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Epidemiology Subcommittee

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Epidemiology Subcommittee

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  1. NCI Workshop on the Biology, Prevention and Treatment of Relapse after Allo-HCT Subcommittee III Report: Epidemiology and Natural History of RelapseCo-Chairs:Steven Pavletic, NCI; Daniel Weisdorf, U. MinnesotaCommittee Members:James M. Foran, U. AlabamaShaji Kumar, Mayo ClinicMarcos de Lima, MDACC Mohamad Mohty, U.NantesMarcelo Pasquini, CIBMTRMei-Jie Zhang, CIBMTRUpdate November 2, 2009

  2. Epidemiology Subcommittee Committee Charge: Review available data on relapse after allo-HCT a) incidence b) risk factors c) survival after relapse d) statistical methods

  3. Too many topics AML MDS CML ALL Myeloma Lymphoma CLL GVHD/GVL Common Risk Factors for relapse Statistics

  4. Epidemiology of RelapseModerators: Pavletic and Weisdorf Myeloid malignancies and ALL (Mohty, de Lima, Weisdorf) Lymphoma, CLL (Foran, Pavletic) Myeloma (Kumar) GVHD/GVL (Pasquini, Pavletic, Weisdorf,) Statistics (Zhang) Discussion

  5. Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation: AML, MDS, CML and ALL Mohamad Mohty, Marcos de Lima and Daniel Weisdorf NCI Workshop on Biology, Prevention and Treatment of Relapse After Allogeneic HCT Subcommittee III: Epidemiology and Natural History of Relapse

  6. AML: Relapse Incidence post Allo-HCT • Leukemia relapse is the major cause of treatment failure after allo-HCT in AML • AML in CR1: 10-40% • Advanced disease stage: >40-50% • After RIC allo-HCT: 18-50% Martino et al, Blood 2006

  7. AML: Risk Factors for Relapse post Allo-HCT • - Transplant beyond first CR • - Poor risk cytogenetics, FLT3-ITD mutations • - Secondary AML (prior chemo/radiotherapy; prior MDS) • - Age >60 years and comorbidities • - HLA-matching • Single CB transplantation • Reduced intensity and non-myeloablative conditioning • - In vitro and in vivo T cell depletion • - Gender donor/recipient combinations other than FM • - Specific KIR haplotypes

  8. AML: Outcome post Relapse after Allo-HCT •  Generally poor long-term survival and limited DLI response • Risk factors influencing outcome - Patient age • - Remission duration • - Use of DLI • - Favorable cytogenetics • - Presence of comorbidities • - Disease stage at relapse (e.g. lower tumor burden at relapse)

  9. MDS: Relapse Incidence post Allo-HCT  Probability of relapse: 20% - 60% (outcomes frequently reported ‘mixed’ with AML patients)  Trends that may confound comparisons with historic data: - new treatments (ie, hypomethylating agents, lenalidomide ) - treatment of older patients - use of reduced-intensity regimens - length of follow-up

  10. MDS: Risk Factors for Relapse post Allo-HCT  Not controversial - disease stage (driven mostly by blasts and poor prognosis chromosomal abnormalities - T cell depleted grafts  Controversial - Secondary MDS - Preparative regimen intensity - Development of chronic GVHD - Mixed chimerism - Stem cell source  Unlikely/no evidence - Recipient age / Donor age - Acute GVHD / Related versus unrelated donor

  11. MDS: Outcome post Relapse after Allo-HCT  Poor (0-40% long-term survival)  Major determinants for survival : - remission duration - MDS stage at relapse  Covariates that may influence outcome: - comorbidities, age, patient preference, ongoing GVHD

  12. Areas needing study AML MDS • - Relapse rates after hypomet. agents • - Impact of new MDS class. • - Incidence of relapse after haplo and CBT • - Preferred timing in light of availability of haplo and UCB • - Hypomethylating agents, angiogenesis inhibitors and other medications as maintenance therapy • Role of MRD detection in predicting relapse

  13. CML: Relapse after Allo-HCT  Influence of BCR-ABL kinase mutations on HSCT outcomes ?  Impact of new TKI in predicting peri-HCT outcomes ? Will pts who failed TKI pre-HCT respond following post-HCT relapse ?  Relapse rates after transplants from alternative donors ?

  14. ALL: Relapse Incidence post Allo-HCT • Leukemia relapse is the major cause of treatment failure after allo-HCT in ALL  25-50% in CR1  40-60% in CR2 Goldstone, Blood, 2008

  15. ALL: Risk Factors and outcome after Relapse  Short survival and limited DLI response  Early relapse worse; no other data Sib vs URD: ALL Adjusted Multivariate risk of Relapse Ringden et al, Blood, 2009

  16. ALL: Areas needing study • Who will relapse? - Detailed epidemiology - Age/WBC/cytogenetics/time to HCT - Duration of CR1 - MAC vs. RIC • Impact of MRD pre-allo-HCT: - What assay? Does it predict relapse? - Can intervention prevent relapse?

  17. James Foran & Steven Pavletic NCI Workshop on Biology, Prevention and Treatment of Relapse After Allogeneic HCT Subcommittee III: Epidemiology and Natural History of Relapse Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation for Lymphoma & CLL

  18. Issues in Studying Epidemiology of Lymphoma Relapse After Allo-HCT Lymphoma most common hematologic malignancy No prospective studies incorporate Allo-HCT into initial treatment planning (*MCL – exception) Small retrospective studies with limited power Heterogeneous studies Divergent histologies Mix of refractory & sensitive patients Multiple lines of prior therapy including Auto-SCT Heterogeneity of transplant regimens GVL effect may have variable potency

  19. GVL in NHL Similar relapse rate in allogeneic vs. syngeneic HCT CIBMTR/EBMT analysis Graft-versus-lymphoma effect in question, particularly for intermediate-grade histology LG • Emerging evidence of • GVL in HL; seen with RIC • Lower relapse risk for • indolent, T-cell, mantle-cell • lymphoma Int. Grade CIR Syngeneic vs. Allo-HCT & Auto-SCT (p=ns) HG Bierman, J Clin Oncol 21:3744, 2003

  20. Relapse Risk & Histology • Greatest relapse risk with aggressive histology (DLBCL) • & Hodgkin Lymphoma • Lower relapse risk with Follicular lymphoma, Mantle-Cell (esp. after RIC/NMA), & PTCL • RIC/NMA: Relapse rate related to histology & disease status: Corradini, Leukemia 21:2316, 2007

  21. NMA: Relapse Rates by Diagnosis & Disease Stage Groups StagenRelapse Rate per PY LowRisk CLL CR 7 0.00 NHL, low grade Not CR 34 0.15 NHL, low grade CR 9 0.18 Waldenström ‘s Advanced 9 0.19 NHL, mantle cell CR 16 0.19 NHL, mantle cell Not CR 25 0.20 NHL, high grade CR 26 0.23 StandardRisk CLL Not CR 75 0.26 HighRisk NHL, high grade Not CR 36 0.57 HD CR 13 0.62 HD Not CR 38 0.72 Adapted from: Kahl, Blood 110:2744, 2007

  22. Allo-HCT after Auto-SCT Very high relapse rate after salvage MA Allo-HCT following prior Auto-SCT (n=114) Disease progression 45% at 1yr, 70% at 5yrs Increase risk of progression if: no TBI for NHL RR 3.02 (95% CI 1.71-5.32) Chemoresistant RR 2.90 (95% CI 1.38-6.08) 10 Induction Failure, untreated RR 3.45 (95% CI 1.74-6.87) Freytes, Blood 104:3797, 2004

  23. Hodgkin Lymphoma • Refractory disease and after failure of Auto-SCT Relapse greatest contributor to treatment failure1, more common with bulky disease 60% disease progression at 3-5 yrs Disease status at Allo-HCT (presence of CR & chemosensitivity) only factor significantly associated with relapse after MA2 (n= 167, 42% chemoresistant) 1Peggs, Br J Haematol 143:468, 2008 2Peniket, BMT 31:667, 2003

  24. Hodgkin Lymphoma – EBMT RIC Series (n=285) Disease progression: 41% at 1yr, 58% at 5yrs1 Increase disease progression: Refractory RR 2.1 (95% CI 1.5-2.9) >3 lines prior therapy RR 1.7 (95% CI 1.2-2.5) Donor ♀: recipient ♂ RR 1.5 (95% CI 1.0-2.2) Similar rate progression/relapse after URD in CIBMTR2 Suggestion of lower relapse risk with haploidentical donor3 Related HR 0.35 (95% CI 0.2-0.8), p=0.01 Unrelated HR 0.43 (95% CI 0.2-0.9), p=0.03 DLI for HL (n=64)1 13/41 evaluable achieved CR Median survival 20 months after DLI 1Robinson, Haematologica 94:230, 2009 2Devetten, BBMT 15:109, 2009 3Burroughs, BBMT 14:1279, 2008

  25. Hodgkin Lymphoma – RIC vs. MA ↑ relapse rate RIC (57%) vs. MA (30%)1 RIC RR 2.48 (95% CI 0.77-2.79) Bulk disease @ Dx RR 3.10 (95% CI 1.32-7.24) Refractory Disease RR 1.51 (95% CI 0.95-2.39) Low-dose TBI in RIC RR 3.10 (95% CI 1.32-7.24) Children: ↑ relapse with RIC vs. MA (RR 4.4, p=0.05)3 No adverse effect of alemtuzumab in RIC regimens2 • * cGVHD- lower risk relapse1 → 1Sureda, J Clin Oncol 26:455, 2008 2Peggs, Br J Haematol 139:70, 2007 3Claviez, Blood 114:2060, 2009

  26. Aggressive NHL Disease sensitivity predicts relapse risk Relapse at 3 yrs: refractory 70% vs. chemosensitive 30%2,8 RR ~3 if progression within 12 months initial therapy >3 prior regimens associated with ↑ relapse risk5 ‘Stable’ refractory better than ‘progressive’3 No clear benefit of rituximab pre-Allo-HCT6 No clear impact of GVHD on relapse7 Responses to withdrawal immunosuppression or DLI reported4 1Doocey, Br J Haematol 131:223, 2005 2Aksentijevich BBMT 12:965, 2006 3Hamadani, BBMT 15:547, 2009 4Bishop, Ann Oncol 19:1935, 2008 5Law, BBMT 12:703, 2006 6Ratanatharathorn, Br J Haematol 145:816, 2009 7Ramadan, BMT 42:601, 2008 8Corradini, Leukemia 21:2316, 2007

  27. Aggressive NHL – RIC & NMA Generally less chemo-resistant patients Increase relapse rate NMA (36%) vs. MA (11%), p<0.011 NMA RR relapse 3.3 (95% CI 1.2-9.2), p=0.03 In NMA – risk of relapse2: Age HR ↑ 0.68 (p=0.08) each decade Chemosensitive HR 0.2 (p=0.009) In RIC – relapse rate 33%3 *Lower relapse rate with Mantle-Cell lymphoma & PTCL4-8 Chemo-refractory AITL ↑ relapse (28% vs. 15% at 3 yrs), p=0.04 1Tomblyn, BBMT14:538, 2008 2Rezvani, Br J Haematol 143:395, 2008 3Thomson, J Clin Oncol 27:426, 2009 4Khouri, J Clin Oncol 21:4407, 2003 5Kyriakou, J Clin Oncol 27:3951, 2009 6Ganti, Ann Oncol 16:618, 2005 7Kim, Blood 108:382, 2006 8Baron, J Clin Oncol 24:4150, 2006

  28. Indolent Lymphoma Less relapse than aggressive NHL or HL, generally <20% Significantly lower after Allo-HCT than Auto-SCT1-3 (*not compared with syngeneic) Increase risk of relapse with MA: Chemo-resistant RR 1.69 (95% CI 1.27-2.23) Abnormal LDH RR 1.51 (95% CI 1.21-1.87) KPS<90% RR 1.31 (95% CI 1.07-1.61) BM+ RR 1.31 (95% CI 1.04-1.65) >2 yrs from dx RR 1.40 (95% CI 1.06-1.84) 1van Besien, Blood 92:1832, 1998 2van Besien, Blood 102:3521, 2002 3Ingram, Br J Haematol 141:235, 2008

  29. Indolent Lymphoma RIC/NMA Relapse risk after NMA1: Transformed disease HR 4.85 (95% CI 1.5-15) Tandem Auto-Allo HR 5.47 (95% CI 1.5-21) Chemo-refractory HR 5.37 (95% CI 1.7-17) Increase risk relapse after RIC vs. MA, RR ~3 (p=0.04)2,5 Impact of mixed chimerism on relapse unclear3 Increase relapse risk for MRD by PCR (Bcl-2 or IgH) after RIC (40% vs. 0% if PCR-, p=0.010)4 1Rezvani, J Clin Oncol 26:211, 2008 2Vigouroux, Haematologica 92:627, 2007 3Khouri, Blood 111:5530, 2008 4Corradini, Leukemia 21:2316, 2007 5Hari, BBMT 14:236, 2008

  30. CLL: Progression after Allo-HCT • MA data older than RIC • CLL notorious for slow • disappearance of • malignant clone – kinetics • of response! • - Late relapses 5% 1Delgado, Blood 114:2581, 2009 2Montserrat, Blood, 107:1276, 2006 3Ben-Bassat, BMT, 39:441, 2007 4Gribben, Blood, 106:4389, 2005 5Pavletic, Leukemia, 21:2452, 2007 Relapse % PFS % MA1,2 2-32 30-65 RIC3 7-48 34-47 TCD4 68 24 Twins5 50 45

  31. CLL & Relapse • Risk factors for relapse or progression • Chemorefractory, >CR/PR (consistently reported) • Lymphadenopathy > 5 cm • >3 lines of chemotherapy • T-cell depletion in vivo or ex vivo • Slow donor T-cell chimerism • MRD positive post transplant • No known impact: • 17p deletion or ZAP-70 status • URD versus MSD

  32. CLL: Epidemiology of Relapse after Allo-HCT: Future Research • Few data on outcomes after relapse • DLI reported responses 15-50% • No data on risk factors or other interventions • Other questions • Outcomes of Allo-HCT vs. conventional therapy • Optimal timing of transplant • Role of MRD pre and post alloHCT • High Priority Studies • Retrospective, single center: CLL relapse index • Retrospective, community based: survival HCT vs. other • Prospective, multicenter cohort study, high detail of data • Obstacles – lack of funding mechanisms and proposals

  33. Lymphoma Relapse After Allo-HCT –More Data Needed! GVL potency controversial in aggressive lymphoma & HL more clearly identify GVL (except for MCL & PTCL) understanding relapse in relation to TCD, T-cell chimerism & cGVHD requires larger multicenter study Standardization of patient population definitions including IPI score, molecular pathology, and disease state Focus on chemosensitive, HCT earlier in disease course in pre-determined target patient populations Improved strategy for design of RIC regimens: targeted vs. disease-specific vs. maintenance Alternative donors (esp. Haplo in HL)

  34. Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation for Myeloma Shaji Kumar NCI Workshop on Biology, Prevention and Treatment of Relapse After Allogeneic HCT Subcommittee III: Epidemiology and Natural History of Relapse

  35. Allo-HCT in myeloma Evidence to support graft vs. myeloma effect High treatment related mortality, historically Relapse along with TRM remains the principal reasons for treatment failure Bulk of existing data in the setting of relapsed disease

  36. Trends Myeloablative conditioning Decreasing TRM, but increased relapse risk Reduced intensity conditioning Auto SCT followed by Reduced intensity conditioning

  37. Auto  RIC allo Bruno et al, Blood (2009). 113 (14), 3375-3382; Rotta et al, Blood (2009). 113 (14), 3383-3391

  38. Risk Factors for relapse Poor patient performance status Gender donor/recipient combination Allo-HCT > 1 year from diagnosis Durie stage 3 at diagnosis Chemoresistant disease, advanced disease Elevated B2 microglobulin, Deletion chromosome 13, deletion 17p RIC regimens T-cell depleted grafts, Campath or ATG use Lack of complete response

  39. How can we decrease risk of relapse? Allo-HCT early in disease course: needs better prognostic markers of the right group. Novel agents to obtain CR prior to allo-HCT or use of auto  allo-HCT? Novel agents as maintenance post allo-HCT? Immunomodulatory drugs (lenalidomide) in conjunction with DLI? Use of bortezomib to separate GVM from GVH?

  40. Outcome after relapse form allo-HCT • Little data available, need retrospective studies • Trials needed to explore novel approaches for post-relapse Rx • Use of novel agents in conjunction with DLI: • To reduce tumor bulk • To enhance GVM effect • To alter GVM/ GVH ratio • Explore novel drug combinations

  41. GVHD/GVT and RelapseMarcelo Pasquini, Steven Pavletic & Daniel Weisdorf NCI Workshop on Biology, Prevention and Treatment of Relapse After Allogeneic HCT Subcommittee III: Epidemiology and Natural History of Relapse

  42. Donor Recipient Immune Interactions: GVHD/GVT vs. Graft Rejection/Relapse GVHD prophylaxis GVHD/GVT Rejection/ Relapse Donor Cells Recipient

  43. Lower relapse rates in patients with GVHD Horowitz, M et al. Blood 1990

  44. Chronic, but not acute GVHD reduces relapse in leukemia after Sib or URD HCT Ringden, Blood 2009

  45. Relapse after HCT with non-myeloablative conditioning and importance of full donor chimerism (N=322) Acute GVHD HR 95% CI P No 1.0 - Grade 1 0.3 0.1 to 1.1 .07 Grade 2 1.0 0.7 to 1.6 .91 Grade 3-4 0.7 0.3 to 1.7 .44 Chronic GVHD No 1.0 - Extensive 0.4 0.2 to 0.8 .006 >95% chimerism No 1.0 - Yes 0.5 0.3 to 0.8 .002 Baron, JCO 23:1993, 2005

  46. Chronic GVHD severity does not impact leukemia relapse Relapse Non-relapse Mortality DF survival Black-no CGVHD Blue-good risk CGVHD (50%),Green-intermediate (30-35%), Red-worst risk group (15-20%) Lee et al. Blood, 2002

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