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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 Transplantation volume 53, pages 361–365 (2018)Cite this article

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Use of Post-transplant Cyclophosphamide (PTCy) has recently been introduced specifically in the haplo-identical transplant setting with promising results [1]. This intervention has also shown a significant reduction of acute graft versus host disease (aGVHD) and a trend towards improving chronic graft versus host disease (cGVHD) [2]. The efficacy of PTCy has mainly been demonstrated in patients with bone marrow (BM) as the stem cell source [3]; and has been associated with clinically significant acute and chronic GVHD in patients with peripheral blood as the stem cell source (PBSC) [4]. Anti-thymocyte globulin (ATG) has previously been shown to reduce the incidence of cGVHD at around 1 year post transplantation [5], without increasing the incidence of relapse [6]. The incidence of Gr III-IV aGVHD was 28% using ATG, cyclosporine and mycophenolate mofetil (ATG-CSA-MF), as the GVHD prophylaxis regimen, in the recently concluded randomized trial [7]. We hypothesized that a combination of both ATG and PTCy would reduce the incidence of both acute and chronic GVHD in our patient cohort; effectively reducing the morbidity and mortality associated with severe forms of GVHD. Here we present the preliminary outcome in our unrelated patients using this regimen.

This is a retrospective study of the patient cohort treated from 1 October 2015 until 31 March 2016 in a single center. This study was approved by the institutional Research Ethics Board. This study cohort was compared to the earlier historical study cohort of patients who received pre transplant ATG as part of GVHD prophylaxis at our center [7]. Patients received transplant from HLA- Matched (10/10) or mismatched (9/10) unrelated donors. The graft source was Filgrastim stimulated PBSC. The treatment schema initially for ages <60 years was a myeloablative regimen using the FBT400 protocol and for ages >60 years consisted of FBT200 as the reduced intensity conditioning (RIC) regimen [8]. The FBT400 regimen consisted of a combination of Fludarabine (50 mg/m2 on days −5,−4,−3,−2), Busulphan (once daily dose of 3.2 mg/kg on days −5,−4,−3,−2) along with 2 doses of total body irradiation (TBI) of 200 cGy on Day −1. The regimen of FBT200 comprised of reduced dose of Fludarabine at 30 mg/m2 on same days but with only 2 days of Busulphan (on days −2,−1) and only one dose of 200 cGy TBI on day −1 [9]. We subsequently decided to use FBT200 for all patients in view of increased liver and kidney toxicities observed with FBT400 regimen with post-transplant cyclophosphamide. The GVHD prophylaxis consisted of ATG (rabbit, Thymoglobulin; Genzyme-Sanofi, Lyon, France) on days −3, −2 and −1 with a total dose of 4.5 mg/kg. Patients additionally received 50 mg/kg/day IV cyclophosphamide on days +3 and +4 (PTCy), with the first dose starting 72 h after PBSC infusion. This was further followed by post transplant administration of IV cyclosporine (2.5 mg/kg twice daily) on day + 5 onwards, with change to oral route when the patient was able to tolerate orally.

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Author contributions

UD: Conception and design of study, data collection, data analysis, manuscript preparation. EA: Statistical analysis and manuscript preparation. DL, FM, DK, ST, JL: Manuscript preparation. HM: Data analysis, manuscript preparation. AV: Conception and design of study, data analysis, manuscript preparation, program leader and senior author.

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Authors and Affiliations

  1. Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Uday Deotare, David Loach, Fotios V. Michelis, Dennis (Dong-Hwan) Kim, Santhosh Thyagu, Jeffrey H. Lipton, Hans A. Messner & Auro Viswabandya

  2. Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Eshetu G. Atenafu

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Correspondence to Auro Viswabandya.

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Presented in part at the 58th American Society of Hematology Annual Meeting in San Diego, California, 2–6 December 2016 and at the American Society of Blood and Marrow Transplantation meeting at Orlando, Florida, 22–26 February 2017.

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Deotare, U., Atenafu, E.G., Loach, D. 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 53, 361–365 (2018). https://doi.org/10.1038/s41409-017-0053-9

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