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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 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 • role of local radiotherapy • current results with ASCT • strategies to improve ASCT outcome • standard approaches – chemotherapy • second transplants • - reduced intensity allogeneic SCT
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
Prognostic factors at relapse • age • B symptoms • performance status • time to recurrence • anemia • extranodal sites • primary treatment (RT v chemo) … etc
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
Outcome of relapsed HL according to number of risk factors(anemia, early relapse, stage III,IV)
Impact of clinical variables in transplant eligible patients Age <60, KPS 90-100)
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
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
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
Primary Refractory HL • New lesions or progression of prior lesions within 3 months of completing therapy Josting A et al. J Clin Oncol 2000
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
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
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
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
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%
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
Long – term outcome: Royal Marsden Hospital 5y 10y PFS 44% 37% OS 55% 49%` Ann Oncol 2008
Multivariate Analysis: Prognosis determined by:sensitivity to salvage chemotherapyHasenclever index
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
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
Stem Cell Mobilization Efficiency Kuruvilla et al. Cancer 2006
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)
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)
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 %
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)
Princess Margaret Hospital experience All patients, from time of treatment failure
Princess Margaret Hospital experience Patients undergoing ASCT, from time of transplant
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
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
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
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
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
Improvement in outcome with tandem transplant? Morschhauser, JCO 2008
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
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
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
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
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
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
Reduced Intensity Regimens: ATG, -CD52 DLI Flu Mel CnI Bu Flu + 2 Gy TBI Flu
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
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
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
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
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