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Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies. Xiao-Jun Huang M.D. Ph.D. Peking University Institute of Hematology, Peking University People’s Hospital & Beijing Key Laboratory of HSCT, Beijing, P.R.China. Clinic. Research. Education. 1.

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Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies

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  1. Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies Xiao-Jun Huang M.D. Ph.D. Peking University Institute of Hematology, Peking University People’s Hospital & Beijing Key Laboratory of HSCT, Beijing, P.R.China

  2. Clinic Research Education 1

  3. The Cumulative Hematopoietic Stem Cell Transplantation (HSCT) Cases of PUIH • PUIH • The Largest HSCT center in Asia • Now >400 cases of HSCT per year • Now >60% Allo-HSCT cases are Unmanipulated Haploidentical HSCT 24%

  4. Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies 1 • In vitro T-cell-depleted HSCT 2 • Non-Myeloablative Haploidentical HSCT 3 • Unmanipulated Myeloablative Haploidentical HSCT Current Clinical Results Strategy to Improve the Clinical Results

  5. 3. Unmanipulated Haploidentical HSCT GIAC protocol • G: donor treatment with rhG-CSF • I: intensified immunological suppression • A: anti-human thymocyte immunoglobulin (ATG) for the prevention of GVHD • C: combination of G-PB and G-BM Huang XJ, et al. Blood, 2006, 107(8):3065-3073 Huang XJ, et al. Annals of Medicine, 2008, 40,444-455 Huang XJ, et al. Clin Cancer Res. 2009;15:4777-4783 Huang XJ, et al. BBMT. 2011 Jun;17(6):821-30.

  6. Effects of G-CSF on Bone Marrow in Healthy Donors 3. Unmanipulated Haploidentical HSCT HuangXJ, et al. Clin Transplant 2011: 25: 13–23

  7. 3. Unmanipulated Haploidentical HSCT Immunoregulatroy Effects after G-CSF Administration to Healthy Donors Huang XJ, et al. Biol Blood Marrow Transplant.2011;17(2):197-204

  8. 3. Unmanipulated Haploidentical HSCT Engraftment n=348 n=348 CD34+ cells≥2.19×106/kg Early stage Advanced stage CD34+ cells<2.19×106/kg P=0.008 P<0.0001 Huang XJ, et al. Biol Blood Marrow Transplant,2009, 15(5):632-8

  9. 3. Unmanipulated Haploidentical HSCT Characteristics of the Allo-Grafts Huang XJ, et al. Bone Marrow Transplant, 2006, 38:291

  10. 3. Unmanipulated Haploidentical HSCT Cumulative incidence of aGVHD after HLA-mismatched allo-HSCT Haplo=81 Identical=36 P=0.11 Huang XJ, et al. Biol Blood Marrow Transplant 2009, 15(2) Huang XJ, et al. Biol Blood Marrow Transplant 2011; 17(6)

  11. Probability of aGVHD with locus disparity 3. Unmanipulated Haploidentical HSCT Huang XJ, et al. Bone Marrow Transplant. 2006;38(4):291-7.

  12. 3. Unmanipulated Haploidentical HSCT DFS & OS compared with HLA Matched Donor OS LFS Huang XJ, et al. Blood, 2006, 107(8):3065-3073

  13. 3. Unmanipulated Haploidentical HSCT Relapse compared with Unrelated Donor（URD） PMRD=219 URD=78 PMRD=160 URD=60 Huang XJ, et al. Clin Cancer Res, 2009, 15:4777-4783

  14. 3. Unmanipulated Haploidentical HSCT Relapse compared with Identical Sibling（ISD） Haplo=81 Identical=36 HuangXJ, et al. Biol Blood Marrow Transplant. 2011;17(6)

  15. 3. Unmanipulated Haploidentical HSCT OS & DFS compared with ISD Haplo=81 Identical=36 PMRD=81 ISD=36 P = 0.029 P = 0.048 HuangXJ, et al. Biol Blood Marrow Transplant. 2011;17(6)

  16. 3. Unmanipulated Haploidentical HSCT > Haploidentical HLA-identical sibling Superior Graft-versus-Leukemia effect High risk acute leukemia HuangXJ, et al. Biol Blood Marrow Transplant. 2011 ;17(6):821-30

  17. No. of Haploidentical HSCT accumulated in PUIH 3. Unmanipulated Haploidentical HSCT PUIH data

  18. 3. Unmanipulated Haploidentical HSCT The changing of Composition of Haploidentical allo-HSCT in PUIH from 2007 to 2009 PUIH data

  19. Studies on HLA-mismatched/haploidentical stem cell transplantation (GIAC)

  20. 3. Unmanipulated Haploidentical HSCT Composition of HSCT Donor Types in 24 Transplant Units in China PUIH collected

  21. 3. Unmanipulated Haploidentical HSCT Part I Conclusions • G-BM combined with PBSC from haploidentical family donors, without in vitro TCD, may be used as a good source of stem cells for allo-HSCT • There is no difference in OS and LFS between patients receiving allografts from PMRD and URD Huang XJ, et al. BMT, 2006, 38:291 Huang XJ, et al. Blood, 2006, 107(8):3065-3073 Huang XJ, et al. Clin Cancer Res, 2009, 15: 4777-4783 Huang XJ, et al. BBMT. 2011 Feb;17(2):197-204

  22. 3.Unmanipulated Haploidentical HSCT Huang XJ, et alUnpublished，Blood Reversed

  23. 3. Unmanipulated Haploidentical HSCT Part II：Strategy to Improve the Clinical Results 1 • Modified Donor Lymphocyte Infusion(DLI) 2 • Manipulating the Graft 3 • Optimize KIR ligand match/mismatch 4 • Improve Immune Reconstitution

  24. High risk leukemia 3. Unmanipulated Haploidentical HSCT Relapse Remains a Problem after HSCT Especially for advanced leukemia (58%- 74%) Huang XJ et al, Biol Blood Marrow Transplant. 2009 Feb;15(2)

  25. 3. Unmanipulated Haploidentical HSCT Strategy-1Our modified DLI G-CSF primed peripheral blood progenitor cells instead of steady donor lymphocyte harvests GPBSCI Short-term CsA/MTX for prevention of DLI-associated GVHD Huang XJ et al, LEUKEMIA, 2006；20，365-368 Huang XJ et al, Bone Marrow Transplant. 2009;44(5):309-16

  26. 3. Unmanipulated Haploidentical HSCT GVHD prophylaxis Reduced GVHD occurrence None MTX Huang XJ, et al. Hematologica, 2007,92:414-417

  27. Prevention of relapse using modified DLI can significantly increase survival following HLA-mismatched/Haplo-identical HSCT in patients with advanced-stage, acute leukemia 3. Unmanipulated Haploidentical HSCT Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  28. 3. Unmanipulated Haploidentical HSCT Patients Characteristic Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  29. Prophylactic GPBPCI Performed at 70 (20 ~ 314) d after HSCT MNC 1.0 (0.5-2.0) 108/kg CD3+ 0.93 (0.2-2.12) 108/kg No patients had profound and lasting pancytopenia after the prophylactic infusion 3. Unmanipulated Haploidentical HSCT

  30. 3. Unmanipulated Haploidentical HSCT The risk factor of DLI-associated acute GVHD Cumulative incidence of grade Ⅲ to Ⅳ acute GVHD GVHD prophylaxis < 2w: 49.5% GVHD prophylaxis 2～4w: 31.6% GVHD prophylaxis 4～6w: 14.4% GVHD prophylaxis >6w: 9.3% Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  31. Cumulative incidence of aGVHD 3. Unmanipulated Haploidentical HSCT P=0.55 Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  32. Cumulative incidence of cGVHD 3. Unmanipulated Haploidentical HSCT P=0.42 Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  33. Cumulative incidence of TRM 3. Unmanipulated Haploidentical HSCT P=0.95 Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  34. Cumulative incidence of relapse 3. Unmanipulated Haploidentical HSCT P=0.018 Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  35. Probability of OS 3. Unmanipulated Haploidentical HSCT (P=0.013) Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  36. 3. Unmanipulated Haploidentical HSCT Modified prophylactic DLI after HLA-mismatched/Haplo-identical HSCT • Lower relapse rate, a similar NRM, and a higher survival probability compared with non-DLI • Can significantly increase the survival of patients with advanced-stage, acute leukemia even after HLA-mismatched, T-cell-replete HSCT Huang XJ ,et al. Bone Marrow Transplant. 2011 Sep accepted

  37. Risk stratification-directed DLI could reduce relapse of standard-risk acute leukemia after allo-HSCT Institute of Hematology Peking University Beijing, China ASH 2111 Oral Presentation

  38. Efficacy of intervention Groups 3yr-Relapse TRM OS LFS A 18.1% 19.7% 66.0% 61.6% B 68.0% 11.2% 23.9% 20.8% C 29.8% 15.6% 55.4% 52.5% ASH 2111 Oral Presentation

  39. 3. Unmanipulated Haploidentical HSCT Strategy-1 Conclusion m-DLI can be used for the treatment andprophylaxis of relapse afterhaplo-identical HSCT

  40. Predictive value of Th17 cells and Tc17 cells in allo-graft on acute GVHD p=0.00017 （n=12） p=0.005 （n=17） （n=12） p=0.001 HuangXJ，et al, Eur J Immunol. 2011 Feb;41(2):514-26

  41. Treating donor mice with rhIL-11 and rhG-CSF promotes transplant-tolerance and preserves the effects of GVL after allogeneic bone marrow transplantation Effects of different cytokines treatment on the recipients’ T cells proliferation activity in response to host alloantigens +14 d after BMT. HuangXJ, et al. Leuk Res. 2009 Jan;33(1):123-8

  42. Strategy-2 Conclusion 3. Unmanipulated Haploidentical HSCT We may decrease the incidence of GVHD by manipulating the cell contents or function of graft? Mobilization with IL-11 plus G-CSF ?

  43. Strategy-3 KIR ligand match/mismatch to outcome on pretransplantation category TRM Relapse aGVHD KIR mismatch KIR match OS Huang XJ, et al. Biol Bone Marrow Transplant, 2008,14(3)

  44. 3. Unmanipulated Haploidentical HSCT Strategy-3 Conclusion • KIR ligand mismatch is associated with higher aGVHD, a greater relapse rate, and inferior survival in our haploidentical GIAC protocol---Donor Slection ?

  45. P<0.001 n=206 ALC-30>300/ul ALC-30≤300/ul ALC-30≤300/ul ALC-30＞300/ul 3. Unmanipulated Haploidentical HSCT Strategy-4 Immune Reconstitution TRM Huang XJ, et al. Bone Marrow Transplant, 2009,43: 29-36

  46. Comparison of Reconstituted T cells subgroup between HLA match and mismatch ** The counts of reconstituted CD3+ cells (cells/μl ) were significantly lower in HLA-mismatched patients at days 30 than those in HLA-matched patients, which reached normal level at days 60 in both HLA-matched and -mismatched patients. ** P＜0.001 HuangXJ, J Cli Imm Online Publication

  47. Comparison of Reconstituted T cells subgroup between HLA match and mismatch ** * * ** The counts of reconstituted CD4+ cells (cells/μl ) were significantly lower in HLA-mismatched patients at days 30, 60, 90, and 120 than those in HLA-matched patients, which did not reached normal level until 360 in both HLA-matched and mismatched patients, respectively. * P＜0.05, ** P＜0.001 HuangXJ, J Cli Imm OnlinePublication

  48. 3. Unmanipulated Haploidentical HSCT Strategy-4 Conclusion Novel approach to improve the recovery of immune reconstitution are greatly required. IL-2 after HSCT ? A Randomized Clinical Trial Is Undergoing For Evaluing IL-2 After Haplo-identical HSCT In PUIH

  49. Acknowledgements Department of Bone Marrow Transplant Dai-Hong Liu Feng-Rong Wang Huan Chen Jing-Zhi Wang Kai-Yan Liu Lan-Ping Xu Wei Han Xiao-Hui Zhang Yu-Hong Chen Yu Wang Stem cell collection center Hai-Yin Zheng Hong Xu Qing Zhao Su Wang Laboratory of PUIH Dan Li Ya-Zhen Qin Yan-Rong Liu Yue-Yun Lai

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