1. THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE TREATMENT OF NON-HODGKIN’S LYMPHOMA Christos Kosmas, M.D., Ph.D., Consultant Medical Oncologist, Department of Medical Oncology & Head Hematopoietic Cell Transplant Program “Metaxa” Cancer Hospital, Pireaus, Greece

2. Dose intensification by HDC+auto-HCT represents a curative treatment option for certain malignancies Malignancies highly-responsive and potentially curable NHLs and Hodgkin’s disease (sensitive relapses in particular) GCTs (relapsed high-risk, refractory) ES/PNET (1 st -line high-risk; R2-R3, 1 st relapse non-bone mets) Some pediatric STs (WT at relapse-limited phase II data, RMS, etc) Introduction

3. Rituximab effect in B-NHL Major breakthrough with the combination of rituximab with chemotherapy R-CHOP became the standard for the majority of patients But some patients continue to not respond to or relapse after R-CHOP

4. Indications of HDC + autologous stem cell transplantation (ASCT) in Diffuse Large Cell Lymphoma (DLCL) Intensification after initial (R-CHOP or -like) therapy in H/HI-risk (aaIPI) patients (controversial studies, no OS gain, PFS benefit…?) After salvage chemotherapy at first relapse (confirmed  PARMA study) Incomplete response/refractory after induction – No benefit in pre-Rituximab era – test sensitivity with R-based salvage (new regimens-limited data)

5. HDC + ASCT at first-line in CR/PR in unfavorable DLCL Phase III studies (pre-Rituximab era)

6. HDC + ASCT at first-line in unselected unfavorable DLCL patients Phase III studies (pre-Rituximab era)

7. HDT + ASCT in unfavorable DLBCL patients Phase II studies (Rituximab era)

8. Autologous Transplantation as Consolidation for Aggressive NHL high- intermediate/ high-risk NHL (R)-CHOP x 5 (R)-CHOPx1 (R)-CHOPx3 RANDOMIZERANDOMIZE TBI (1.0-1.2Gy) +CTX 60mg/kg x 2 days  ASCT F/U → CR/ PR → → → HDC  ASCT at relapse Stiff PJ, et al. N Engl J Med 2013;369:1681-1690

9. Stiff PJ, et al. NEJM 2013; 369: 1681-1690 ASCT as consolidation for aggressive NHL

10. Stiff PJ, et al. NEJM 2013; 369: 1681-1690 ASCT as consolidation for aggressive NHL

11. months from inclusion Event-free survival (%) ABMT (n=55) DHAP (n=54) Parma study: event-free survival 100 80 60 40 20 0 0153045607590 Chemo-sensitive responders: ORR 58%: CR 25% p=0.002 (Updated from JY Blay et al., Blood 1998)

12. CORAL Trial of R-ICE vs R-DHAP R x 6 Obs N=400 CD20+ DLBCL Relapsed/Refractory R-ICE x 3 R-DHAP x 3 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE SD/POD → Off PR/CR → → A BS EC AT MA BS EC AT M Which salvage regimen is the best? Place of immunotherapy post transplantation? Gisselbrecht C. J Clin Oncol 2010

13. R-ICE R-DHAP N 239% N 230% Response including deaths COMPLETE RESPONSE 57 24 60 26 UNCONFIRMED COMPLETE RESPONSE 30132511 PARTIAL RESPONSE 65276327 STABLE DISEASE 26112611 PROGRESSIVE DISEASE 46193917 DEATH 73 115 PREMATURE WITHDRAWAL / NOT EVALUATED/missing 8262 Total 239100230100 RESPONSE TO SALVAGE INDUCTION TREATMENTS 63.6 % 64.3 % Arm of treatmentNb patients Nb responders with successful mobilizationMARR (%) R-ICE23912351.5 R-DHAP23013056.5 Gisselbrecht C et al. asco 2011

14. Arm of treatment ARM A / R-ICEARM B / R-DHAP N%N% Consolidation treatment (BEAM) 1235113257 Yes No 116499843 Total 197100191100 CONSOLIDATION with BEAM Main Reasons for premature withdrawals: Progressive lymphoma: 53% Toxicity: 7% Collection failure: 7-11% (CD 34/kg < 2x10 6 ) Deaths: 4% Gisselbrecht C et al. asco 2011

15. EFS (induction ITT)OS (induction ITT) EFS and OS by induction treatment Survival probability 0.0 0.2 0.4 0.6 0.8 1.0 0122436486072 OS (months) Survival probability EFS (months) 0.0 0.2 0.4 0.6 0.8 1.0 0122436486072 p = 0.2672p = 0.3380 R-ICE R-DHAP R-ICE R-DHAP No. of subjectsEventCensoredMedian R-ICE23971% (170)29% (69)6.51 R-DHAP23067% (153)33% (77)7.49 No. of subjects EventCensoredMedian R-ICE23952% (125)48% (114)34.53 R-DHAP23049% (112)51% (118)58.97 481 patients first randomised from 24 July 2003 to 30 June 2008 245 patients randomised in the second part from 21 October 2003 to 21 October 2008

16. PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) N=160 N=228 N=147 N=241 31% 64% 30% 62%

17. Failure from diagnosis =>= 12 months EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT Failure from diagnosis > 12 months Standard salvage regimen does not overcome poor prognosis of early relapse Failure from diagnosis =< 12 months N= 106 N= 54 N= 41 N= 187

18. Response p Patients CR/CRu/PR All patients 245 63 % CR/CRu 147 38% Prior RituximabNo12283% <0.0001 Yes12451% Relapse> 12 months14088% <0.0001 Refractory< 12 months10646% sIPI< 216071% <0.0002 > 17652% CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS

19. TAKE HOME MESSAGES based on CORAL study A new profile of relapses and refractory patients after rituximab is seen Prognostic factors affecting response and survival are: relapse < 12 months secondary IPI>1 prior rituximab exposure When rituximab has been used during first-line therapy: optimal salvage combination remains to be determined? New drugs mandatory

20. CORAL Trial of RICE v DHAP CD20+ DLBCL Relapsed/Refractory R-ICE x 3 R-DHAP x 3 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE SD/POD → Off PR/CR → → A BS EC AT MA BS EC AT M R x 6 Obs N=400 Which salvage regimen is the best? Place of immunotherapy post transplantation? Gisselbrecht C. J Clin Oncol 2010

21. PFSOS CORAL maintenance: PFS/OS by treatment arm Survival probability Overall survival (months) Survival probability PFS (months) 0.0 0.2 0.4 0.6 0.8 1.0 0122436486072 p = 0.8314p = 0.7547 Observation Rituximab Observation Rituximab 0.0 0.2 0.4 0.6 0.8 1.0 0122436486072 nEventCensoredMedian Observation12043% (52)57% (68)58.22 Rituximab12245% (55)55% (67)57.59 nEventCensoredMedian Observation12033% (40)67% (80)62.92 Rituximab12236% (44)64% (78)NA

22. MATERIAL : Paraffin blocks Primary Biopsy N = 189 (47%) Relapse Biopsy N = 147 (37%) Matched pairs N = 87 (22%) Diagnosis Relapse = CORAL Patients randomized N = 400 Patients analyzed N = 249 (63%)

23. Subclassification of de novo DLBCL (Hans CP et al. Blood. 2004) 34%76% non-GCBGCB 5-Year OS CD10 GCB bcl6 MUM1 non-GCB GCB non-GCB + _ + _ + _

24. ABC GC Hans algorithm progression free survival GCB profile (n=115 49.5%) non-GCB profile (n=117, 30.5%) BioCoral Thieblemont C et al JCO 2011

25. Progression Free Survival R-DHAP R-ICE p = 0.04 p = NS Non GC GC 31% 27% 52% 32% 3 years Hans algorithm R-ICE (n=61)R-DHAP (n=54). R-ICE (n=56)R-DHAP (n=61) Thieblemont C et al JCO 2011

26. C-MYC probe, split-signal PatternYYYGR

27. Patients analysed ( n=161) n MYC + 28 17 % Simple 7 Complex BCL2 BCL6 BCL2 and BCL6 21 13 4 MYC - No breakpoint 133 83 % MYC+ DLBCL treated in CORAL study Cuccuini W. et al., Blood 2012

28. p = 0.0113 p = 0.0322 MYC+ n=28 MYC- n=133 42% 18% 62% 29% MYC + DLBCL is associated with a poor prognosis PROGRESSION FREE SURVIVALOVERALL SURVIVAL 4 years Cuccuini W. et al Blood 2012

29. R-DHAP R-ICE p =.1832 p =.0324 MYC+ MYC- OVERALL SURVIVAL 26%31% MYC+ DLBCL : No impact of treatment arm 3 years Cuccuini W. et al Blood 2012

30. TAKE HOME MESSAGES  Molecular characteristics are “similar” at diagnosis and relapse. Differential efficacy of non-anthracycline based chemotherapy within molecular subtypes of DLBCL MYC rearrangement is associated with a bad prognosis, independently from the type or treatment or other biological prognostic classification  Importance of realizing molecular characterization in DLBCL for a rational development of treatment.  Clinical prognostic factors remain very important

31. MCL Network Trial: R-CHOP/R-DHAP, High-Dose Ara-C and ASCT vs R-CHOP Hermine O, et al. ASH 2012. Abstract 151. Patients 65 yrs of age or younger with previously untreated stage II-IV MCL (N = 497) R-CHOP/R-DHAP Arm Alternating courses of 3 x R-CHOP and 3 x R-DHAP with stem cell mobilization after cycle 6 followed by high-dose Ara-C–containing myeloablative regimen (10 Gy TBI, Ara-C 4 x 1.5 g/m 2, melphalan 140 g/m 2 ) and ASCT (n = 248) R-CHOP Arm 4 x R-CHOP 2 x R-CHOP Followed by stem cell mobilization, myeloablative radiochemotherapy (12 Gy TBI, cyclophosphamide 2 x 60 mg/kg), and ASCT (n = 249)

32. MCL Network Trial: Time to Treatment Failure Median follow-up: 53 mos Median TTF: 88 vs 46 mos (HR: 0.68; P =.0382) Hermine O, et al. ASH 2012. Abstract 151. Patients Not in Treatment Failure, % R-CHOP/R-DHAP (n = 232) R-CHOP (n = 233) 36 mos7760 48 mos6949 60 mos6340 TTF Event, n R-CHOP/R-DHAP (n = 232) R-CHOP (n = 233) TTF events69122 SD410 Progression during induction812 Death in remission1312  Death related to ASCT88  Death due to secondary malignancy34 Relapse after CR/CRu/PR4488

33. MCL Network Trial: Secondary Outcomes Hermine O, et al. ASH 2012. Abstract 151. Patients receiving R-CHOP/R-DHAP had significantly longer OS vs those in the R-CHOP arm (P =.0485) Treatment approach beneficial in all MIPI scores Patients in Remission According to Time Point After ASCT, % R-CHOP/R-DHAP (n = 167) R-CHOP (n = 167) 36 mos8167 48 mos7653 60 mos7444 VariableHR for TTF (95% CI)P Value R-DHAP vs R-CHOP0.54 (0.40-0.71)<.0001 R-DHAP vs R-CHOP0.49 (0.37-0.65)<.0001 MIPI score (+1)2.08 (1.69-2.56)<.0001

34. The role of HDC+ASCT in T-Cell NHLs

35. TrialRegimenNOS RatePFS Rate GEL-TAMO* [1] HDT/ASCT11556% @ 5 yrs60% @ 5 yrs GEL-TAMO [2] MEGA-CHOP, then ASCT or IFE-ASCT 2673% @ 3 yrs53% @ 3 yrs Nordic Group [3] CHOEP-ASCT10567% @ 2 yrs– Italian Group [4] HDT/ASCT6234% @ 12 yrs30% @ 12 yrs EBMT* [5] HDT/ASCT AITL 146 59% @ 4 yrs56% @ 4 yrs Reimer et al [6] CHOP-ASCT8348% @ 3 yrs36% @ 3 yrs Sieniawski et al [7] IVE/MTX-ASCT5767% @ 3 yrs59% @ 3 yrs *Retrospective study. 1. Rodriguez J, et al. Ann Oncol. 2003;14:1768-1775. 2. Rodriguez J, et al. Eur J Haematol. 2007;79:32- 38. 3. D’Amore F, et al. Ann Oncol. 2005;16(suppl 5):v56. 4. Kyriakou C, et al. J Clin Oncol. 2008;26:218- 224. 5. Kyriakou C, et al. J Clin Oncol. 2008;27:218-224. 6. Reimer P, et al. J Clin Oncol. 2008;27:106- 113. 7. Sieniawski M, et al. ASH 2009. Abstract 1660. First-line Chemotherapy and ASCT in PTCL: OS and PFS

36. 1234 56 90 pts (78%) in CR/CRu at first assessment after SCT 115 (72%) pts ASCT 166 pts CHOEP-14 2 pts TRD 25 (16%) pts primary refract 4 pts NE 16 off protocol 160 28 pts PD D’Amore F, et al. J Clin Oncol. 2012;30:3093-3099. Phase II NLG-T-01 Study: Up-front HDT/ASCT in PTCL

37. 5-yr PFS: 44% D’Amore F, et al. J Clin Oncol. 2012;30:3093-3099. 5-yr OS: 51% Up-Front HDT/ASCT in PTCL (NLG-T-01): OS and PFS by Entire Cohort and Subtypes 0 12 24 36 48 60 72 Mos 1.0 0.8 0.6 0.4 0.2 0 Overall Survival (proportion) 0 12 24 36 48 60 72 Mos 1.0 0.8 0.6 0.4 0.2 0 Overall Survival (proportion) 0 12 24 36 48 60 72 Mos 1.0 0.8 0.6 0.4 0.2 0 Overall Survival (proportion) 0 12 24 36 48 60 72 Mos 1.0 0.8 0.6 0.4 0.2 0 Overall Survival (proportion) No. at risk 160 113 96 76 59 46 17No. at risk 160 100 95 65 52 39 17 95% Cl Survivor function PTCL-NOS AILT Alk-negative ALCL EATL

38. ACT-1 Trial: CHOP-14 HDT ± Alemtuzumab Followed by HDT + ASCT in PTCL D’Amore F, et al. ASH 2012. Abstract 57. Patients aged 18-60 yrs with newly diagnosed systemic PTCL (N = 63*) Alemtuzumab † + CHOP-14 for 6 cycles (n = 32) CHOP-14 for 6 cycles (n = 31) Consolidated with HDT with ASCT *Enrollment ongoing. N reflects number of patients with complete treatment data included at time of data cutoff in June 2011. † Cumulative alemtuzumab dose tapered early on from 360 mg (30 mg on Days 1, 2 of CHOP courses 1-6) to 120 mg (30 mg on Day 1 of courses 1-4) due to systemic fungal infection (aspergillosis) in patients aged older than 60 yrs (in ACT-2). Only 7 patients in ACT-1 received cumulative alemtuzumab 360 mg prior to dose amendment.

39. ACT-1 Preliminary Results: Survival D’Amore F, et al. ASH 2012. Abstract 57. Outcome Value (N = 63) Response rates, n (%)  ORR42 (67) CR/CRu38 (61) PR4 (6)  SD3 (5)  PD16 (25) Time-related endpoints at 1 yr, % (95% CI)  EFS55 (42-67)  PFS54 (42-67)  OS78 (67-88)

40. Autologous Transplantation in PTCL Prospective studies Moderately better PFS/OS than population-based series with CHOP Selection Often younger patients Frail patients less likely to go on a HDT study Does not address the high rates of primary failures in PTCL Randomized study?

41. High dose infusional Gemcitabine +Bu/Mel  ASCT in refractory lymphoid malignancies Event-free survival (EFS) and overall survival (OS) of the main histologic subsets. (A) Hodgkin lymphoma, (B) B-large cell lymphoma post-HDC Nieto et al. Biol Blood Marrow Transplant 2012; 18: 1677

42. Ofatumumab in combination with ICE or DHAP chemo-tx in rel/ref intermediate grade B-cell NHL Matasar et al., Blood 2013; 122: 499-506

43. Radioimmunotherapy in conventional or high dose as part of conditioning regimens for ASCT in B-cell lymphoma

44. Phase III randomized study of Rituximab-BEAM vs 131 I-tositumomab/BEAM with ASCT for relapsed DLBCL: BMTCTN0401 Trial

46. Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation BCR signaling up-regulated in B-cell malignancies New inhibitors are targeting multiple components of BCR signaling including PI3K-δ, BTK, and Syk. Idelalisib IPI-145 TGR-1202 LYN SYK BCR BTK PLCγ2 PKC PI3K Delta AKT mTOR p70s6kelf4E GSK-3 NF-kβ Pathway Ibrutinib AVL-292 ┬ ┬ ┬ Fostamatinib GS-9973

47. Conclusions HDC + ASCT represents a strategy of proven value in relapsed DLBCL that is sensitive to salvage chemotherapy+R No particular salvage regimen (+R) appears to be superior to others (R-DHAP, R-ICE, R-ESHAP) Patients with HI/H-risk disease at Dx may benefit from HDC+ASCT consolidation (however no OS gain so far). Incorporation of hd-AraC (+R) improves the results after HDC+ASCT in mantle-cell lymphoma – R maintenance RIT potential to combine targeted radiation and HDC (e.g. BEAM) with promising results in refractory poor prognosis pts. Novel HDC regimens might improve results in refractory pts. Novel anti-CD20 MAbs (e.g. Ofatumumab)+salvage regimens may hold promise in relapsed DLBCL after Rituximab.