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Peking University People’s Hospital & Institute of Hematology

Donor Lymphocyte Infusion in Patients with Hematological Malignancies after Transplantation: Past, Present and Future. Xiao-Jun Huang M.D. Peking University People’s Hospital & Institute of Hematology Beijing Key Laboratory of HSCT, Beijing, P.R.China. Background.

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Peking University People’s Hospital & Institute of Hematology

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  1. Donor Lymphocyte Infusion in Patients with Hematological Malignancies after Transplantation: Past, Present and Future Xiao-Jun Huang M.D Peking University People’s Hospital & Institute of Hematology Beijing Key Laboratory of HSCT, Beijing, P.R.China

  2. Background DLI is the most effective methods for relapse Patients receiving DLI (n=228) Patients not receiving DLI (n=171) P＜0.0001 Kolb HJ, et al. Blood,1995,86:2041-50 Schmid, et al. J Clin Oncol,2007,25:4938-45

  3. Background Limitation of traditional DLI • High occurrence of acute GVHD (49-91%) • Pancytopenia • Less effective for acute leukemia • Can not be used successfully for prophylaxis • of relapse after allo-HSCT Kolb HJ, et al. Blood,1995,86:2041-50 Schmid, et al. J Clin Oncol,2007,25:4938-45 Deol A, et al. Cancer Treatment Reviews,2010,36:528

  4. Background New strategies for DLI • Count control of infused lymphocyte • Infusion of allo-depleted donor T cells • Infusion of mHAg-specific CTLs • Infusion of in vivo G-CSF primed lymphocyte Kolb HJ, et al. Blood,2008,112:4371-4383 Cicei F, et al. Lancet Oncol,2009,10:489-500 Deol A, et al. Cancer Treatment Reviews,2010,36:528 Huang XJ. et al. Blood Rev. 2013 Jan;27(1):55-62.

  5. Background Effects of G-CSF on immune and hematopoietic cells in healthy donors HuangXJ, et al. Clin Transplant 2011: 25: 13–23

  6. Modified Donor Lymphocyte Infusion(mDLI) Background mDLI Safety G-CSFmobilized PB mDLIFeasibility Modified DLI Advantage of mDLI ⑴ Safety：Lower aGVHD rate ⑵ Feasibility:Keeping GVL Effect Short course of Immunosuppressive Agents Huang XJ, et al. Haematologica. 2007 Mar;92(3):414-7. Huang XJ, et al. Bone Marrow Transplant. 2009,44(5) Huang XJ, et al. BBMT. 2011 ;17(2):197-204

  7. Short-term MTX/CSA prophylaxis reduces incidence of GVHD Background Matched-DLI Haplo-DLI 49.5% 31.6% 14.4% 9.3% Huang XJ, et al, Leukemia, 2006,20:365-368 Huang XJ, et al. Haematologica 2007,92:414-417 Huang XJ, et al, Bone Marrow Transplant. 2009;44(5):309-16

  8. 1. Therapeutic mDLI mDLI for the treatment of leukemia relapse after unmanipulated Haplo-HSCT Retrospective study (n=20) Patient charactersitics Male/Female: 15/5 Median age: 23 (6-50) years Diagnosis: AML (7 cases), ALL (10 cases), and CML (3 cases) Transplant protocol: unmanipulated HBMT using modified Bu/Cy+ATG conditioning regimens Follow-up: 1118 (754-1468) days after transplant and 808 (627-1388) days after DLI Huang, et al. Haematologica,2007,92(3):414-417

  9. 1. Therapeutic mDLI Results Median counts of MNCs in PBPCs 1.55 (0.8-11.02) ×108/kg Median counts of CD3+ cells in PBPCs 0.61 (0.23-4.56) ×108/kg Grades III-IV acute GVHD 30% Cumulative incidence of cGVHD 64% Our results suggest that mDLI is a potentially effective therapeutic option for patients who relapsed after unmanipulated haploidentical HSCT. Two-year probability of LFS 40% Huang, et al. Haematologica,2007,92(3):414-417

  10. 1. Therapeutic mDLI mDLI for the treatment of leukemia relapse after unmanipulated HSCT—Update data Leukemia patients relapsed after HSCT (n=84) Chemotherapy alone (n=34) Chemotherapy plus DLI (n=50) No differences in patient characteristics, except for patients in chemotherapy plus DLI group had a higher number of BM blast than chemotherapy group. Huang, et al. PUIH, unpublished data

  11. 1. Therapeutic mDLI B A P=0.016 P=0.000 2-4 acute GVHD Chronic GVHD C D P=0.000 P=0.000 Relapse Leukemia free survival Chemotherapy + DLI Chemotherapy alone Huang, et al. PUIH, unpublished data

  12. Conclusion of Part one 1. Therapeutic mDLI • mDLI was a potentially effective therapeutic option for patients who relapsed after HSCT • Chemotherapy plus DLI is superior to chemotherapy alone for treatment of patients who relapsed after transplantation Huang XJ, et al, Leukemia, 2006,20:365-368 Huang XJ, et al. Haematologica 2007,92:414-417 Huang XJ, et al, Bone Marrow Transplant. 2009;44(5):309-16 Huang XJ, et al. PUIH, unpublished data

  13. 2.Prophylactic DLI Relapse prevention using mDLI after HLA-identical transplant A multi-center study Retrospective study (n=123) Patient characteristics Male/Female: 88/35 Median age: 37 (range, 11-56) years Diagnosis: AML (86 cases), ALL (37 cases Transplant protocol: HLA-identical sibling transplant using modified Bu/Cy conditioning regimens Follow-up: As of December 31, 2010 Wang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.x

  14. 2.Prophylactic DLI Patients who received prophylactic DLI had a higher incidence of chronic GVHD P=0.021 P=0.35 Wang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.x

  15. 2.Prophylactic DLI Prophylactic mDLI significantly decrease relapse rate and increase the survival of patients with advanced-stage P=0.001 66% 46% 36% 11% P=0.02 Wang Y, Huang XJ, et al. Clin Transplant, 2012 DOI: 10.1111/j.13990012.2012.01626.x

  16. 2.Prophylactic DLI mDLI for the prophylaxis of relapse after Haplo-HSCT in patients with advance leukemia—Risk-factor analysis Retrospective study (n=88) Patient characteristics Male/Female: 53/35 Median age: 30 (range, 8-57) years Diagnosis: AML (54 cases), ALL (34 cases） Transplant protocol: unmanipulated HBMT using modified Bu/Cy+ATG conditioning regimens Follow-up: A median time of 248 (34-2777) days after transplantation Wang Y, Huang XJ, et al. BMT,2012.213

  17. 2.Prophylactic DLI Our results suggest that higher OS was associated with use of prophylactic GPBSCI, AML and female sex in patients who underwent umanipulated HBMT Wang Y, Huang XJ, et al. BMT, 2012.213

  18. 2.Prophylactic DLI Conclusion of Part Two • Prophylactic mDLI can significantly decrease the relapse rate and increase the survival of patients with advanced stage acute leukemia • It can be recommended as a routine therapy choice after either HLA-identical sibling or Haplo-HSCT Huang, et al. J Clin Immunol,2008,28:276-283 Wang Y, Huang XJ, et al. BMT, doi:10.1038/bmt.2012.213

  19. 3. Risk directed mDLI Hypothesis Patients with Leukemia High-risk Standard-risk ? ? MRD(-) MRD(+) Therapeutic Prophylactic mDLI Prophylactic mDLI ? ? Decrease relapse Improve survival Decrease relapse ? Improve survival ?

  20. The levels of WT1 could predict relapse of acute leukemia 3. Risk directed mDLI Zhao XS, et al. Ann Hematol. 2012;91:183-192. Zhao XS, et al. BMT. 2012;47:499-507

  21. 3. Risk directed mDLI Our objects- reduce relapse? Reduce relapse and improve survival? Monitoring of MRD Risk-stratification based on MRD state Intervention with DLI or IL-2

  22. 3. Risk directed mDLI Patients Subgroups MRD (-): 709 patients (Group A) IL-2: 49 patients (Group B) 814 patients MRD (+): 105 patients DLI: 56 patients (Group C) Huang XJ, et al. Blood,2012,119(14):3256-62

  23. 3. Risk directed mDLI Relapse Total: 22.0% (95% CI 18.4-25.6%) Group A: 18.1% (95% CI 14.6-21.6%) Group B: 64.4%(95% CI 44.8-84.0%) Group C 27.8% (95% CI 12.1-43.5%) Yan CH, Huang XJ, et al. Blood,2012,119(14):3256-62

  24. 3. Risk directed mDLI Risk factors of relapse Huang XJ, et al. Blood,2012,119(14):3256-62

  25. 3. Risk directed mDLI GVHD and TRM Group A: Acute GvHD of any grade posttransplant: 30.2% 2-4 acute GvHD: 15.2% 3-4 acute GvHD: 4.9%. Chronic GvHD posttransplants: 38.8% Extensive chronic GvHD posttransplants: 32.9% Huang XJ, et al. Blood,2012,119(14):3256-62

  26. 3. Risk directed mDLI Disease-free survival Huang XJ, et al. Blood,2012,119(14):3256-62

  27. 3. Risk directed mDLI Risk factors of DFS Huang XJ, et al. Blood,2012,119(14):3256-62

  28. 3. Risk directed mDLI Overall survival Huang XJ, et al. Blood,2012,119(14):3256-62

  29. 3. Risk directed mDLI Risk factors of OS Huang XJ, et al. Blood,2012,119(14):3256-62

  30. 3. Risk directed mDLI Conclusion of Part Three Risk stratification-directed modified DLI could reduce relapse and improve survival of patients with standard risk acute leukemia patients after HSCT Huang XJ, et al. Ann Hematol. 2012;91:183-192. Huang XJ, et al. BMT. 2012;47:499-507 Huang XJ, et al. Blood,2012,119(14):3256-62

  31. Future of DLI Which graft for DLI is better ? • G-CSF-mobilized peripheral blood progenitor cell, • in vitro generated donor T cells against leukemia-antigens, • Positive selected T cells, NK cells, • Suicide gene-transduced donor T cells What is the optimal dose ? What is the optimal schedule to maintain GVL effect? Huang XJ. et al. Blood Rev. 2013 Jan;27(1):55-62.

  32. Acknowledgements Stem cell collection center Hai-Yin Zheng Hong Xu Qing Zhao Su Wang Department of bone marrow transplant Xiao-Jun Huang Kai-Yan Liu Dai-Hong Liu Lan-Ping Xu Huan Chen Wei Han Xiao-Hui Zhang Yu-Hong Chen Feng-Rong Wang Jing-Zhi Wang Yu Wang Chen-Hua Yan Yuan-Yuan Zhang Yu Ji Yu-Qian Sun Laboratory of PUIH Dan Li Ya-Zhen Qin Yan-Rong Liu Yue-Yun Lai

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