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Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma:

Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma:. Ginna G. Laport, MD Associate Professor of Medicine Division of Blood & Marrow Transplantation Stanford University Medical Center.

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Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma:

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  1. Hematopoietic Stem Cell Transplantation:High Risk Diffuse Large Cell Lymphoma: Ginna G. Laport, MD Associate Professor of Medicine Division of Blood & Marrow Transplantation Stanford University Medical Center

  2. Diffuse Large B-Cell Lymphoma:Stem Cell Transplantation for High Risk Patients • Identifying “High Risk” Patients • Autologous HSCT in High Risk Patients • Phase II Trials • Phase III Trials • Allogeneic HCT

  3. Transplant Activity Worldwide1968-2012 Transplants

  4. Indications for Hematopoietic Stem Cell Transplants in the U.S. Number of Transplants

  5. Diffuse Large B-Cell Lymphoma • Most common NHL: 31% • Peak incidence in 6th decade • Large cells with loss of follicular architecture of node • 30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms • Frontline chemotherapy (anthracycline-based + RTX) • CR  50-60% • Long term remission -> 30-35%

  6. Overall Survival According to Revised International Prognostic Index • Age >60 • PerfStatus • Stage 3-4 • LDH • Extranodal 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 P < .001 0 0 1 2 3 4 5 Yrs Sehn LH, et al. Blood. 2007;109:1857

  7. Survival by Gene Expression Profiling: DLBCL Diffuse Large B-Cell Lymphoma 1.0 0.8 0.6 OS 0.4 0.2 0 0 2 4 6 8 10 Yrs Rosenwald A, et al. J Exp Med. 2003;198:851-862.

  8. Prognosis By Interim PET Scanning • Mixed results seen in 4 studies • 2 studies confirm predictive value, 2 studies did not Progression Free Survival n= 98 Progression Free Survival n= 112 1.0 100 • PET Negative • PET negative (n=73) 0.8 80 • PET Positive 0.6 60 • PET positive (n=12) 40 0.4 20 0.2 • P=0.02 • P=0.146 0 0 0 20 40 60 80 100 0 1 2 3 4 5 6 7 Moskowicz et al. J ClinOncol 2010;11: 1896 Time (months) Time (years) Safar et al, J ClinOncol 2012;30:184

  9. High Risk DiffuseLarge Cell Lymphoma Autologous HSCT in First CR/PR

  10. High Risk Diffuse Large B Cell NHL:Frontline Autologous HCTPhase II Trials containing rituximab

  11. Meta-analysis:Autologous HSCT as Front Line Therapy Cochrane Database Sys Rev 2008;CD004024 N = 2228 No survival advantage for autologous HSCT in CR1 Haematologica 2003;88:1304 N = 3079 Overall survival advantage for autologous HSCT in CR1 compared to chemotherapy

  12. R-CHOP x 8 vsR-CHOP x 6 Cycles + Autologous HSCT (SWOG S9704) Eligibility: Bulky stage 2-4 Hi-int/High IPI CHOP ± Rituximab x 1 + Autologou HSCT* (n = 125) Ptswith ≥ PR after CHOP ± RTX x 5 (N = 253) CHOP ± Rituximab x 3 (n = 128) Stiff PJ, et al. ASCO 2011. Abst 8001.

  13. ASCT After CHOP ± Rtx Improves PFS in Advanced High-Risk Diffuse NHL • Autologous HSCT prolonged PFS • high-intermediate • high-IPI • Autologous HSCT prolonged OS • high-IPI Stiff PJ, et al. ASCO 2011. Abstr 8001.

  14. Italian Lymphoma Foundation2 x 2 Randomized Trial with Autologous HSCT inHigh Risk Patients R-CHOPx 3 R A N D O M IZE R A N D O M I Z E BEAM  AutoHCT PR, CR Newly diagnosed DLBCL, aaIPI> 2 n = 399 Observation only R-megaCHOP SD, PDoff study Ann Oncol 2011; 22 suppl 4: abstr 72.

  15. Italian Lymphoma Foundation2 x 2 Randomized Trial with Autologous HCT in High Risk Patients(median followup = 23 mos) Progression Free Survival 1.00 HDT 0.75 0.50 No-HDT 0.25 P=.008 0.00 0 6 12 18 24 30 36 42 48 Months - Risk of relapse was 53% lower in BMT patients - No overall survival difference between two arms`

  16. High Risk DiffuseLarge Cell Lymphoma • Is there a role for allogeneic HSCT??

  17. Survival after Allogeneic HCT for Diffuse Large B-Cell Lymphoma, 2000-2009- By Disease Status - 100 100 90 90 80 80 70 70 60 60 Probability of Survival, % 50 50 Sensitive (N=383) 40 40 30 30 20 20 Resistant (N=124) 10 10 P < 0.0001 0 0 1 3 0 2 4 5 6 Years

  18. Reduced Intensity Allogeneic HSCT (after autologous HSCT relapse) • Factors affecting outcomes • Dz status at time of allogeneic HCT • Time to relapse after autologous HCT (< 12 m vs > 12 m) • Did not affect outcome • Prep regimen Rigacci et al , Ann Heme 2012;91:931 van Kampen et al. JCO 2011;29:1342

  19. Hematopoietic SCT for High Risk DLBCL • Need better tools to identify high risk patients • Current studies suggest that high-IPI subtype may benefit from autologous HCT early as front line therapy • More studies needed to further define role of autologous HSCT as front line therapy • Need study that includes only ABC-subtype • Role of allogeneic HSCT in high risk population?

  20. Stanford University

  21. CORAL Trial:Collaborative Trial in Relapsed Aggressive Lymphoma Which salvage regimen is the best? R-ICEx 3 R A N D O M IZE R A N D O M I Z E Rituximab q2mos x 6 Auto SCT PR, CR Relapsed/ refractory DLBCL n = 396 Observation only R-DHAPx 3 SD, PDoff study Role of maintenance rituximab J ClinOncol 2010; 28:4184–4190.

  22. CORAL TrialSurvival according to Salvage Regimen OverallSurvival Event Free Survival 1.0 1.0 0.8 0.8 R-ICER-DHAP 0.6 0.6 0.4 0.4 0.2 0.2 P = .49 P = .27 0 0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Mos Mos GCB vs ABC 3 yr PFS: 70% vs 28% R-DHAPvs R-ICE in GCBpts: 3 yrPFS:100% vs 27%

  23. CORAL Trial: EFS byrelapse timeafter initial therapy Relapse > 12 mos fromdx Relapse < 12 mos fromdx Relapse < 12 mos from dx predicted for poor outcome after autologous HCT

  24. EFS PFS Female RTX Obs Male p=.74 p=.04 Female pts benefited from RTX maintenance JCO 2012, In press

  25. CORAL: Factors affecting survival in relapsed DLCL patients EFS OS Prior rituximab.0007 .01 Relapse < 12 mos<.0001 <.0001 sIPI<.0004 <.0001 R-DHAP vs R-ICE0.3 0.7 (Except for GCB pts) p

  26. PARMA Study: BMT vs Salvage Chemotx for Relapsed DLBCL Event Free Survival OverallSurvival Transplantation Conventional treatment 100 100 80 80 60 60 EFS (%) OS (%) 40 40 20 20 P = .001 P = .038 0 0 0 15 30 45 60 75 90 0 15 30 45 60 75 90 Mos After Randomization Mos After Randomization Philip T, et al. N Engl J Med. 1995;333:1540

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