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Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation

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Abstract

The efficacy of minimal residual disease (MRD)-directed immunotherapy, including interferon-α (IFN- α) treatment and chemotherapy plus granulocyte colony-stimulating factor-primed donor leukocyte infusion (chemo-DLI), was investigated in patients with high-risk myelodysplastic syndrome (MDS) who were MRD-positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT). High-risk MDS patients who received non-T-cell-depleted allo-HSCT at the Peking University Institute of Hematology and were MRD-positive after allo-HSCT were studied (n = 47). The MRD-positive status was considered if leukemia-associated aberrant immune phenotypes or Wilms’ tumor gene 1 expression is present in a single bone marrow sample. The cumulative incidence of the relapse and non-relapse mortality 2 years after immunotherapy were 14.5% and 21.4% (P = 0.377) and 9.1% and 0.0% (P = 0.985) for patients in the IFN-α and chemo-DLI groups, respectively. The probability of disease-free and overall survival 2 years after immunotherapy were 76.4% and 78.6% (P = 0.891) and 84.3% and 84.6% (P = 0.972) for patients in the IFN-α and chemo-DLI groups, respectively. Persistent MRD after immunotherapy was associated with poor survival. Thus, the MRD-directed immunotherapy was effective for patients with high-risk MDS who were MRD-positive after allo-HSCT, and the efficacy was comparable between chemo-DLI and IFN-α treatment.

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References

  1. Wang Y, Wang HX, Lai YR, Sun ZM,Wu DP, Jiang M, Liu DH, Xu KL, Liu QF, Liu L, Wang JB, Gao F, Ou-Yang J, Gao SJ, Xu LP, Huang XJ. Haploidentical transplant for myelodysplastic syndrome:registry-based comparison with identical sibling transplant. Leukemia 2016; 30(10): 2055–2063

    Article  CAS  PubMed  Google Scholar 

  2. Mo XD, Qin YZ, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ. Minimal residual disease monitoring and preemptive immunotherapy in myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2016; 95(8): 1233–1240

    Article  CAS  PubMed  Google Scholar 

  3. Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, Klut IM, Knoth H, Röllig C, Schetelig J, Mohr B, Graehlert X, Ehninger G, Bornhäuser M, Thiede C. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT:results of the RELAZA trial. Leukemia 2012; 26(3): 381–389

    Article  CAS  PubMed  Google Scholar 

  4. Mo XD, Lv M, Huang XJ. Preventing relapse after haematopoietic stem cell transplantation for acute leukaemia:the role of posttransplantation minimal residual disease (MRD) monitoring and MRD-directed intervention. Br J Haematol 2017; 179(2): 184–197

    Article  CAS  PubMed  Google Scholar 

  5. Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ. Salvage chemotherapy followed by granulocyte colony-stimulating factorprimed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation:prognostic factors and clinical outcomes. Eur J Haematol 2016; 96 (3): 297–308

    Article  CAS  PubMed  Google Scholar 

  6. Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H, Han W, Wang Y, Qin YZ, Huang XJ. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 2012; 119(14): 3256–3262

    Article  CAS  PubMed  Google Scholar 

  7. McSweeney EN, Worman CP, Tsakona CP, Jewel AP, Hoffbrand AV, Milligan DW, Burnett AK, Lewis ML, Goldstone AH. Lowdose recombinant α-2a-interferon:a feasible maintenance therapy in acute myeloid leukaemia in the older patient. Acta Haematol 1993; 89(1): 1–5

    Article  CAS  PubMed  Google Scholar 

  8. Smits EL, Anguille S, Berneman ZN. Interferon α may be back on track to treat acute myeloid leukemia. OncoImmunology 2013; 2(4): e23619

    Article  PubMed  PubMed Central  Google Scholar 

  9. Anguille S, Lion E, Willemen Y, Van Tendeloo VF, Berneman ZN, Smits EL. Interferon-α in acute myeloid leukemia:an old drug revisited. Leukemia 2011; 25(5): 739–748

    Article  CAS  PubMed  Google Scholar 

  10. Gesundheit B, Shapira MY, Resnick IB, Amar A, Kristt D, Dray L, Budowski E, Or R. Successful cell-mediated cytokine-activated immunotherapy for relapsed acute myeloid leukemia after hematopoietic stem cell transplantation. Am J Hematol 2009; 84(3): 188–190

    Article  PubMed  Google Scholar 

  11. Tang X, Song YH, Sun A, Zhu X, Ruan C, Wu D. Successful treatment of relapsed acute myeloid leukemia without chemotherapy. J Clin Oncol 2016; 34(13): e117–e119

    Article  PubMed  Google Scholar 

  12. Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ. Interferon-α:a potentially effective treatment for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015; 21 (11): 1939–1947

    Article  CAS  PubMed  Google Scholar 

  13. Huang XJ, Xu LP, Liu KY, Liu DH, Wang Y, Chen H, Chen YH, Han W, Wang JZ, Chen Y, Zhang XH, Shi HX, Wang FR, Tang FF. Partially matched related donor transplantation can achieve outcomes comparable with unrelated donor transplantation for patients with hematologic malignancies. Clin Cancer Res 2009; 15(14): 4777–4783

    Article  CAS  Google Scholar 

  14. Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, Fan ZP, Wu DP, Huang XJ. Haploidentical vs. identical-sibling transplant for AML in remission:a multicenter, prospective study. Blood 2015; 125(25): 3956–3962

    Article  CAS  PubMed  Google Scholar 

  15. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Wang JZ, Gao ZY, Zhang YC, Jiang Q, Shi HX, Lu DP. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006; 38(4): 291–297

    Article  PubMed  Google Scholar 

  16. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Zhang XH, Lu DP. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15(2): 257–265

    Article  CAS  PubMed  Google Scholar 

  17. Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, Huang XJ. Monitoring MRD with flow cytometry:an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2012; 91(2): 183–192

    Article  CAS  PubMed  Google Scholar 

  18. Zhao XS, Jin S, Zhu HH, Xu LP, Liu DH, Chen H, Liu KY, Huang XJ. Wilms’ tumor gene 1 expression:an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant 2012; 47(4): 499–507

    Article  CAS  PubMed  Google Scholar 

  19. Zhao XS, Yan CH, Liu DH, Xu LP, Liu YR, Liu KY, Qin YZ,Wang Y, Huang XJ. Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity. Ann Hematol 2013; 92(8): 1111–1119

    Article  CAS  PubMed  Google Scholar 

  20. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W. Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica 2007; 92(3): 414–417

    Article  PubMed  Google Scholar 

  21. Huang XJ, Wang Y, Liu DH, Xu LP, Liu KY, Chen H, Chen YH, Han W, Shi HX. Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect. Bone Marrow Transplant 2009; 44(5): 309–316

    Article  CAS  PubMed  Google Scholar 

  22. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15(6): 825–828

    CAS  PubMed  Google Scholar 

  23. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease:I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11(12): 945–956

    Article  Google Scholar 

  24. Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Hadzic N, Shaw BE, Potter MN; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. Diagnosis and management of acute graft-versus-host disease. Br J Haematol 2012; 158(1): 30–45

    Article  CAS  PubMed  Google Scholar 

  25. Dignan FL, Amrolia P, Clark A, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Shaw BE, Potter MN; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol 2012; 158(1): 46–61

    Article  CAS  PubMed  Google Scholar 

  26. Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007; 25(23): 3503–3510

    Article  PubMed  Google Scholar 

  27. Alessandrino EP, Della Porta MG, Bacigalupo A, Van Lint MT, Falda M, Onida F, Bernardi M, Iori AP, Rambaldi A, Cerretti R, Marenco P, Pioltelli P, Malcovati L, Pascutto C, Oneto R, Fanin R, Bosi A; Gruppo Italiano Trapianto di Midollo Osseo (GITMO). WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome:a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood 2008; 112(3): 895–902

    Article  CAS  PubMed  Google Scholar 

  28. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks:new representations of old estimators. Stat Med 1999; 18(6): 695–706

    Article  CAS  PubMed  Google Scholar 

  29. Zhang C, Cui G, Chen Y, Fan K. Antitumor effect of interferon-α on U937 human acute leukemia cells in vitro and its molecular mechanism. J Huazhong Univ Sci Technolog Med Sci 2007; 27(5): 513–515

    Article  CAS  PubMed  Google Scholar 

  30. Rohatiner AZ. Growth inhibitory effects of interferon on blast cells from patients with acute myelogenous leukaemia. Br J Cancer 1984; 49(6): 805–807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C, Vindelov LL, Blaise D, Janssen JJ, Petersen E, Socié G, Nagler A, Rocha V, Mohty M. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia:a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia 2012; 26(12): 2462–2468

    Article  CAS  PubMed  Google Scholar 

  32. Mo XD, Xu LP, Zhang XH, Liu DH, Wang Y, Chen H, Yan CH, Chen YH, Han W,Wang FR,Wang JZ, Liu KY, Huang XJ. Chronic GVHD induced GVL effect after unmanipulated haploidentical hematopoietic SCT for AML and myelodysplastic syndrome. Bone Marrow Transplant 2015; 50(1): 127–133

    Article  PubMed  Google Scholar 

  33. Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ. IFN-α is effective for treatment of minimal residual disease in patients with acute leukemia after allogeneic hematopoietic stem cell transplantation:results of a registry study. Biol Blood Marrow Transplant 2017; 23 (8): 1303–1310

    Article  CAS  PubMed  Google Scholar 

  34. Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ. Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2017; 96(5): 829–838

    Article  PubMed  Google Scholar 

  35. Pusic I, Choi J, Fiala MA, Gao F, Holt M, Cashen AF, Vij R, Abboud CN, Stockerl-Goldstein KE, Jacoby MA, Uy GL, Westervelt P, DiPersio JF. Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2015; 21(10): 1761–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schroeder T, Rautenberg C, Haas R, Kobbe G. Hypomethylating agents after allogeneic blood stem cell transplantation. Stem Cell Investig 2016; 3:84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, Giagounidis A, Zohren F, Bruns I, Wolschke C, Rieger K, Fenk R, Germing U, Haas R, Kröger N, Kobbe G. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia 2013; 27 (6): 1229–1235

    Article  CAS  PubMed  Google Scholar 

  38. Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK, Wolf D, Ringhoffer M, Czibere A, Nachtkamp K, Dienst A, Kondakci M, Stadler M, Platzbecker U, Uharek L, Luft T, Fenk R, Germing U, Bornhäuser M, Kröger N, Beelen DW, Haas R, Kobbe G. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions—a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant 2015; 21 (4): 653–660

    Article  CAS  PubMed  Google Scholar 

  39. Sockel K, Wermke M, Radke J, Kiani A, Schaich M, Bornhäuser M, Ehninger G, Thiede C, Platzbecker U. Minimal residual disease-directed preemptive treatment with azacitidine in patients with NPM1-mutant acute myeloid leukemia and molecular relapse. Haematologica 2011; 96(10): 1568–1570

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Editage for their English editing assistance as well as Drs. Daoxing Deng, Yujia Chi, andWei Guo for their assistance in data collection. This work was supported by the Capital’s Funds for Health Improvement and Research (No. 2018-4-4089), the Key Program of the National Natural Science Foundation of China (No. 81530046), Foundation for Innovative Research Groups of the National Natural Science Foundation of China (No. 81621001), the Science and Technology Project of Guangdong Province of China (No. 2016B030230003), the National Science and Technology Support Program (No. 2014BAI09B13), and the Project of Health Collaborative Innovation of Guangzhou city (No. 201704020214).

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Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China

    Xiaodong Mo, Xiaohui Zhang, Lanping Xu, Yu Wang, Chenhua Yan, Huan Chen, Yuhong Chen, Wei Han, Fengrong Wang, Jingzhi Wang, Kaiyan Liu & Xiaojun Huang

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100044, China

    Xiaojun Huang

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  1. Xiaodong Mo
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Mo, X., Zhang, X., Xu, L. et al. Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Front. Med. 13, 354–364 (2019). https://doi.org/10.1007/s11684-018-0665-5

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