Abstract
Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II–IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14–3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48–1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II–IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.
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Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-Meade J et al. Graft-versus-host disease treatment: predictors of survival. Biol Blood Marrow Transplant 2010; 16: 1693–1699.
Pidala J, Anasetti C . Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 1504–1518.
Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000; 96: 2062–2068.
Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 92: 2303–2314.
Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant 2005; 11: 383–388.
Kharfan-Dabaja M, Mhaskar R, Reljic T, Pidala J, Perkins JB, Djulbegovic B et al. Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2014; (7): CD010280.
Eapen M, Logan BR, Horowitz MM, Zhong X, Perales M-A, Lee SJ et al. Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation. J Clin Oncol 2015; 33: 364–369.
Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood 2007; 109: 3108–3114.
Furlong T, Kiem H-P, Appelbaum FR, Carpenter PA, Deeg HJ, Doney K et al. Sirolimus in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-versus-host disease following hematopoietic cell transplantation from unrelated donors. Biol Blood Marrow Transplant 2008; 14: 531–537.
Rodriguez R, Nakamura R, Palmer JM, Parker P, Shayani S, Nademanee A et al. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood 2010; 115: 1098–1105.
Pidala J, Kim J, Jim H, Kharfan-Dabaja MA, Nishihori T, Fernandez HF et al. A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica 2012; 97: 1882–1889.
Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014; 124: 1372–1377.
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.
Perkins JB, Kim J, Anasetti C, Fernandez HF, Perez LE, Ayala E et al. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18: 1099–1107.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. 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: 945–956.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.
McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED . Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116–122.
Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 571–575.
Kellum JA, Lameire N, KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 2013; 17: 204.
Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 2015; 125: 1333–1338.
Gray R . A class of K-sample tests for comparing the cumulative incidence of competing risk. Ann Stat 1988; 16: 1141–1154.
Fine J, Gray R . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
Armand P, Kim HT, Sainvil M-M, Lange PB, Giardino AA, Bachanova V et al. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol 2016; 173: 96–104.
Törlén J, Ringdén O, Garming-Legert K, Ljungman P, Winiarski J, Remes K et al. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Haematologica 2016; 101: 1417–1425.
Martin PJ, McDonald GB, Sanders JE, Anasetti C, Appelbaum FR, Deeg HJ et al. Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2004; 10: 320–327.
Pidala J, Kim J, Alsina M, Ayala E, Betts BC, Fernandez HF et al. Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease. Haematologica 2015; 100: 970–977.
Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, Linden E et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood 2008; 112: 4425–4431.
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FK, JK, LC, ED, VR, CA, JP contributed in designing the research, data collection, analyzing the data and writing the manuscript. BB, TN, FL, AM, LP, EA, MK-D, MN and HF contributed in research design, the data analysis critical review and manuscript writing.
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Khimani, F., Kim, J., Chen, L. et al. Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention. Bone Marrow Transplant 52, 1003–1009 (2017). https://doi.org/10.1038/bmt.2017.63
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DOI: https://doi.org/10.1038/bmt.2017.63
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