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

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

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

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)

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

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

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

Autologous Transplantation as Consolidation for Aggressive NHL high- intermediate/ high-risk NHL (R)-CHOP x 5 (R)-CHOPx1 (R)-CHOPx3 RANDOMIZERANDOMIZE TBI ( Gy) +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:

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

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

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

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

R-ICE R-DHAP N 239% N 230% Response including deaths COMPLETE RESPONSE UNCONFIRMED COMPLETE RESPONSE PARTIAL RESPONSE STABLE DISEASE PROGRESSIVE DISEASE DEATH PREMATURE WITHDRAWAL / NOT EVALUATED/missing 8262 Total RESPONSE TO SALVAGE INDUCTION TREATMENTS 63.6 % 64.3 % Arm of treatmentNb patients Nb responders with successful mobilizationMARR (%) R-ICE R-DHAP Gisselbrecht C et al. asco 2011

Arm of treatment ARM A / R-ICEARM B / R-DHAP N%N% Consolidation treatment (BEAM) Yes No Total 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

EFS (induction ITT)OS (induction ITT) EFS and OS by induction treatment Survival probability OS (months) Survival probability EFS (months) p = p = 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) patients first randomised from 24 July 2003 to 30 June patients randomised in the second part from 21 October 2003 to 21 October 2008

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%

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

Response p Patients CR/CRu/PR All patients % CR/CRu % Prior RituximabNo12283% < Yes12451% Relapse> 12 months14088% < Refractory< 12 months10646% sIPI< % < > 17652% CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS

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

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

PFSOS CORAL maintenance: PFS/OS by treatment arm Survival probability Overall survival (months) Survival probability PFS (months) p = p = Observation Rituximab Observation Rituximab 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

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%)

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 + _ + _ + _

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

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

C-MYC probe, split-signal PatternYYYGR

Patients analysed ( n=161) n MYC % Simple 7 Complex BCL2 BCL6 BCL2 and BCL MYC - No breakpoint % MYC+ DLBCL treated in CORAL study Cuccuini W. et al., Blood 2012

p = p = 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

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

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

MCL Network Trial: R-CHOP/R-DHAP, High-Dose Ara-C and ASCT vs R-CHOP Hermine O, et al. ASH 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)

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 Abstract 151. Patients Not in Treatment Failure, % R-CHOP/R-DHAP (n = 232) R-CHOP (n = 233) 36 mos mos 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

MCL Network Trial: Secondary Outcomes Hermine O, et al. ASH 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 mos mos mos7444 VariableHR for TTF (95% CI)P Value R-DHAP vs R-CHOP0.54 ( )<.0001 R-DHAP vs R-CHOP0.49 ( )<.0001 MIPI score (+1)2.08 ( )<.0001

The role of HDC+ASCT in T-Cell NHLs

TrialRegimenNOS RatePFS Rate GEL-TAMO* [1] 5 5 yrs GEL-TAMO [2] MEGA-CHOP, then ASCT or IFE-ASCT 3 3 yrs Nordic Group [3] 2 yrs– Italian Group [4] yrs EBMT* [5] HDT/ASCT AITL yrs Reimer et al [6] 3 3 yrs Sieniawski et al [7] 3 3 yrs *Retrospective study. 1. Rodriguez J, et al. Ann Oncol. 2003;14: Rodriguez J, et al. Eur J Haematol. 2007;79: D’Amore F, et al. Ann Oncol. 2005;16(suppl 5):v Kyriakou C, et al. J Clin Oncol. 2008;26: Kyriakou C, et al. J Clin Oncol. 2008;27: Reimer P, et al. J Clin Oncol. 2008;27: Sieniawski M, et al. ASH Abstract First-line Chemotherapy and ASCT in PTCL: OS and PFS

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 pts PD D’Amore F, et al. J Clin Oncol. 2012;30: Phase II NLG-T-01 Study: Up-front HDT/ASCT in PTCL

5-yr PFS: 44% D’Amore F, et al. J Clin Oncol. 2012;30: yr OS: 51% Up-Front HDT/ASCT in PTCL (NLG-T-01): OS and PFS by Entire Cohort and Subtypes Mos Overall Survival (proportion) Mos Overall Survival (proportion) Mos Overall Survival (proportion) Mos Overall Survival (proportion) No. at risk No. at risk % Cl Survivor function PTCL-NOS AILT Alk-negative ALCL EATL

ACT-1 Trial: CHOP-14 HDT ± Alemtuzumab Followed by HDT + ASCT in PTCL D’Amore F, et al. ASH Abstract 57. Patients aged 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 † 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.

ACT-1 Preliminary Results: Survival D’Amore F, et al. ASH 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)

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?

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

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

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

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

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

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.