Abstract
Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3ā6.6, pā=ā0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.
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References
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface. Bone Marrow Transplant. 2009;44:453ā5.
Hahn T, McCarthy PL Jr., Hassebroek A, Bredeson C, Gajewski JL, Hale GA, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31:2437ā49.
DāSouza A, Fretham C, Lee SJ, Arora M, Brunner J, Chhabra S, et al. Current use of and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2020;26:e177āe82.
Mehta RS, Bassett R, Olson A, Chen J, Ahmed S, Alousi AM, et al. Myeloablative conditioning using timed-sequential busulfan plus fludarabine in older patients with acute myeloid leukemia: long term results of a prospective phase II clinical trial. Haematologica. 2019;104:e555ā7.
Popat UR, Mehta RS, Bassett R, Chen J, Valdez BC, Kawedia J, et al. Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial. Lancet Haematol. 2018;5:e532āe42.
Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002;100:406ā14.
Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204ā17.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295ā304.
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;15:825ā8.
Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007;13:1469ā76.
Patel SS, Rybicki LA, Corrigan D, Bolwell B, Dean R, Liu H, et al. Prognostic factors for mortality among day +100 survivors after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24:1029ā34.
Wojnar J, Giebel S, Holowiecka-Goral A, Markiewicz M, Wylezol I, Kopera M, et al. Prediction of nonrelapse mortality for patients surviving 100 days after allogeneic hematopoietic stem cell transplantation. Transpl Proc. 2007;39:3375ā9.
Storb R, Deeg HJ, Fisher L, Appelbaum F, Buckner CD, Bensinger W, et al. Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials. Blood. 1988;71:293ā8.
Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729ā35.
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;96:2062ā8.
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;92:2303ā14.
Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17:164ā73.
Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855ā64.
Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006;12:560ā5.
Kanakry CG, OāDonnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32:3497ā505.
Mielcarek M, Furlong T, OāDonnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502ā8.
Bolanos-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6:e132āe43.
Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35:4003ā11.
Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2020;7:e100āe11.
Mountjoy L, Jain T, Kunze KL, Khera N, Sproat LZ, Jennifer W, et al. Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. Leuk Lymphoma. 2020;61:1996ā2002.
Ruggeri A, Labopin M, Bacigalupo A, Afanasyev B, Cornelissen JJ, Elmaagacli A, et al. Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. J Hematol Oncol. 2018;11:40.
Oltolini C, Greco R, Galli L, Clerici D, Lorentino F, Xue E, et al. Infections after allogenic transplant with post-transplant cyclophosphamide: impact of donor HLA matching. Biol Blood Marrow Transplant. 2020;26:1179ā88.
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Ramdial, J.L., Mehta, R.S., Saliba, R.M. et al. Acute graft-versus-host disease is the foremost cause of late nonrelapse mortality. Bone Marrow Transplant 56, 2005ā2012 (2021). https://doi.org/10.1038/s41409-021-01274-1
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DOI: https://doi.org/10.1038/s41409-021-01274-1
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