Peripheral T-Cell Lymphoma. Pro auto. Peter Reimer. Klinik für Hämatologie / intern. Onkologie und Stammzelltransplantation

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1 Peripheral T-Cell Lymphoma Pro auto Peter Reimer Klinik für Hämatologie / intern. Onkologie und Stammzelltransplantation Kliniken Essen Süd, Evang. Krankenhaus Essen-Werden ggmbh COSTEM, Berlin

2 Background - PTCL Rare diseases with no satisfying standard treatment Gesamtüberleben (%) Gesamtüberleben (%) Poor results following conventional (anthracycline-based) chemotherapy (except ALK+ anaplastic large cell lymphoma) Lack of randomised phase III trials

3 Background Conventional Chemotherapy Overall survival Overall survival Gisselbrecht et al. Blood (1998) Falini et al. Blood (1999)

4 Rationale for AutoSCT - Impact of Anthracyclines 1.0 Overall survival probability 0.4 p= time (years) Anthracycline-based 1 st line therapy Median OS yes 2.1 no 1.57 Armitage et al. J Clin Oncol (2008)

5 Rationale for AutoSCT 1.0 Overall survival 1.0 Failure-free survival Proportion p= p< Proportion Time Time HD Therapy yes no CENSOR FAIL TOTAL MEDIAN Transplantation CENSOR FAIL TOTAL MEDIAN 1. line line Armitage et al. J Clin Oncol (2008)

6 Rationale for AutoSCT 2 nd Line Therapy Retrospective studies (n >15 pts.) Author n CR OS Comment Author n CR OS Comment Vose (1990) 17 59% 35% (2y) Fanin (1999) 64 n.d. 70% (5y) ALCL Rodriguez (2001) 29 79% 39% (3y) subgroup Blystad (2001) 40 80% 58% (3y) Song (2003) 36 42% 48% (3y) Rodriguez (2003) 78 68% 56% (5y) subgroup Schetelig (2003) 15 67% 44% (5y) AIL, subgroup Jantunen (2004) 37 76% 54% (5y) subgroup Kewalramani (2006) 24 n.d. 33% (5y) Nademanee (2006) 57 n.d. 45% (2y) subgroup Kim (2007) 40 n.d. 11.5m subgroup Smith (2007) 32 n.d. 43% (3y) subgroup Chen (2008) 53 79% 40% (5y) CR/PR 30% (5y) refr. subgroup Khouri (2008) 59 80% 43.5m subgroup Zamkoff (2004) 16 50% 72w ALK-neg ALCL Jagasia (2004) 28 50% 69% (3y) incl. CTCL

7 Rationale for AutoSCT Blystad Song Kewalramani

8 Prospective Trials 1 st Line AutoSCT n Age Regimen Tx-Rate (%) CR/PR TRM OS FU Corradini (Leukemia 2006) 62 (incl. ALK+ ALCL) APO DHAP HD Mito/Mel 2. MACOP-B HD AraC/Mito BEAM 74% 72% 5% 34% (12y) 21%* non ALK+ ALCL 7m Rodriguez (Eur J Haematol 2007) MegaCHOP/IFE BEAM 73% 81% 0 73 (3y) 3m Mercadal (Ann Oncol 2008) HighCHOP + ESHAP altern. 41% 59% n.d. 39% (4y) 3.2y (survivors) Reimer (J Clin Oncol 2009) CHOP DexaBEAM/ESHAP HD Cy + TBI 66% 71% 4% 48% (3y) 33m D`Amore (EHA 2009) CHOEP-14 BEAM 71% 83% 4% 57% (3y) 45m

9 Prognostic Factors for AutoSCT Reimer et al. J Clin Oncol (2009)

10 Prospective trials 1 st Line AutoSCT 1 Overall survival 1 Overall survival Overall survival 0,8 0,8 0,6 0,6 0,4 0,4 0,2 0, Time (months) Time (months) (n=160) D`Amore al. EHA (2009) (n=83) Reimer et al. JCO (2009) OS NLG-T-01 (EHA 09) Reimer et al. (JCO 09) Induction Conditioning PFS NLG-T-01 (EHA 09) Reimer et al. (JCO 09) 3-yrs 57% 48% NLG-T-01 EHA 2009 CHOEP-14 x 6 BEAM 3-yrs 49% 36% 5-yrs 50% 40% Reimer et al. JCO 2009 CHOP-21 x 4-6 +DexaBEAM HDCy+TBI 5-yrs 43% n.d. Courtesy F. d`amore (2010)

11 Prognostic Factors for AutoSCT Corradini Rodriguez Mercadal Reimer D`Amore Chemosensitive disease/cr n.d. aaipi/pit no n.d.

12 Failing AutoSCT autosct 20% 10% 20-30% Progressive Disease Early Relapse Late Relapse n= 83 PTCL n= 28 34% No autosct n= 24 progressive disease n= 2 patient request n= 2 other n = CR 2 n = AWD 3 n= 23 Dead Reimer et al. J Clin Oncol (2009)

13 Failing AutoSCT autosct 20% 10% 20-30% Type of failure Clinical course Possible strategy Primary refractory No signs of chemosensitivity; progression during induction treatment New biological induction approach needed Early relapse Responds to induction, if eligible Improvement of autosct; induction relapses shortly after Early consolidation completion of 1 st line therapy Late relapse Chemosensitive; reaches CR, long ccr, relapses > 1 y after completion of 1 st line therapy Improvement of induction Consolidation and/or maintenance Adapted from F. d`amore (2011)

14 Improving Induction Etoposide? Event-free survival NHL B1 trial 6 x CHOEP (n= 42) 6 x CHOP (n= 41) Etoposide (n= 103) NHL B1 and Hi-CHOEP trials non-etoposide (n= 41) p= p= Etoposide (n= 34) Alk+ ALCL non-etoposide (n= 12) Etoposide (n= 89) No Alk+ ALCL p= p= non-etoposide (n= 29) Schmitz N et al. Blood (2010)

15 Improving Induction - Alemtuzumab Alemtuzumab promising response rate, but: toxic (infectious complications, EBV-associated B-cell lymphoma) Phase II Trials Enblad 2004 Blood Weidmann 2010 Leuk Lymphoma Kim 2007 Cancer Chemother Pharmacol Gallamini 2007 Blood 2nd line 1st line n Regimen monotherapy + FCD + CHOP + CHOP ORR 36% 1st Line: 63% 2nd Line: 45% 65% 71% Toxicity panzytopenia: 4/14 opport. infect: 10/14 neutropenie 3/4: 73% CMV-reactivation: 33% CMV-pneumonia: 3% neutropenia 4: 90% CMV-reactivation: 25% CMV-pneumonia: 15% neutropenia 3/4: 34% CMV-reactivation: 9% severe infections: 8 TRM 35%, study closed TRM: 3% 10%, study closed no

16 Pro AutoSCT? Other Therpeutic Options Conventional chemotherapy poor results

17 Pro AutoSCT? Other Therpeutic Options Conventional chemotherapy poor results Allogeneic stem cell transplantation data for relapsed/refractory PTCL, only

18 Pro AutoSCT? Other Therpeutic Options Conventional chemotherapy poor results Allogeneic stem cell transplantation data for relapsed/refractory PTCL, only Novel agents data for relapsed/refractory PTCL, only, only pralatrexate approved (relapsed/ refractory PTCL, only in the U.S.)

19 Pro AutoSCT - Conclusions AutoSCT widely accepted treatment in relapsed/refractory setting (results comparable to B-cell lymphoma); So far, autosct best upfront approach for non-alk+ PTCL, especially for pts. in remission after induction therapy; Improvement of induction therapy is needed; Other options either not effective, toxic or approved only for refractory/relapsed setting; Randomised trials urgently needed;

20 Nordic Lymphoma Group NLG-T-02 (ACT-1 Trial) CHOP 14 CHOP 14 CHOP 14 CHOP 14 CHOP 14 CHOP 14 R A-CHOP 14 A-CHOP 14 A-CHOP 14 A-CHOP 14 PBS C harv est CHOP 14 CHOP 14 CR/PR BEAM Auto SCT PI: F. d`amore - Max. age: 60 yrs - ALCL excluded regardless of alk-status (low CD52 expression; good NLG-T-01 results: 5y OS 73%) - ALZ dose reduction: from 60 mg pr course to 30 mg pr course (course 1-4), no antibody in course 5 and 6

21 DSHNHL A Trial R CHOEP 14 CHOEP 14 CHOEP 14 CHOEP 14 CHOEP 14 CHOEP 14 CHOEP 14 CHOEP 14 CR/PR/NC CR/PR/NC DHAP DHAP PBS C harv est no donor available BEAM FBC Auto SCT Allo SCT PI: N. Schmitz Inclusion criteria - Age years - No severe concomitant disease - PTCL except ALK+ ALCL - No CNS involvement - All stages and IPI except stage I with aaipi 0 - No pregnancy and lactation - ECOG performance status Written consent