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Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD

Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD. Allogeneic Marrow Transplantation. Treatment of choice for selected high-risk patients with: Acute Leukemia (ALL, AML) Chronic Leukemia (CML, CLL) Follicular Lymphomas Aplastic Anemia

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Cord Blood v s. Unrelated Donor Transplantation Elizabeth J. Shpall , MD

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  1. Cord Blood vs. Unrelated Donor Transplantation Elizabeth J. Shpall, MD

  2. Allogeneic Marrow Transplantation • Treatment of choice for selected high-risk patients with: • Acute Leukemia (ALL, AML) • Chronic Leukemia (CML, CLL) • Follicular Lymphomas • Aplastic Anemia • Several Genetic and Immunologic Diseases • Less than 30% of patients have a related donor • Increasing use of unrelated and cord blood donors

  3. Potential Advantages of Cord Blood • Procurement non-invasive • Expanded donor pool: minorities targeted • Immediate availability (overnight shipping) • Requires less stringent HLA matching(4/6, 5/6) • Less GVHD than marrow transplants

  4. NMDPTransplants by Cell Source 1988–2010 4

  5. M. D. Anderson BMT Department Minority Allo-transplants by Stem Cell Source 59% 25% N=3038 Bone marrow Peripheral blood Transplants Year 1980 - 2003 N=280 Cord blood transplants Year 1996 - 2010

  6. Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia Eurocord data compared to EBMTR data on MUD bone marrow transplants Cord blood n = 98 Bone marrow n = 584 HLA matching Cord blood: 94% with at least one mismatch Bone marrow: 100% matched Median cell dose Cord blood: 0.23 x 108 Bone marrow: 2.9 x 108 Rocha, V. et al. N Engl J Med 2004;351:2276-2285

  7. Adult Single MyeloablativeCB

  8. MyeloablativeCBT For AML/ ALL (CR1/ 2): Survival Relapse 1.0 0.8 p = 0.05 0.6 Single 30% (16 - 44%) 0.4 Double 9% (0 - 21%) 0.2 1.0 0.0 0 4 8 12 16 20 24 Months I I I 0.8 I I I I I I I I I I I I I I I I I I I I I I Doubles (n = 29) 72% (56 - 88%) 0.6 Probability I I I I I I I I Singles (n = 67) 47% (51-75%) 0.4 0.2 p = 0.16 0.0 0 1 2 3 Years Verneris et al, Blood 2005, 106; 93a

  9. Non-Myeloablative Conditioning Cyclosporine Tacrolimus Tacrolimus Tacrolimus Sirolimus MMF Fludarabine 30 mg/m2/d ATG 1.5 mg/kg/d Melphalan 100 mg/m2/d

  10. 1.0 0.8 I I I 45% (95%CI 36-54) I I I I I I I I I 0.6 I I I I I I I I I I I I I I I I I I I I I I I Cumulative Proportion I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 0.4 0.2 0.0 0 1 2 3 4 5 Years Promising Overall Survival after NonmyeloablativeCB Transplantation Brunstein et al. Blood 2007

  11. Methods-Eapen et al • Explored whether there were survival differences by conditioning regimen within each graft source: • survival after dCB with TBI200/Cy/Flu ± ATG vs. dCB with other regimens • No differences in the PB group • Therefore 4 treatment groups were created: • MUD (8/8 allele matched unrelated donor) • MMUD (7/8 allele matched unrelated donor) • dCB, TCF • dCB, other

  12. Patient Characteristics

  13. Disease Characteristics

  14. Conditioning Regimens

  15. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Neutrophil Recovery MUD: 96% MMUD: 95% dCB, TCF: 83% Cumulative Incidence, % dCB, other: 83% P=0.0007 0 7 14 21 28 35 42 Days Fk10_54.ppt

  16. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Platelet Recovery MUD: 90% MMUD: 89% dCB, TCF: 66% Cumulative Incidence, % dCB, other: 58% P <0.0001 0 1 2 3 4 5 6 Months Fk10_53.ppt

  17. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Grade 3-4 Acute GVHD P=NS Cumulative Incidence, % dCB, TCF: 17% MMUD: 22% dCB, other: 18% MUD: 13% 0 1 2 3 4 5 6 Months Fk10_51.ppt

  18. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Chronic Graft vs. Host Disease P<0.0001 MUD: 56% Cumulative Incidence, % MMUD: 54% dCB, other: 36% dCB, TCF: 34% 0 6 12 18 24 30 36 Months Fk10_50.ppt

  19. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Leukemia-Free Survival P=0.017 Probability, % dCB, TCF: 26% MUD: 31% MMUD: 25% dCB, other: 9% 0 6 12 18 24 30 36 Months Fk10_49.ppt

  20. Double CBT LFS is comparable to MRD and MUDFred Hutchison Ca Center and Univ Minnesota P<0.01 P=NS MRD p<0.01 MUD p=0.13 MMUD p<0.01 N=536 CBT 128 MRD 204 MUD 152 MMUD 52 Brunstein and Delaney, Blood 2010

  21. Disadvantages of Cord Blood vs. Bone Marrow or Peripheral Blood Progenitor Cell (PBPC) Transplantation • Low Cell Dose • Delayed Engraftment • Delayed Immune Reconstitution • Increased Graft Failure • PBPC remains the “gold standard” against which performance of CB compared: • Neutrophil engraftment (>500/µl) 11 days • Platelets engraftment (>20,000/µl) 13 days • Engraftment failure rate <1%

  22. Mesenchymal Stem Cells (MSC) • MSC are a stromal component • of the hematopoietic microenvironment. • They provide cellular and extracellular components of the stem cell “niche”. • When isolated and used in vitro • in combination with cytokines, MSC markedly increase the expansion of CB hematopoietic progenitors.

  23. M. D. Anderson CB Expansion Trial with “off-the-shelf” Angioblast MPC (N=24) Single vial of Angioblast MSC Frozen CB unit Day 14: Non-adherent cells washed and infused CB MNC thawed and washed Day 7-14 culture SCF G-CSF Flt-3L TPO 1 liter 10 bags T150 Day 1- 7 co-culture 10 flasks + 4 days 14 day ex vivo expansion culture

  24. MSC-CB Expansion Trial Day 0 Infuse unmanipulated CB unit AND Ex vivo expanded CB unit GvHD Prophylaxis: Tacrolimus and MMF

  25. MSC-CB Expansion Trial Engraftment Data Median time to engraftment (range) Neutrophil (>500/µl) 15 days (range 9-42) Platelet (>20,000/µl) 40 days (range 13-62) Cumulative Incidence of Engraftment Neutrophil (>500/µl) 97% (n=31) Platelet (>20,000/µl) 81% (n=26) - One patient died before engraftment de Lima et al. Blood (ASH Annual Meeting Abstracts), 2010; 116: 362

  26. Cumulative Incidence of Neutrophil Recovery 100 80 Angioblast (@26 days, 88%, N=24) 60 Cumulative Incidence (%) CIBMTR (@26 days, 53%, N=80) 40 20 @26 days P<0.0001 0 0 6 12 18 24 30 36 42 Days after Transplant M. Horowitz et al.

  27. Cumulative Incidence of Platelet Recovery 100 @26 days P=0.0008 80 60 Cumulative Incidence (%) Angioblast (@60 days, 67%, N=24) 40 20 CIBMTR (@60 days, 31%, N=80) 0 0 6 12 18 24 30 36 42 48 54 60 Days after Transplant M. Horowitz et al.

  28. Obstacles to Successful Outcomes after Cord Blood Transplantation: GVHD • Potential Solution: • Cord Blood Regulatory T cells (Tregs) co-expressing CD4/CD25 have been shown to inhibit alloreactive T cell function • We hypothesized that prophylactic infusion of 3rd party CB Tregs would abrogate GVHD

  29. CD4+25+ CB cells isolated magnetically and cultured with IL2 and • Xcyte Bead CD3/28 co-expression (cell: bead=1:3) or • Clone 4 K562-APCs (cell:bead=1:4) OKT3 IL-15 CD64 CD69 CD187c APC Parmar et al. CD86

  30. Expanded CD25+ cells show phenotype consistent with Tregs

  31. Ex vivo expanded CB Tregs reduce GVHD and enhance survival in mice Log rank test Treg+PBMC p < 10-4 PBMC alone Parmar et al. Days post Transplant

  32. NO Treg WITH Treg LUNG LIVER Recipients of Tregs do not show signs of GVHD – Parmar et al. A clinical trial with CB Tregs is being designed NO Treg WITH Treg

  33. Obstacles to Successful Outcomes after Cord Blood Transplantation: Relapse • Large granular lymphocytes, comprising 10-15% of all peripheral blood lymphocytes • CD56+CD3- • Have the ability to directly kill target cells in an MHC-independent manner • GVL without GVH

  34. Potential Solution:Expansion of CB-NK cells Nina Shah et al

  35. CB-derived NK Cells can kill Primary CLL Cells in vitro – Bollard Laboratory

  36. Specific cell populations will be generated in the GMP Lab: Tumor- Specific CB NK cells Viral-Tumor Specific CB T cells CB#2 CB#1 B Cell Myeloid Tumors CB Tregs MSC-Expansion +/- FTVI for neut and plat engraftment AdenoCMV EBV -6 -5 -4 -3 -2 -1 0 30 100 Future Directions: Cord Blood Transplantation in the Next 5 Years

  37. Acknowledgements Richard Champlin Marcos de Lima Elizabeth Shpall Laurence Cooper Frank Marini John McMannis Simrit Parmar Chitra Hosing Nina Shah Borje Andersson Michael Andreeff Simon Robinson Steven Kornblau Sergio Giralt Hong Yang Roy Jones Peter Thall Dongxia Xing Martin Korbling Paolo Anderlini William Decker Amin Alousi Issa Khouri Michael Thomas Naoto Ueno Jeffrey Molldrem Patrick Zweideler Partow Kebriaei Muzaffar Qazilbash Tara Sadeghi Laura Worth Demetri Petropoulos Indreshpal Kaur Mark Munsell Marcelo Fernandez-Viña Sufang Li Jingjing Ng Ping Fu Jared Burks Doyle Bosque Lori Griffin Susan Kelly Gabriela Rondon Rima Saliba Sufira Kiran Catherine Bollard Gianpietro Dotti Ann Leen Barbara Savoldo Mary Horowitz Mary Eapen Funding NCI : R01- CA061508 NCI : PO1- CA148600 CPRIT: RP100469 CPRIT: RP 100430 CLL Global Research Found HRSA: 234200737 Ian McNiece Krishna Komanduri Paul Simmons Natalie Brouard

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