Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients

Yu Wang, De-Pei Wu, Qi-Fa Liu, Lan-Ping Xu, Kai-Yan Liu, Xiao-Hui Zhang, Wen-Jing Yu, Yang Xu, Fen Huang, Xiao-Jun Huang, Yu Wang, De-Pei Wu, Qi-Fa Liu, Lan-Ping Xu, Kai-Yan Liu, Xiao-Hui Zhang, Wen-Jing Yu, Yang Xu, Fen Huang, Xiao-Jun Huang

Abstract

Background: Low-dose post-transplant cyclophosphamide (PTCy) in conjunction with anti-thymocyte globulin (ATG) appears as a potentially effective graft-versus-host disease (GVHD) prevention strategy in haploidentical hematopoietic cell transplant (haplo-HCT). Our study aims to assess the efficacy of this regimen.

Methods: We extended our prospective study in patients treated with low-dose PTCy (14.5 mg/kg on days 3 and 4) in ATG/granulocyte colony-stimulating factor (G-CSF)-based regimen and compared the results to the contemporary cohort of patients without low-dose PTCy (ATG cohort). Both study cohort and control are transplanted from maternal donor or collateral relatives.

Results: We identified 239 consecutive patients (ATG-PTCy cohort = 114; ATG cohort = 125). All patients but one in ATG cohort achieved myeloid engraftment by day 30 post-HCT. We found that both the cumulative incidence of 100-day grade III-IV aGvHD and non-relapse-mortality (NRM) in the ATG-PTCy cohort was significantly reduced than that in the ATG group (5% vs 18%; P = 0.003; and 6% vs 15%; P= 0.045); the 2-year cumulative incidences of relapse and overall survival were comparable between the two cohorts (13% vs 14%; P = 0.62; and 83% vs 77%; P = 0.18, respectively). Furthermore, GVHD-free, relapse-free survival (GRFS) was significantly improved in the ATG-PTCy arm (63% vs 48%; P = 0.039). In multivariate analysis, the joint treatment resulted in lower grade II-IV acute GVHD (HR 0.58; P = 0.036), grade III-IV aGvHD (HR 0.28; P = 0.006), chronic GVHD (HR 0.60; P = 0.047), NRM (HR 0.26; P = 0.014), and higher GRFS (HR 0.59; P = 0.021) but slower myeloid and platelet recovery (HR 0.29 and 0.30; both P < 0.001).

Conclusions: These results suggested that ATG/PTCy (low-dose) can reduce both acute and chronic GVHD as compared with standard ATG-based prophylaxis using maternal donor or collateral relatives at particular high GVHD risk.

Trial registration: ClinicalTrials.gov NCT02412423.

Keywords: Anti-thymocyte globulin; Graft-versus-host disease; Haploidentical; Low-dose; Post-transplant cyclophosphamide.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Rates of graft-versus-host disease (GVHD), non-relapse-mortality (NRM), relapse incidence (RI), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) according to treatment group. Rates of grades III–IV acute GVHD (a), chronic GVHD (b), NRM (c), RI (d), OS (e), and GRFS (f)

References

    1. Apperley J, Niederwieser D, Huang XJ, Nagler A, Fuchs E, Szer J, et al. Haploidentical hematopoietic stem cell transplantation: a global overview comparing Asia, the European Union, and the United States. Biol Blood Marrow Transplant. 2016;22:23–26. doi: 10.1016/j.bbmt.2015.11.001.
    1. Rubio MT, Savani BN, Labopin M, Piemontese S, Polge E, Ciceri F, et al. Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol. 2016;9:25. doi: 10.1186/s13045-016-0248-3.
    1. Wang Y, Chang YJ, Xu LP, Liu KY, Liu DH, Zhang XH, et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood. 2014;124:843–850. doi: 10.1182/blood-2014-03-563130.
    1. Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, 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. Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, et al. Haploidentical versus matched-sibling transplant in adults with Philadelphia-negative high-risk acute lymphoblastic leukemia: a biologically phase III randomized study. Clin Cancer Res. 2016;22:3467–3476. doi: 10.1158/1078-0432.CCR-15-2335.
    1. Wang Y, Wang HX, Lai YR, Sun ZM, Wu DP, Jiang M, et al. Haploidentical transplant for myelodysplastic syndrome: registry-based comparison with identical sibling transplant. Leukemia. 2016;30:2055–2063. doi: 10.1038/leu.2016.110.
    1. Robinson TM, O'Donnell PV, Fuchs EJ, Luznik L. Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin Hematol. 2016;53:90–97. doi: 10.1053/j.seminhematol.2016.01.005.
    1. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126:1033–1040. doi: 10.1182/blood-2015-04-639831.
    1. Kasamon YL, Bolanos-Meade J, Prince GT, Tsai HL, McCurdy SR, Kanakry JA, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol. 2015;33:3152–3161. doi: 10.1200/JCO.2014.60.4777.
    1. Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120:4285–4291. doi: 10.1182/blood-2012-07-438408.
    1. Law AD, Salas MQ, Lam W, Michelis FV, Thyagu S, Kim DDH, et al. Reduced-intensity conditioning and dual T lymphocyte suppression with antithymocyte globulin and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplants for hematological malignancies. Biol Blood Marrow Transplant. 2018;24:2259–2264. doi: 10.1016/j.bbmt.2018.07.008.
    1. Dulery R, Menard AL, Chantepie S, El-Cheikh J, Francois S, Delage J, et al. Sequential conditioning with thiotepa in T cell- replete hematopoietic stem cell transplantation for the treatment of refractory hematologic malignancies: comparison with matched related, haplo-mismatched, and unrelated donors. Biol Blood Marrow Transplant. 2018;24:1013–1021. doi: 10.1016/j.bbmt.2018.01.005.
    1. Dawsari G, Hassanein M, Rasheed W, Almohareb F, Chaudhri NA, Alsharif F, et al. Addition of ATG to myeloablative haplo conditioning with post-transplantation cyclophosphamide might decrease the risk of GVHD and TRM without increasing the risk of relapse. Blood. 2016;128:5871.
    1. Lin CC, Chen TT, Lo WJ, Lein MY, Hiseh CY, Lin CY, et al. Post-transplant cyclophosphamide (PTCy) with anti-thymocyte globulin (ATG) as GVHD prophylaxis is effective in haploidentical peripheral stem cell transplantation and without increasing risk of relapse. Blood. 2017;130:1978.
    1. Prem S, Atenafu EG, Al-Shaibani Z, Loach D, Law A, Lam W, et al. Low rates of acute and chronic GVHD with ATG and PTCy in matched and mismatched unrelated donor peripheral blood stem cell transplants. Eur J Haematol. 2019;102:486–493.
    1. Deotare U, Atenafu EG, Loach D, Michelis FV, Kim DD, Thyagu S, et al. Reduction of severe acute graft-versus-host disease using a combination of pre transplant anti-thymocyte globulin and post-transplant cyclophosphamide in matched unrelated donor transplantation. Bone Marrow Transplant. 2018;53:361–365. doi: 10.1038/s41409-017-0053-9.
    1. Yang J, Jiang J, Cai Y, Li S, Wan L, Zhu J, et al. Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood for patients with hematologic malignancies: a prospective, phase II study. Bone Marrow Transplant. 2019;54:1049–1057. doi: 10.1038/s41409-018-0382-3.
    1. Wang Y, Chang YJ, Chen L, Xu LP, Bian ZL, Zhang XH, et al. Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G-CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes. Oncoimmunology. 2017;6:e1356152. doi: 10.1080/2162402X.2017.1356152.
    1. Zhang YY, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. HLA-haploidentical hematopoietic SCT from collateral related donors without in vitro T-cell depletion for hematological malignancies. Bone Marrow Transplant. 2014;49:496–501. doi: 10.1038/bmt.2013.223.
    1. Mo XD, Zhang YY, Zhang XH, Xu LP, Wang Y, Yan CH, et al. The role of collateral related donors in haploidentical hematopoietic stem cell transplantation. Science Bulletin. 2018;63:1376–1382. doi: 10.1016/j.scib.2018.08.008.
    1. Armand P, Gibson CJ, Cutler C, Ho VT, Koreth J, Alyea EP, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120:905–913. doi: 10.1182/blood-2012-03-418202.
    1. Wang Y, Chen H, Chen J, Han M, Hu J, Jiong H, et al. The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China. Cancer Lett. 2018;438:63–75. doi: 10.1016/j.canlet.2018.08.030.
    1. Xu L, Chen H, Chen J, Han M, Huang H, Lai Y, 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. Wang Y, Fu HX, Liu DH, Xu LP, Zhang XH, Chang YJ, et al. Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transplant. 2014;49:426–433. doi: 10.1038/bmt.2013.191.
    1. Chang YJ, Zhao XY, Xu LP, Zhang XH, Wang Y, Han W, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol. 2015;8:84. doi: 10.1186/s13045-015-0182-9.
    1. Yan CH, Wang Y, Wang JZ, Chen YH, Chen Y, Wang FR, et al. Minimal residual disease- and graft-vs-host disease-guided multiple consolidation chemotherapy and donor lymphocyte infusion prevent second acute leukemia relapse after allotransplant. J Hematol Oncol. 2016;9:87. doi: 10.1186/s13045-016-0319-5.
    1. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997;97:855–864. doi: 10.1046/j.1365-2141.1997.1112925.x.
    1. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21:984–999. doi: 10.1016/j.bbmt.2015.02.025.
    1. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest. 2019;130:2357–2373. doi: 10.1172/JCI124218.
    1. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using posttransplantation 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. Colson YL, Li H, Boggs SS, Patrene KD, Johnson PC, Ildstad ST. Durable mixed allogeneic chimerism and tolerance by a nonlethal radiation-based cytoreductive approach. J Immunol. 1996;157:2820–2829.
    1. Jang JE, Hwang DY, Chung H, Kim SJ, Eom JI, Jeung HK, et al. Early cytomegalovirus reactivation and expansion of CD56brightCD16dim/−DNAM1+ natural killer cells are associated with antileukemia effect after haploidentical stem cell transplantation in acute leukemia. Biol Blood Marrow Transplant. 2019. 10.1016/j.bbmt.2019.06.008.
    1. Hu LJ, Cao XH, Yu XX, Liu XF, Zhao XS, Chang YJ, et al. NK cell reconstitution following unmanipulated HLA-mismatched/haploidentical transplantation compared with matched sibling transplantation. Sci China Life Sci. 2019. 10.1007/s11427-018-9565-5.
    1. Kanakry JA, Kasamon YL, Bolanos-Meade J, Borrello IM, Brodsky RA, Fuchs EJ, et al. Absence of post-transplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2013;19:1514–1517. doi: 10.1016/j.bbmt.2013.07.013.

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