; early REL; 17p-/TP53_R/R) Novel agents No ResponseResponse Continue NAHSCT Factors favoring options (if no clinical trial comparing HSCT with novel agent is available) High disease risk - High-risk cytogenetics (17p-, TP53mut, 11q-) Low transplant risk - Younger age - No comorbidity - Well-matched donor Lower disease risk - No high-risk cytogenetics Higher transplant risk - Older age - Significant comorbidity - Mismatched donor Patient’s desires/expectations consider (after alternative novel agent) Blood 2014; 124:3841

37. Can pathway inhibitors make transplant better?

38. Median OS after CLL progression after allo-SCT: 36 (24-4) months 5 CLL patients on ibrutinib (N = 52) (N = 20)

39. Overall survival from relapse after HSCT (n = 25 of 87) MRD-neg after DLI + R 11.03.2015

40. Overall survival from relapse after HSCT (n = 25 of 87) 31.03.2015 MRD-neg after DLI + R On Ibrutinib MRD-neg after Ibrutinib + DLI

41. Thank you CLL3X trial S Stilgenbauer R Busch M Ritgen S Böttcher D Beelen S Cohen J Schubert N Schmitz M Hallek T Zenz H Döhner LWP/CMWP A Boumendil H Finel C Kyriakou JJ Luan Anna Sureda A van Biezen R Brand D Milligan N Kröger M Sobh J Schetelig T de Witte M Michallet MRD P Corradini C Moreno S Böttcher M Ritgen Med V M Hahn S Dietrich L Sellner AD Ho T Luft U Hegenbart …and you for your interest!