allogeneic stem cell transplant for hodgkins lymphoma

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  1. 1. 2015/8/28 B.S. Andersson Timing of Allogeneic sCT for Hodgkins Lymphoma Borje S. Andersson, MD, Ph.D. Molecular Pharmacology and Translat. Drug Development Program, Department of Stem Cell Transplantation UT MD Anderson Cancer Center August 28, 2015.
  2. 2. Gemcitibine+Busulfan+Melphalan Improve Survival in Refractory Hodgkins Lymphoma Carmustine (BiCNU) Etoposide Cytarabine (Ara-C) Melphalan
  3. 3. -3 -2 -1-4-6 -5 +14 +21 +100 >1800 Graft RIC ? Conditioning Supportive Care GVHD prophylaxis and therapy Patient (age, gender, CMV, comorbidities) 1 2 3 5 6 4 Malignant Disease Features Optimize Therapy to Improve outcome?
  4. 4. Myeloablative allo-SCT in HL 0 10 20 30 40 50 60 70 Early TRM (%) Total TRM (%) PFS (%) OS (%) PD (%) IBMTR JHOC FHCRC
  5. 5. Hodgkin Lymphoma: current issues in allogeneic stem cell transplantation (allo-SCT) Reduced-intensity conditioning (RIC) now widely used. No consensus on optimal regimen. Transplant-related mortality (TRM) low but disease progression (PD) major problem. Patient outcome negatively affected. Recognition of prognostic value of complete response (CR) pretransplant. Availability of brentuximab vedotin and optimization of its use.
  6. 6. G-FM140: treatment schema G8: Gemcitabine 800 mg/m2; ADM: Hospital admission; F= Fludarabine 33 mg/m2; M = Melphalan 70 mg/m2; T= Thymoglobulin 2 mg/kg (MUDs/MM); SCT: stem cell transplant; GVHD prophylaxis: tacrolimus miniMTX. DAYS -7 -1-6 -5 -4 -3 -2 0 F F F F M M SCTRest TT ADMG
  7. 7. Patient Characteristics Total N=27 Age a 31 (20-46) Gender 15 M / 12 F Prior chemotherapy regimensa 4 (2-10) Prior autologous SCTb, n (%) 19 (70%) Donor type Matched related Matched unrelated 16 (60%) 11 (40%) Response status at allo-SCT, n (%) CR/CRu 17 (63%) PR 9 (33%) Other 1 (4%) TTP after autologous SCT (mo) 5 (1-68) a Median (range). SCT: stem cell transplant; TTP: time to progression. CR/CRu: complete response/undetermined. PR: partial response.
  8. 8. Brentuximab Vedotin (BV) SGN-35 antibody-drug conjugate CD30-targeted antibody (cAC10) conjugated to an auristatin (MMAE), an anti-tubulin agent Selectively induces apoptosis in HL and ALCL cells: Binds to CD30 Becomes internalized Releases MMAE SGN-35 Antibody-Drug Conjugate SGN-35 binds CD30 Endocytosis ADC traffics to lysosome Enzymatic linker cleavage releases MMAE from ADC MMAE binds tubulin G2/M cell cycle arrest & apoptosis CD30 SGN-35 Antibody-Drug Conjugate SGN-35 binds CD30 Endocytosis ADC traffics to lysosome Enzymatic linker cleavage releases MMAE from ADC MMAE binds tubulin G2/M cell cycle arrest & apoptosis CD30 BV was granted accelerated approval by the FDA in Aug 2011 Courtesy of Dr. A. Younes
  9. 9. PFS by Best Response (by PET/CT) - HL Time (months) %PatientsFreeofPDorDeath
  10. 10. Brentuximab (BV)-treated vs BV- nive: Complete Response (CR) rates The seven patients who received BV as last line of tx prior to allo-SCT are a/w in CR/CRu BV-treated n=14 n (%) BV-nive n=13 n (%) Total N=27 p value CR rate pre-allo SCT 11/14 (79%) 6/13 (46%) 0.12 (Fishers) CR-rate post-allo SCT 12/14 (85%) 11/13 (85%) ns
  11. 11. Patient outcomes Six deaths, three early ones (< day 100). Causes of death: PD n=2, graft rejection n=1, pneumonia n=2, respiratory failure n=1. 21 patients alive. TRM (day 100/overall): 15%. Acute GVHD (grade II-IV): 19% (95% CI 9-42). Chronic GVHD: 39% (95% CI 24-65). Median follow up: 18 months (4-55). PD: progressive disease. TRM: Transplant-related mortality
  12. 12. Overall survival (OS) and progression-free survival (PFS) 0 10 20 30 40 50 60 Months Post Transplant 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 CumulativeProportionSurviving OS PFS 69% 55% N= 27
  13. 13. Disease progression (PD) Median time to PD: 13 months (2-22) 0 3 6 9 12 15 18 21 24 Months Post Transplant 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 CumulativeIncidenceofDiseaseProgression 30% (95% CI 15-61)
  14. 14. FM140 vs G-FM140 comparison a Haematologica 2008; 93:257 b Study group included patients (n=28) with < PR Variable FM140a n=58 n (%) G-FM140 n=27 n (%) Age (yrs) 32 (19-59) 31 (20-46) Brentuximab vedotin pre-SCT (Y/N) 0 / 58 14 / 13 CR/CRu pretransplant 24%b 63% TRM (day 100/overall) 7% / 15% 15% / 15% OS (2-year) 64% 78% PFS (2-year) 32% 55% PD (2-year) 55% 30% Time to PD after allo-SCT (mo) 4.5 (1-35) 13 (2-22)
  15. 15. Progression-Free Survival after RIC Matched Sib SCT Hodgkins lymphoma, N. America - by disease status - CR Resistant PR n = 87
  16. 16. Summary Even in the face of refractory relapse or relapse after a previous auto-SCT, allo-SCT may yield long-term disease control in Hodgkins Lymphoma. The outcomes with RIC-conditioning is becoming the preferred choice. The relatively high TRM-risk suggests that auto-SCT should still be the preferred initial choice for most patients with recurrent HL