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How do transplants fit in the current therapeutic schema?

How do transplants fit in the current therapeutic schema?. Guenther Koehne, MD, PhD Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York. Autologous SCT. Who? When? How? Maintenance?.

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How do transplants fit in the current therapeutic schema?

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  1. How do transplants fit in the current therapeutic schema? Guenther Koehne, MD, PhD Adult Bone Marrow Transplant ServiceDivision of Hematologic OncologyDepartment of MedicineMemorial Sloan-Kettering Cancer CenterNew York, New York

  2. Autologous SCT Who? When? How? Maintenance? Allogeneic SCT Who? When? How? Maintenance?

  3. Multiple Myeloma Treatment Lines in Transplant-Eligible Patients Frontline treatment Maintenance Relapsed Induction Consolidation Conditioning? Maintenance Rescue Bz/Dex Bz/Dex/Dox Bz/Thal/Dex Len/Dex Rev/Len/Dex CRd Observation Thal Thal/Pred Rev SCT

  4. CurrOpinOncol, Sept 2012

  5. Allogeneic Transplantation for Multiple Myeloma • Treatment with curative potential • Lack of myeloma cell contamination in graft • Graft vs. myeloma effect • Reserved for fit patients • Conventional/Myeloablative studies: TRM >50% • Non-myeloablative transplants – BMT CTN #0201 • No clear survival benefit • High rate of acute and chronic GVHD GVHD, graft versus host disease; TRM, transplant-related mortality.

  6. Allogeneic Vs. Autologous US intergroup trial (S9321) n=39 <55 years HLA matched sibling n= 36 Mel/TBI allotransplant GVHD prophylaxis x N = 813 Induction Therapy VAD n=213 HDT Mel/TBI autotransplant TRM:53% n=261 HD-CTX collection RANDOMI ZE N=255 HD-CTX collection n=211 SDT VBMCP autotransplant HD-CTX, high-dose cyclophosphamide; HDT, high dose therapy; HLA, human leukocyte antigen; MEL, melphalan; SDT, standard dose therapy; TBI, total body irradiation; VAD, continuous infusion of vincristine and doxorubicin plus high-dose dexamethasone; VBMCP, vincristine, carmustine, melphalan, cyclophosphamide, and prednisone. Barlogie B, et al. J ClinOncol. 2006; 24:929-936.

  7. Summary of Recent Studies With Non-Myeloablative Conditioning for Multiple Myeloma FC, fludarabine plus cyclophosphamide; FLU, fludarabine; HR, high risk; OS, overall survival; PFS, progression-free survival; SR, standard risk. Koehne G, Giralt S. CurrOpinOncol. 2012;24:720-726.

  8. Allogeneic SCT Who? Risk stratification based on high-risk factors When? Sooner than later How & Where? TCD HSCT & MSKCC Maintenance? Immunotherapeutic Approaches

  9. Approaches to Allogeneic SCT for High-Risk Multiple Myeloma Induction Consolidation/ Conditioning Maintenance Relapse # lines of treatment VDT-PACE 2nd salvage auto SCT Upfront Induction Auto SCT 1. Immunotherapy DLI Antigen-specific CTLs TCD HSCT 2.

  10. Cytogenetics and Disease • High-risk cytogenetics: 25% of patients • Deletion 17p: del(17p) • 10% of newly diagnosed patients • Associated with aggressive disease and shorter overall survival • No conclusive evidence that any currently available treatments are effective for patients with del17p • Translocation of the immunoglobulin heavy chain (IgH) locus on chromosome 14 • t(4;14); t(14;16) • Deletion 13q: del13q • Related to association with t(4;14) and del17p • Hypodiploidy High risk disease affects outcome and should therefore affect treatment

  11. Current Study at MSKCC: TCD HSCT for Multiple Myeloma – IRB #10-051 • Phase II study of TCD Allogeneic Transplantation for High-Risk Multiple Myeloma • Principle Investigator: Guenther Koehne MD, PhD • Eligibility Criteria: • Relapsed multiple myeloma following ASCT High risk cytogenetics or relapse ≤ 15 months postASCT At least PR to salvage therapy • Conditioning: Bu/Mel/Flu (+ ATG) • TCD: CliniMacsdevice: CD34+ cells positively selected ASCT, allogeneic hematopoietic stem cell transplantation; ATC, antithymocyte globulin; Bu: busulfan; FISH, fluorescent in situ hybridization; IRB, internal review board; MSKCC, Memorial Sloan-Kettering Cancer Center; TCD, T-cell depleted, VGPR, very good partial response.

  12. Design of Study: TCD (CD34+ selection) HSCT for Multiple Myeloma Busulfan:0.8 mg/kg x 10 doses Melphalan:70 mg/m2 x 2 doses Fludarabine:25mg/m2x 5 d ATG: 2.5 mg/kg x 2 d • DLI (5x105 CD3+/Kg) at earliest 5-6 months post SCT • DLI (5x105 CD3+/Kg) at earliest 8-9 months post SCT • DLI (1x106 CD3+/Kg) at earliest 12-13months post SCT Prophylactically in recipients of HLA-matched allografts • DLI (1x105 CD3+/Kg) at earliest 5-6 months post SCT • DLI (5x105 CD3+/Kg) at earliest 1-3months post SCT, following the first infusion • DLI (1x106 CD3+/Kg) at earliest 3-4months post SCT, following the second infusion Preemptively in recipients of HLA-mismatched allografts DLI, donor lymphocyte infusion. Courtesy of Koehne G, et al. MSKCC.

  13. Acute GVHD (grade II – IV) at 12 months (N = 34) Transplant-related Mortality (at 12 months) (N = 34) 0.06 (0.01-0.17) 0.09 (0.02-0.23) Courtesy of Koehne G, et al. MSKCC.

  14. Chronic GVHD Graft failure or rejection None observed Courtesy of Koehne G, et al. MSKCC.

  15. OS + PFS of pts with multiply relapsed MM following allo TCD HSCT(N=34) Among survivors, median f/u is 44 mos (range: 18-79) 07/2014 Courtesy of Koehne G, et al. MSKCC.

  16. OS (a) + PFS (b) of pts with multiply relapsed MM by previous lines of therapy prior to allo TCD HSCT a. b. p = 0.02 p = 0.05 Courtesy of Koehne G, et al. MSKCC.

  17. OS (a) and PFS (b) of pts with multiply relapsed MM with < 6 previous lines of therapy prior to allo TCD HSCT based on donor selection(related vs. unrelated) a. b. At 2yrs Related: 0.60 (0.36-0.99) Unrelated: 0.72 (0.51-0.99) At 2yrs Related: 0.30 (0.12-0.77) Unrelated: 0.36 (0.17-0.76) Courtesy of Koehne G, et al. MSKCC.

  18. OS (a) + PFS (b) of pts with multiply relapsed MM by previous lines of therapy prior to allo TCD HSCT G. Koehneet al. MSKCC.

  19. Clinical responses induced by Bu/Mel/Flu conditioning chemotherapy

  20. Clinical responses induced by Bu/Mel/Flu conditioning chemotherapy

  21. Clinical responses after initial DLIs (when receiving at least 2 doses) given for relapsed or residual MM

  22. Single Patient Response DLI 5x10e5/kg 06/09 July -1, 2014 39-year-old male dx stage III IgA lambda, multiple myeloma (MM) high-risk cytogenetics (del 13; t(4;14). Bortezomib /Dexamethasone (Dex) x 6, autoSCT9/07 with relapse disease 12/07, Lenalidomide/Dexx1, Bort/Dex x2, alloHSCTfrom matched related donor (10/10) in 06/08, in complete remission (CR) since 5/09. 65 months in CR 72 months post allo BMT

  23. DLI and Disease Course DLI 5x10e5/kg Allo BMT DLI 5x10e5/kg DLI 1x10e6/kg 55-year-old male dx stage III IgG lambda, MM high-risk cytogenetics(del 17p by FISH, del 13q by karyo). Thalidomide/Dex x 4 months with PD + ARF, Bort–MI–CAGB with EF 35%, VP-16 + cyclophosphamide (CY) with PR, auto SCT 08/07 with relapse disease 08/08, VAD with PD, VP-16 + CY x 3, allo HSCT from matched unrelated donor (10/10) in 03/09.

  24. WT1-Specific T-Cell Responses in Patients with Multiple Myeloma • 04/09 Blood 01/11 Bone Marrow 01/11 4/2/09 WT1-specific T cells by MHC tetramer 3.5% 1.0 % 2.9 % CD8+ A2-RMF A2-RMF CD8+ A24-CMV A2-RMG, HLA-A2 restricted peptide; CMB, cytomegalovirus; MHC, major histocompatibility complex; WT1, Wilms tumor gene product 1. Tyler EM, et al. Blood. 2013;121:308-317.

  25. WT1—A Potential Target for Multiple Myeloma? • WT1: zinc finger transcription factor • Roles in cell proliferation, differentiation, apoptosis and organ development • Preferentially expressed during embryogenesis, but also at low levels in kidney, ovary, endometrium, testis and spleen of adults • Frequently overexpressed in a number of solid and hematologic malignancies • Expression correlates with disease progression in MDS, ALL, & CML • Molecular marker for risk assessment • Emergence of WT1-specific T cells correlates with better relapse-free survival post allogeneic transplant in leukemia1 • MM cells are efficiently lysed by WT1-specific cytotoxic T lymphocytes2 • WT1 expression in the BM of myeloma patients correlates with disease stage3 ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome. 1. Rezvani K, et al. Blood. 2007;110:1924-1932; 2. Azuma T, et al. Clin Cancer Res. 2004;10:7402-7412; 3. Hatta Y, et al. J ExpClin Cancer Res. 2005;24:595-599.

  26. WT1-Specific T Cells and Disease Course

  27. WT1-Specific T Cells and Disease Course DLI 5x10e5/kg Allo BMT DLI 1x10e6/kg DLI 5x10e5/kg 55-year-old male dx stage III IgG lambda, MM high risk cytogenetics (del 17p by FISH, del 13q by karyo). Thal/Dex x 4 months with PD + ARF, Bort– MI – CAGB with EF 35%, VP-16 + CY with PR, auto SCT 08/07 with relapse disease 08/08, VAD with PD, VP-16 + CY x 3, alloHSCT from MUD (10/10) in 03/09.

  28. WT1-Specific T Cell Frequencies Increase in All Patients Following DLI • Max response to DLI: 47 WT1-specific T cells/μL blood • 6.6-fold increase over pre-DLI frequencies • Results from the selective expansion of WT1-specific T cells rather than general immune reconstitution Figure 1. WT1-specific T-cell numbers and function increase following transplant and DLI. Tyler EM, et al. Blood. 2013;121:308-317.

  29. IHC With WT1 mAb 6F-H2 WT1 (red) co-staining of kidney biopsy CD138 (brown) staining of BM biopsy CD138 (brown)/ WT1 (red) co-staining of BM biopsy BM, bone marrow; IHC, immunohistochemistry.Tyler EM, et al. Blood. 2013;121:308-317.

  30. IHC Analyses of WT1 Expression in the BM of MM pts CD138 (MI15; DAB) = brown; WT1 (6F-H2, nFu) = red ++++ +++ ++ 90% PC’s by biopsy 50 -60 % PC’s by biopsy 45% PC’s by biopsy Grading Neg 0 Focal < 5% + < 25% ++ 25 – 50% +++ 50 – 75% ++++ > 75% Focal Negative 5% PC’s by biopsy No PC’s by biopsy DAB 3,3-diaminobenzidine; nFU, nFu1 antibody; PC, plasma cell. Tyler EM, et al. Blood. 2013;121:308-317.

  31. Phase I Trial #IRB 12-175:TCD (CD34+ selection) Allo SCT Followed by WT1-Specific T-Cell Infusions for Patients With Relapsed/Refractory Multiple Myeloma or Plasma Cell Leukemia Busulfan:0.8 mg/kg x 10 doses Melphalan:70 mg/m2 x 2 doses Fludarabine:25mg/m2x 5 d ATG: 2.5 mg/kg x 2 d WT W WT1-specific CTLs • WT1 CTLs - Dose levels 1, 3 and 5 x10e6/kg; • -3 doses/recipient of HLA-matched and HLA-mismatched allografts. • First dose at 6-10 weeks post transplant. • The second dose will be given 4-8 weeks following the first infusion and a third dose will be administered 4-8 weeks following the second infusion. • The second and third dose will only be administered in the absence of grade III-IV toxicity and grade II-IV acute GvHD following the preceding T-cell dose. CTL, cytotoxic T lymphocytes. Courtesy of Koehne G, et al. MSKCC.

  32. Plasma Cell Leukemia Overall Survival (OS) in pPCL and sPCL, showing superior survival of pPCL vs sPCL from the time of leukemia diagnosis. pPCL, primary plasma cell leukemia; sPCL, secondary plasma cell leukemia. Albarracin F, Fonseca R. Blood Rev. 2011;25:107-112.

  33. Case―61-Year-Old AA Female With Secondary Plasma Cell LeukemiaUndergoing TCD HSCT Followed by WT1 CTLs Residual Disease Post VDT-PACE, but HLA-Matched Brother TCD HSCT 02/13/12 WT1 #1 1x10e6/kg 04/18/12 WT1 #2 1x10e6/kg 05/16/12 WT1 #3 1x10e6/kg 06/13/12

  34. Immune Reconstitution Post-WT1-CTL Infusions WT1 all pools 6/13/12 IFN-γ CD8 IFN-γ CD4 TCD HSCT 02/13/12 TCD HSCT 02/13/12 WT1 #1 1x10e6/kg 04/18/12 WT1 #1 1x10e6/kg 04/18/12 WT1 #2 1x10e6/kg 05/16/12 WT1 #2 1x10e6/kg 05/16/12 WT1 #3 1x10e6/kg 06/13/12 WT1 #3 1x10e6/kg 06/13/12

  35. WT1 CTLs + Disease Course M-Spike Gamma # Feb 2014 WT1 #1 1x10e6/kg 04/18/12 WT1 #3 1x10e6/kg 06/13/12 WT1 #2 1x10e6/kg 05/16/12 WT1 #4 5x10e6/kg 09/26/12 WT1 #5 5x10e6/kg 11/02/12 WT1 #6 5x10e6/kg 12/05/12 TCD HSCT 02/13/12 Kappa: Lambda Ratio # Feb 2014 WT1 #3 1x10e6/kg 06/13/12 WT1 #5 5x10e6/kg 11/02/12 WT1 #6 5x10e6/kg 12/05/12 WT1 #1 1x10e6/kg 04/18/12 WT1 #2 1x10e6/kg 05/16/12 WT1 #4 5x10e6/kg 09/26/12

  36. IHC With CD138 + WT1 mAb 6F-H2 Post allo BMT + WT1 CTL #1 05/16/12 Relapse 11/11

  37. WT1 CTLs + Disease Course

  38. Future Approaches to Treatment for High-Risk Multiple Myeloma 1. Induction Conditioning Maintenance Relapse Upfront Suicide-gene modified DLI WT1-specific CTLs TCD HSCT Do we need an auto SCT? CRD x 6 cycles TCD HSCT WT1 CTLs ? 2. Do we need an allo SCT? Induction auto SCT MM-specific CARS? 3.

  39. Acknowledgement • Research Team • Eleanor Tyler, PhD, Cornell Weill College • Achim Jungbluth, MD, Pathology, MSKCC • Denise Frosina, Senior Research Technician • Sean Devlin, PhD, Biostatistics, MSKCC • Evelyn Orlando, RSA • Eric Smith, MD, PhD • Satya Kosuri, MD Myeloma Service Heather Landau MD Hani Hassoun MD Alex Lesokhin MD Nikoletta Lendvai MD PhD David Chung MD, PhD Sergio Giralt MD Ola Landgren, MD Adoptive Immune Cell Therapy Facility (AICT lab) Ekaterina Doubrovina MD PhD Richard O’Reilly, MD Otsuka Pharmaceutical Co, Ltd – for generous research support

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