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Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma. Michael Crump, MD, FRCPC Division of Medical Oncology & Hematology Princess Margaret Hospital Department of Medicine, University of Toronto. Outline of this talk. prognostic factors following disease recurrence

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Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

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  1. Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma Michael Crump, MD, FRCPC Division of Medical Oncology & Hematology Princess Margaret Hospital Department of Medicine, University of Toronto

  2. Outline of this talk • prognostic factors following disease recurrence • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy • second transplants • - reduced intensity allogeneic SCT

  3. Recurrent HL • ~10-20% of early stage (I and II), 20-40% of pts with advanced disease • Refractory: progression during or within 3 mos of completing therapy

  4. Prognostic factors at relapse • age • B symptoms • performance status • time to recurrence • anemia • extranodal sites • primary treatment (RT v chemo) … etc

  5. Importance of time to recurrence GHSG: 472 pts with relapse / 4754 Median f/u 45 mos FFTF survival Early (< 1y) 33% 46% Late (> 1y) 43% 79% Josting et al. JCO 2002

  6. Outcome of relapsed HL according to number of risk factors(anemia, early relapse, stage III,IV)

  7. Impact of clinical variables in transplant eligible patients Age <60, KPS 90-100)

  8. Outcome of Patients Experiencing Relapse After ABVD x 2 + RT for Early-Stage Favorable HL • Uncommon occurrence: 3-5% of patients on recent trials of NCIC, GHSG • eg: 42 / 1127 pts on GHSG trials • 8 ref, 7 early, 27 late (>12 m) • Rx: 4 RT, 14 chemo, 24 ASCT

  9. Outcome of Patients Experiencing Relapse After ABVD x 2 + RT for Early-Stage Favorable HL 3y FFTF: 52% 3 y OS : 67% Factors associated with poor outcome: • anemia • advanced stage • early relapse Sieniawski et al. J Clin Oncol 2007

  10. Management of very late relapse • No risk factors (normal hemoglobin, limited stage), CR1 >5 y → chemotherapy + IFRT (EFRT?) • eg BEACOPP x 4 • ASCT reserved for subsequent relapse

  11. Primary Refractory HL • New lesions or progression of prior lesions within 3 months of completing therapy Josting A et al. J Clin Oncol 2000

  12. Outline of this talk • prognostic factors following disease recurrence • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy + rads • second transplants • - reduced intensity allogeneic SCT

  13. Radiation After Relapse – Consider it an Option • radiation as component of combined modality • therapy for HL reduces the risk of local • recurrence • HL often recurs in nodal sites, and in sites not • previously irradiated • long-term disease control has been reported • after RT for recurrent HL after primary • chemotherapy (or CMT) Poen et al. Int J Rad Onc Bio Phys 1996 Mundt et al. Int J Rad Onc Bio Phys 1995

  14. Radiation as Salvage Therapy 1) Josting et al (GHSG): non-randomized: 100 pts 62% advanced HL at dx 68% prior radiotherapy 40% in-field relapse 5 yr FFTF 28% OS 51% 2) Wirth et al (Melbourne): 16 pts - 2 or 3 prior regimens 5 yr FFS 14% OS 38% Favourable outcome: Stage I No B sx 1) J Clin Onc 2005 2) Int J Rad Onc Bio Phys 1997, 2005

  15. Outline of this talk • prognostic factors following disease recurrence • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy + rads • second transplants • - reduced intensity allogeneic SCT

  16. Autologous Stem Cell Transplant in HL • Standard of care for relapsed and/or refractory disease • 2 RCTs demonstrated improvement in 3-year Freedom from Treatment Failure with ASCT vs conventional chemotherapy • Schmitz, Lancet 2002: 75% vs 45% • Linch, Lancet 1993: 55% vs 34%

  17. ASCT dexa-BEAM x 2 + IFRT n=117 FFTF (7 y) OS ASCT 49% 57% Chemo 32% 56% p = 0.02 Autologous stem cell transplantation for relapsed/refractory HL Schmitz et al. ASCO, 2005 dexa-BEAM x 2 R dexa-BEAM x 2 n=161

  18. ?

  19. Long – term outcome: Royal Marsden Hospital 5y 10y PFS 44% 37% OS 55% 49%` Ann Oncol 2008

  20. Multivariate Analysis: Prognosis determined by:sensitivity to salvage chemotherapyHasenclever index

  21. Predictors of outcome post-ASCT for relapsed/refractory HL More favorable outcome Less favorable outcome • CR/PR at ASCT • first remission >1 yr • negative pre-ASCT FDG-PET • resistant to 2nd line chemo • high # HL PI risk factors • multiple relapses • primary refractory HL Gopal AK, et al. Cancer 2008 Sirohi B, et al. Ann Oncol 2008 Wadehra N, et al. Biol Blood Marrow Transpl 2006 Ferme C, et al. J Clin Oncol 2003

  22. PMH: Mobilization and ASCT • PBSC Mobilization • Cyclophosphamide 2 g/m2 on day 1 • Etoposide 200 mg/m2 days 1 – 3 • G-CSF 10 g/kg starting on day 6 • High-dose chemotherapy regimen • Etoposide 60 mg/kg on day -4 • Melphalan 180 mg/m2 on day -3 • Involved field RT given if bulk disease ( 5 cm) present at relapse, 6-8 weeks post-ASCT

  23. Stem Cell Mobilization Efficiency Kuruvilla et al. Cancer 2006

  24. Results – Response and Survival

  25. Progression Free Survival vs Overall Survival 1.0 0.8 0.6 0.4 0.2 0.0 n=323 Probability of Survival Progression Free Survival Overall Survival 0 5 10 15 Time (years)

  26. Causes of Treatment Failure 3 yr 5 yr 10 yr Relapse44% 46% 48% TRM 6% 9% 15% 1.0 0.8 0.6 0.4 0.2 0.0 Failure Rate 0 5 10 15 Time (years)

  27. Competing Risks Analysis 3 yrs 10 yrs Survival 68 % 39 % Failure Free Rate 50 % 40 % Probability of 2nd Cancer 5 % 12% Leukemia 3 % 7 % Solid Tumor 2 % 5 %

  28. ASCT for refractory HL:

  29. Princess Margaret Hospital experience—refractory HL • 157 patients referred for ASCT 1999-2006 • Response rate to salvage therapy • refractory (n=73): 49% vs relapsed (84): 83% (p<.0001) • 3 y FF2TF • refractory 49% vs relapsed 67% (p=0.21) • Overall survival • refractory 75% vs relapsed 91% (p=0.097)

  30. Princess Margaret Hospital experience All patients, from time of treatment failure

  31. Princess Margaret Hospital experience Patients undergoing ASCT, from time of transplant

  32. Outline of this talk • prognostic factors following disease recurrence • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy + rads • second transplants • - reduced intensity allogeneic SCT

  33. Treatment Intensification before ASCT:High-dose sequential therapy PBSC collection DHAP x2 CR PR Cyclo 4 g/m2 + gcsf BEAM ASCT Etoposide 2 g/m2 MTX 8 g/m2 Josting et al Ann Oncol 2005

  34. High-dose sequential therapy: Results DHAP all relapsed refract. n 102 85 17 CR (%) 21 24 12 PR (%) 66 68 53 fail (%) 13 8 35 Post ASCT CR (%) 72 75 53 fail (%) 20 17 41

  35. GHSG-EBMT randomized trial BEAM ASCT HDS: cyclo, MTX,etoposide DHAP x2 CR PR R BEAM ASCT n=284 n=240 3y FFTF PFS OS HDS 67% 69% 83% Standard 71% 72% 84% Hematologica 2009; 94[suppl.2]:204 abstract 0501

  36. Tandem autotransplants for high risk relapsed/refractory HLGELA/SFGM H96 trial • 245 pts 1995-2002 • High risk: refractory or 2 risk factors (early relapse, stage 3 or 4, rel in radiation field) → tandem transplant • Intermediate risk: single risk factor → single transplant

  37. Improvement in outcome with tandem transplant? Morschhauser, JCO 2008

  38. Outline of this talk • prognostic factors following disease recurrence • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy • reduced intensity allogeneic SCT

  39. Systemic Chemotherapy: Single Agent or Combination? Response rate vs. Disease control RR (%) PFS (med) vinca alkyloids 46-59% 6-8 m gemcitabine 22-64% 6-9 m gemcitabine – rituximab 61% 3 m gemcitabine, vinorelbine, PEG-liposomal dox. 75% 8.5 m

  40. Problem with Combination Therapy: Myelosuppression eg) GVD Prior SCT No prior SCT (n = 37) (n = 43) MTD: (mg/m2) Gemcitabine 800 1000 Vinorelbine 15 20 Peg-liposomal-doxorubicin 10 15 Gr 4 neutropenia (%) 24 35 Gr 3/4 platelets 43 14 treatment on schedule, full dose (%) 26 32 response rate (%) 75 61 FS (median) 8.5 --- Bartlett N, et al. Ann Onc, 2008

  41. Outline of this talk • prognostic factors following disease recurrence • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy • reduced intensity allogeneic SCT

  42. Allogeneic Stem Cell Transplantation Following Relapse from ASCT for HL Pro • young patient population – going for cure • HL similar to other indolent B-cell lymphomas • - long survival after relapse • - demonstrated GV–lymphoma effect in CLL, • follicular NHL Con • published data from myeloablative alloSCT: • - high treatment-related mortality • - GVHD, regimen-related • - little impact of GVHD on relapse rate

  43. Myeloablative Allo Transplants After ASCT (IBMTR 1990-99) At 3 yrs: • treatment related mortality 22% (16-31) • relapse risk 52% (43-61) • progression-free survival 25% (18-33) - risk of treatment related mortality higher for unrelated donors Freytes, et al. Blood 2004

  44. Reduced Intensity Regimens: ATG, -CD52 DLI Flu Mel CnI Bu Flu + 2 Gy TBI Flu

  45. Recent Results with Reduced Intensity Allogeneic Transplantation for Relapsed HL Prior Prior regimens Tx-related n ASCT (median) mortality PFS OS Peggs 49 44 5 16 (2 y) 32 (4y) 56 (4 y) Sureda 89 55 85% ≥ 3 23 (1 y) 18 (3 y) 35 (3 y) Alderlini 40 30 5 22 (18 m) 55 (18 m) 61 (18 m) Armand 36 34 4 15 (3 y) 22 (3 y) 56 (3 y) Alvarez 40 29 55% ≥ 3 25 (1 y) 32 (2 y) 48 (2 y) Abbreviations: n: number of allogeneic transplants; ASCT autologous stem cell transplantl PFS: progression-free survival; OS: overall survival

  46. Is there a graft vs. HL effect after RIT? 1) Response to Donor Lymphocyte Infusion DLI after Relapse- Author n chemo Response Free Armand 2008 13 NS 2/13 NS Peggs 2005 16 3 9/16 5/16 Alderlini 2008 14 11 6/14 1/14 2) Decreased relapse, improved PFS with chronic GVHD spontaneous Sureda A, et al. JCO 2008 Armand P, et al. BBMT 2008 and after DLI Peggs KS, et al. Lancet 2005

  47. Conclusions • Outcome of second-line therapy is determined by clinical factors, as much as by treatment • Not to mention biology… • ASCT is the standard of care for all patients (suitable age, PS) with few exceptions • Late relapse, localized… think CMT

  48. Conclusions • Novel agents are currently being tested that may be incorporated into primary or second line treatment • HDAC inhibitors, mTOR, antibody-chemo conjugates… • Reduced intensity transplants need to be evaluated in carefully conducted trials

  49. In summary: An algorithm Relapsed HL post-ASCT Systemic recurrence stage III or IV or relapse in prior radiation field Localized (stage I or IIA) No prior RT Extended field radiation ≤ 6 mos from ASCT ≥ 6 mos From ASCT Clinical trial of new agent Single agent or combination chemotherapy Young good PS HLA matched donor RI allotransplant if response to chemotherapy ASCT (if response, >5 yrs from 1st transplant) Clinical trials of new agent at progression

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