Haploidentical versus HLA-matched sibling transplantation for refractory acute leukemia undergoing sequential intensified conditioning followed by DLI: an analysis from two prospective data

Sijian Yu, Fen Huang, Zhiping Fan, Li Xuan, Danian Nie, Yajing Xu, Ting Yang, Shunqing Wang, Zujun Jiang, Na Xu, Ren Lin, Jieyu Ye, Dongjun Lin, Jing Sun, Xiaojun Huang, Yu Wang, Qifa Liu, Sijian Yu, Fen Huang, Zhiping Fan, Li Xuan, Danian Nie, Yajing Xu, Ting Yang, Shunqing Wang, Zujun Jiang, Na Xu, Ren Lin, Jieyu Ye, Dongjun Lin, Jing Sun, Xiaojun Huang, Yu Wang, Qifa Liu

Abstract

Background: Compared with HLA-matched sibling donor (MSD) transplant, the outcomes of haploidentical donor (HID) transplant for refractory acute leukemia need to be further explored. In this study, we compared the outcomes of HID with MSD for refractory acute leukemia.

Patients and methods: This study population came from two prospective multicenter trials (NCT01883180, NCT02673008). Two hundred and seventy-eight patients with refractory acute leukemia were enrolled in this study, including 119 in HID group and 132 in MSD group. Sequential intensified conditioning was employed in all patients, and donor lymphocyte infusion (DLI) was administered in patients in the absence of active GVHD and according to minimal residual disease (MRD) from day + 60 post-transplantation for preventing relapse.

Results: The complete remission of leukemia by day + 30 post-transplant were 94% and 93%, respectively, in HID and MSD groups (p = .802). The 1-year incidence of grades II-IV acute GVHD was 62% and 54% (p = .025), and 3-year incidence of chronic GVHD was 55% and 55% (p = .789), respectively, in two groups. HID transplant had lower incidence of first episode of MRD positivity and relapse than MSD transplant (28% vs 45%, p = .006; 26% vs 38%, p = .034). There was higher infection-related mortality in HID than MSD (8% vs 2%, p = .049) within the first 100 days' post-transplant. The 5-year overall survival was 46% and 42% (p = .832), respectively; the 5-year disease-free survival was 43% and 39% (p = .665), in HID and MSD groups, respectively.

Conclusions: HID transplant has lower relapse, but higher infection-related mortality and similar survival rates in refractory acute leukemia by the strategy of sequential intensified conditioning followed by DLI compared with MSD transplant.

Keywords: HLA-matched sibling; Haploidentical; Refractory acute leukemia; Similar survival; Transplantation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig 1
Fig 1
Flow diagram
Fig 2
Fig 2
Relapse incidence after transplantation for all patients (a), AML patients (b), ALL patients (c), and ALAL patients (d)
Fig 3
Fig 3
Transplant outcomes including NRM (a), OS (b), DFS (c), and GRFS (d)

References

    1. Gyurkocza B, Lazarus HM, Giralt S. Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy. Bone Marrow Transplant. 2017;52:1083–1090. doi: 10.1038/bmt.2017.8.
    1. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992;80:1090–1093. doi: 10.1182/blood.V80.4.1090.bloodjournal8041090.
    1. Middeke JM, Herbst R, Parmentier S, et al. Long-term follow-up and impact of comorbidity before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory acute myeloid leukemia-lessons learned from the prospective BRIDGE trial. Biol Blood Marrow Transplant. 2017;23:1491–1497. doi: 10.1016/j.bbmt.2017.05.014.
    1. Xu L, Chen H, Chen J, et al. The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol. 2018;11:33. doi: 10.1186/s13045-018-0564-x.
    1. Saraceni F, Labopin M, Brecht A, et al. Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) J Hematol Oncol. 2019;12:44. doi: 10.1186/s13045-019-0727-4.
    1. Steckel NK, Groth C, Mikesch JH, et al. High-dose melphalan-based sequential conditioning chemotherapy followed by allogeneic haematopoietic stem cell transplantation in adult patients with relapsed or refractory acute myeloid leukaemia. Br J Haematol. 2018;180:840–853. doi: 10.1111/bjh.15137.
    1. Liu QF, Fan ZP, Zhang Y, et al. Sequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia. Biol Blood Marrow Transplant. 2009;15:1376–1385. doi: 10.1016/j.bbmt.2009.06.017.
    1. Malard F, Labopin M, Stuhler G, et al. Sequential intensified conditioning regimen allogeneic hematopoietic stem cell transplantation in adult patients with intermediate- or high-risk acute myeloid leukemia in complete remission: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2017;23:278–284. doi: 10.1016/j.bbmt.2016.11.002.
    1. Mohty M, Malard F, Blaise D, et al. Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia. Haematologica. 2017;102:184–191. doi: 10.3324/haematol.2016.150326.
    1. Xuan L, Fan Z, Zhang Y, et al. Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT. Oncotarget. 2016;7:32579–32591. doi: 10.18632/oncotarget.8691.
    1. Versluis J, Labopin M, Ruggeri A, et al. Alternative donors for allogeneic hematopoietic stem cell transplantation in poor-risk AML in CR1. Blood Adv. 2017;1:477–485. doi: 10.1182/bloodadvances.2016002386.
    1. Wang Y, Liu QF, Xu LP, et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015;125:3956–3962. doi: 10.1182/blood-2015-02-627786.
    1. Bashey A, Zhang X, Sizemore CA, et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31:1310–1316. doi: 10.1200/JCO.2012.44.3523.
    1. Rashidi A, Hamadani M, Zhang MJ, et al. Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission. Blood Adv. 2019;3:1826–1836. doi: 10.1182/bloodadvances.2019000050.
    1. How J, Slade M, Vu K, et al. T cell-replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplantation cyclophosphamide results in outcomes similar to transplantation from traditionally matched donors in active disease acute myeloid leukemia. Biol Blood Marrow Transplant. 2017;23:648–653. doi: 10.1016/j.bbmt.2017.01.068.
    1. Battipaglia G, Boumendil A, Labopin M, et al. Unmanipulated haploidentical versus HLA-matched sibling allogeneic hematopoietic stem cell transplantation in relapsed/refractory acute myeloid leukemia: a retrospective study on behalf of the ALWP of the EBMT. Bone Marrow Transplant. 2019.
    1. Ottinger HD, Ferencik S, Beelen DW, et al. Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors, and HLA-matched unrelated donors. Blood. 2003;102:1131–1137. doi: 10.1182/blood-2002-09-2866.
    1. Wang Y, Liu DH, Xu LP, et al. Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. Biol Blood Marrow Transplant. 2011;17:821–830. doi: 10.1016/j.bbmt.2010.08.023.
    1. Luo Y, Xiao H, Lai X, et al. T-cell-replete haploidentical HSCT with low-dose anti-T-lymphocyte globulin compared with matched sibling HSCT and unrelated HSCT. Blood. 2014;124:2735–2743. doi: 10.1182/blood-2014-04-571570.
    1. Zhao XS, Liu YR, Xu LP, et al. Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts. Am J Hematol. 2019;94:512–521. doi: 10.1002/ajh.25417.
    1. Yu S, Huang F, Wang Y, et al. Haploidentical transplantation might have superior graft-versus-leukemia effect than HLA-matched sibling transplantation for high-risk acute myeloid leukemia in first complete remission: a prospective multicentre cohort study. Leukemia. 2019.
    1. Chang YJ, Wang Y, Liu YR, et al. Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis. J Hematol Oncol. 2017;10:134. doi: 10.1186/s13045-017-0502-3.
    1. Wang Y, Liu DH, Xu LP, et al. Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis. Bone Marrow Transplant. 2012;47:1099–1104. doi: 10.1038/bmt.2011.213.
    1. Lin R, Wang Y, Huang F, et al. Two dose levels of rabbit antithymocyte globulin as graft-versus-host disease prophylaxis in haploidentical stem cell transplantation: a multicenter randomized study. BMC Med. 2019;17:156. doi: 10.1186/s12916-019-1393-7.
    1. Xuan L, Huang F, Fan Z, et al. Effects of intensified conditioning on Epstein-Barr virus and cytomegalovirus infections in allogeneic hematopoietic stem cell transplantation for hematological malignancies. J Hematol Oncol. 2012;5:46. doi: 10.1186/1756-8722-5-46.
    1. Liu Q, Lin R, Sun J, et al. Antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis. Biol Blood Marrow Transplant. 2014;20:1198–1203. doi: 10.1016/j.bbmt.2014.04.016.
    1. Holtan SG, DeFor TE, Lazaryan A, et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125:1333–1338. doi: 10.1182/blood-2014-10-609032.
    1. Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–828.
    1. Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev. 2006;20:15–27. doi: 10.1016/j.blre.2005.01.007.
    1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405. doi: 10.1182/blood-2016-03-643544.
    1. O'Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15:926–957. doi: 10.6004/jnccn.2017.0116.
    1. Alvarnas JC, Brown PA, Aoun P et al. AcutelLymphoblastic Leukemia, Version 2.2015. J Natl Compr Canc Netw 2015; 13: 1240-1279.
    1. Austin PC, Fine JP. Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med. 2017;36:4391–4400. doi: 10.1002/sim.7501.
    1. Ruggeri A, Battipaglia G, Labopin M, et al. Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: an ALWP-EBMT study. J Hematol Oncol. 2016;9:89. doi: 10.1186/s13045-016-0321-y.
    1. Schmid C, Schleuning M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092–1099. doi: 10.1182/blood-2005-10-4165.
    1. Ringden O, Labopin M, Schmid C, et al. Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT. Br J Haematol. 2017;176:431–439. doi: 10.1111/bjh.14428.
    1. Wu X, Liu Q. Prophylaxis and treatment of relapse after haploidentical stem cell transplantation: What is known vs unknown? Semin Hematol. 2019;56:209–214. doi: 10.1053/j.seminhematol.2019.04.001.
    1. Schmid C, Schleuning M, Ledderose G, et al. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23:5675–5687. doi: 10.1200/JCO.2005.07.061.
    1. Wang Y, Liu DH, Fan ZP, et al. Prevention of relapse using DLI can increase survival following HLA-identical transplantation in patients with advanced-stage acute leukemia: a multi-center study. Clin Transplant. 2012;26:635–643. doi: 10.1111/j.1399-0012.2012.01626.x.
    1. Michallet M, Thomas X, Vernant JP, et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM) Bone Marrow Transplant. 2000;26:1157–1163. doi: 10.1038/sj.bmt.1702690.
    1. Doney K, Hagglund H, Leisenring W, et al. Predictive factors for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2003;9:472–481. doi: 10.1016/S1083-8791(03)00149-6.
    1. Salvatore D, Labopin M, Ruggeri A, et al. Outcomes of hematopoietic stem cell transplantation from unmanipulated haploidentical versus matched sibling donor in patients with acute myeloid leukemia in first complete remission with intermediate or high-risk cytogenetics: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2018;103:1317–1328. doi: 10.3324/haematol.2018.189258.
    1. Ringden O, Labopin M, Ciceri F, et al. Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings? Leukemia. 2016;30:447–455. doi: 10.1038/leu.2015.232.
    1. Han LJ, Wang Y, Fan ZP, et al. Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission. Br J Haematol. 2017;179:120–130. doi: 10.1111/bjh.14854.
    1. Yu S, Fan Q, Sun J, et al. Haploidentical transplantation without in vitro T-cell depletion results in outcomes equivalent to those of contemporaneous matched sibling and unrelated donor transplantation for acute leukemia. Medicine (Baltimore) 2016;95:e2973. doi: 10.1097/MD.0000000000002973.
    1. Yan CH, Liu DH, Liu KY, et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood. 2012;119:3256–3262. doi: 10.1182/blood-2011-09-380386.
    1. Binkert L, Medinger M, Halter JP, et al. Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation. Bone Marrow Transplant. 2015;50:1331–1336. doi: 10.1038/bmt.2015.148.
    1. Lin R, Liu Q. Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation. J Hematol Oncol. 2013;6:94. doi: 10.1186/1756-8722-6-94.

Source: PubMed

3
Tilaa