Allogeneic Transplantation in Follicular Lymphoma. What have we learned?

Transcription

1 Allogeneic Transplantation in Follicular Lymphoma What have we learned?

2 Introduction Conditioning Regimens GVHD Prophylaxis Donor Sources When and how? 2

3 Case : 43 YOM, stg IV FL. R/ CVP x8 : No response Rituxan + idiotype vaccine: good response Jan 2005: LN recurrence Oct 2005: testicular Ca. R/orchiectomy + BEP x1 Apr 2006: Rituxan x 8: no response Jan 2007: FND x4: PR with residual bone marrow involvement. Jun 2007: Temsirolimus: No response, myelosuppression Sep 2007: Ifosf/VP 16:PR

4 Regression of indolent lymphoma after allo-transplant 5

5 MDACC Study 1: the Case for Aggressive Management Age Diag #prio r Rx Largest mass Dis Status % BM inv KPS Late Compl Outcome 28 FL 5 9x6 Refr CGVH Relapse 4 yrs 36 SLL 3 2x3 Refr Aseptic Hip 36 SLL 5 4x5 Refr CGVH 9+ yr 23 FL 3 3x2 Refr CGHV 7+ yr 38 FL 5 2x2 Sens yr 38 FL 3 8x4 Refr 5 70 D d16 VOD 45 FL 6 2x2 Refr CGVH 6+ yr 42 FL 5 3x4 Refr yr 31 MCL 3 8x7 Sens yr 43 FL 5 9x5 Refr D d26 GVH 6+ 9 HLA Id Sib, 1 Ag MM; All TBI JCO 13, 1096, 1995 JCO 18, 702, 2000

6 Survival MDACC Study 1: Survival after allo transplant Years van Besien, JCO 19967

7 SURVIVAL PROBABILITY, % CIBMTR Study 2: Allo-transplant for Follicular Lymphoma Probability of Survival by Year of Transplant Allogeneic, (N = 62) 60 Allogeneic, (N = 64) 40 Allogeneic, (N = 50) Tx between 1990 and YEARS Van Besien, Blood 2003 FLT02_22.ppt

8 Introduction Conditioning Regimens: MA vs NMA vs RIC GVHD Prophylaxis Donor Sources When and how? 10

9 MA vs NMA vs RIC MA Toxic Avoid in older Pts Develop Less Toxic Regimens RIC has Less Intense Conditioning RIC is Superior for Older Patients 11

10 Non Myeloblative Conditioning: FHCRC multi-institutional protocols FLU 30 mg/m 2 /d 2 Gy TBI HSCT CSP 6.25 mg/kg po bid CSP 6.25 mg/kg po bid PBSC HSCT MMF 15 mg/kg po bid 12

11 Non-Myeloablative Transplantaton: the MD Anderson protocol Tacrolimus and Methotrexate Khouri et al, Blood

12 Non-Myeloablative Transplantation: MD Anderson Patient Characteristics N 47 Age (range) 53 (33-68) >3 prior chemo regimens 36% Prior Autologous 19% IPI at study entry 1 (0-3) PR/CR to last chemotherapy 38/62 PET pos 7 (15%) Related/Unrelated donor 96/4 Tx between 1999 and 2005 Khouri, I F. et al. Blood 2008;111: Khouri, I.F. et al. Blood 2012;119:

13 Non Myeloablative Transplantation: MD Anderson Survival and Progression Free Survival Khouri, I. F. et al. Blood 2008;111:5530 Khouri, I.F. et al. Blood 2012;119:6373

14 Non-Myeloablative Transplantaton: the Geltamo Protocol Tacrolimus and Methotrexate Khouri et al, Blood

15 RIC sibling tx for follicular lymphoma: follow-up from two prospective multicenter trials (GELTAMO) CI NRM 24% (d100), 37% 4 yrs, cgvhd 88%, ext 55% 20 Pinana et al, Hematologica, 95:1176,2010

16 CIBMTR Study 3: Conditioning Regimens Ablative (N=120) CY + TBI dose> 500 cgy 62% RIC (N=85) BU + CY 24% Other Ablative 14% Fludarabine+CY 41% MEL dose < 150 mg/m 2 23% BU dose < 9 mg/kg 21% Other RIC 15 % Hari, BBMT 14:236, 2008 New Slide 22 NST05_17.ppt

17 Cumulative Incidence, % CIBMTR Study 3: Cumulative Incidence of TRM after Allotxfor Follicular Lymphoma by Conditioning Regimen Conventional RIC/NST Prob (%) Prob 1 year 23 3 years RR P-Value Conventional 20 RIC/NST Years Hari, BBMT 14:236, 2008 NST05_22.ppt

18 Cumulative Incidence, % Cumulative Incidence of Progression/Relapse after Allotransplants for Follicular Lymphoma by Conditioning Regimen Conventional RIC/NST Prob (%) Prob 1 year 7 3 years 8 17 RR P-Value RIC/NST 0 0 Years Conventional Hari, BBMT 14:236, 2008 NST05_23.ppt

19 Probability, % CIBMTR Study 3: Adjusted Probability of PFS after Allotx for Follicular Lymphoma by Conditioning Regimen Conventional (N=117) RIC/NST (N=84) 20 Conventional RIC/NST Prob (%) Prob 1 year 70 3 years RR P-Value Years Hari, BBMT 14:236, 2008 NST05_24.ppt

20 MA vs NMA vs RIC: A self fulfilling prophecy? MA Toxic Avoid in older Pts Develop Less Toxic Regimens RIC has Less Intense Conditioning RIC is Superior for Older Patients or is It? 28

21 More Significant Covariates TRM PFS OS Variables RR RR RR KPS<90 at transplant P-Value Not chemosensitive disease P-Value New Slide 29 Hari, BBMT 14:236, 2008 NST05_33.ppt

22 Introduction Conditioning Regimens GVHD Prophylaxis: T-depletion vs Not Donor Sources When and how? 30

23 BEAM-alemtuzumab allogeneic tx in relapsed advanced stage follicular lymphoma BCNU (300 mg/m 2 ) Etoposide 200 mg/m2 BID Ara-C 200 mg/m2 BID Melphalan (140 mg/m 2 ) Campath (10-20 mg/day) Cyclosporin d 1-d Day DLI for declining chimerism or for relapse Tx between 1992 and 2005 Ingram et al, BJH 141, 235, 2008

24 BEAM-autologous and BEAM-alemtuzumab allogeneic tx in relapsed advanced stage follicular lymphoma NRM Relapse Progression Free Survival 3 pts with extensive chronic GVHD Survival Ingram et al, BJH 141, 235, 2008

25 UK Cooperative Group: Fludarabine Melphalan Alemtuzumab Fludarabine* (25 mg/m 2 /day) Melphalan (70 mg/m 2 /day) Campath (20 mgday) Tacrolimus d 2-d Day Morris et al, Blood, 2004

26 UK Cooperative Group: Flu Mel Alemtuzumab for Follicular Lymphoma P=0.01 MUD (40) Sibling (45) NRM Sensitive (76) Sibling (45) Refractory (8) MUD (40) P=0.03 P=0.01 cpfs cpfs Update Courtesy K. Peggs, S. Mackinnon 37

27 The only factor that emerged as truly predictive of all outcomes was disease status at transplantation. Patients with progressive/refractory disease had a significantly higher relapse rate and NRM, and also a significantly shorter PFS,current PFS and OS 46 ATG, 42 Alemtuzumab, 76 no TCD 38 Delgado et al, Leukemia 25, 551, 2011

28 Introduction Conditioning Regimens GVHD Prophylaxis: We favor T-cell depletion b/o improved QOL of survivors and probably very long-term survival Donor Sources When and how? 40

29 Mortality in year survivors after allo HCT 2007 by American Society of Hematology Bhatia S et al. Blood 2007;110:

30 Mortality in year survivors after allo HCT Without GVHD 5y 10 y 95% 91% 2007 by American Society of Hematology Bhatia S et al. Blood 2007;110:

31 Mortality in year survivors after allo HCT Without GVHD With GVHD 5y 10 y 5y 10y 95% 91% 85% 78% 2007 by American Society of Hematology Bhatia S et al. Blood 2007;110:

32 Introduction Conditioning Regimens GVHD Prophylaxis: T-depletion vs Not? Donor Sources: MUD and Cord Blood When and how? 44

33 Tx between No info on HLA typing 45 Avivi et al, BJ Haem 147, 719, 2009

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35 8/8 Allele, Available-Match Rates in the Adult Donor Registry NATIONAL MARROW DONOR PROGRAM Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry 47

36 Haplo SCT an effective approach for lymphoid malignancies? Luznik et al, BBMT, 14, 641, 2008

37 Cord Blood Transplant Steinbrook, R. N Engl J Med 2004;351:

38 UCBT in Adults with Lymphoid Malignancies: EBMT MCL Indolent DLCL and HL LD TBI HD TBI No TBI RR P NRM Use of LD TBI* TNC>2 x10^ Relapse/Progr 2CBU PFS Chemosens LD TBI* TNC > OS LD TBI* TNC>2x10^ * LD TBI associates with no ATG Rodrigues C A et al. JCO 2009;27: by American Society of Clinical Oncology

39 UCBT for Lymphoma Minnesota Follicular/CLL HL MCL/DLBCL Brunstein et al, BBMT 15, 214,

40 % Donor Chimerism Cord Blood Haplo- identical transplant Time

41 N= 203 Haplocord 28,HiR 39% Unrelated 83, HiR 41% Related 92, HiR 50% Age 58 (50-73) Haplocord 58 (50-69) A. Artz, Unpublished, 2013

42 Case No matched sib No MUD Haplo-Cord Tx (4/6 MM cord) Conditioning Flu-TT-TBI-ATG. GVHD prophylaxis Tac -MTX Engrafted minimal acute GVHD No chronic GVHD. Alive and Free of Disease 64 mo 54

43 N= 203 Haplocord 28,HiR 39% Unrelated 83, HiR 41% Related 92, HiR 50% Age 58 (50-73) Haplocord 58 (50-69) Lymphoma N=11 Ages: TRM 2 PD 7 Long-Term DFS A. Artz, Unpublished, 2013

44 Introduction Conditioning Regimens GVHD Prophylaxis Donor Sources: MUD, Haplo, UCB may yield equivalent results When and how? 56

45 Introduction Conditioning Regimens GVHD Prophylaxis Donor Sources When and how? 57

46 The University of Chicago Approach (2011) Allogeneic transplant is considered for patients with first or second recurrence. Choice between autologous vs allogeneic is guided by Health and age of the patient Ability to mobilize Availability of HLA-identical related or unrelated donor. Outcome of transplantation is determined by Patient condition PS and comorbidity Disease status Donor type (matched vs mismatched) Conditioning regimen 58

47 The Approach at Weill Cornell (2013) Allogeneic transplant is considered for patients with first or second recurrence. Choice between autologous vs allogeneic is guided by Health and age of the patient Ability to mobilize Availability of HLA-identical related or unrelated donor. Outcome of transplantation is determined by Patient condition PS and comorbidity Disease status Donor type (matched vs mismatched) Conditioning regimen GVHD Prophylaxis 59

48 The Future: Reduce NRM and toxicity while preventing relapse Earlier referral for transplant. Limit GVHD and Recurrence Rituximab post tx Rapamycin post tx Other post tx interventions? 64

49 Thank you! 65