Abstract
Steroid-refractory graft versus host disease (GVHD) represents a fearsome complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective study on outcomes and risk factors associated with acute and chronic steroid-refractory GVHD in a large cohort of 1207 patients receiving HSCT in Saint Louis Hospital between 2007 and 2017. Among patients who developed an acute and/or a chronic GVHD, the cumulative incidences of acute and chronic steroid-refractory disease were 31% and 48%, respectively, at day +100 and 1-year post-HSCT. Through a multivariable analysis we selected several risk factors associated with the development of a steroid-refractory disease. For acute GVHD steroid refractoriness, we identified (1) a very high disease risk index, (2) an unrelated donor, (3) the absence of in vivo T-depletion as GVHD prophylaxis, and (4) a reduced intensity conditioning regimen. For chronic GVHD, (1) the use of peripheral blood stem cells, (2) unrelated donors, and (3) absence of in vivo T-depletion were more likely associated with a steroid-refractory disease. After the construction of a multistate dynamic model, we found that the probability of being alive without relapse after the resolution of all GVHD episodes was about 36% in the long term.
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References
Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med. 2007;357:1472–5.
Pasquini MC, Wang Z, Horowitz MM, Gale RP. Report from the Center for International Blood and Marrow Transplant Research (CIBMTR): Current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clin Transpl 2013;2014:189–97.
Passweg JR, Baldomero H, Peters C, Gaspar HB, Cesaro S, Dreger P, et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transpl. 2014;49:744–50.
Xhaard A, Rocha V, Bueno B, de Latour RP, Lenglet J, Petropoulou A, et al. Steroid-refractory acute GVHD: lack of long-term improved survival using new generation anticytokine treatment. Biol Blood Marrow Transpl. 2012;18:406–13.
Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2012;18:1150–63.
Arora M, Klein JP, Weisdorf DJ, Hassebroek A, Flowers MED, Cutler CS, et al. Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood. 2011;117:6714–20.
Akpek G, Zahurak ML, Piantadosi S, Margolis J, Doherty J, Davidson R, et al. Development of a prognostic model for grading chronic graft-versus-host disease. Blood. 2001;97:1219–26.
Arora M, Pidala J, Cutler CS, Chai X, Kurland B, Jacobsohn DA, et al. Impact of prior acute GVHD on chronic GVHD outcomes: a chronic graft versus host disease consortium study. Leukemia. 2013;27:1196–201.
Calmettes C, Vigouroux S, Labopin M, Tabrizi R, Turlure P, Lafarge X, et al. Risk factors for steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation from matched related or unrelated donors. Biol Blood Marrow Transpl. 2015;21:860–5.
Axt L, Naumann A, Toennies J, Haen SP, Vogel W, Schneidawind D, et al. Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transpl. 2019;54:1805–14.
Food and Drug Administration, HHS. Human subject protection; foreign clinical studies not conducted under an investigational new drug application. Final rule. Fed Regist. 2008;73:22800–16.
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;120:905–13.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the disease risk index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.
Angelucci E, Polchi P, Lucarelli G, Galimberti M, Baronciani D, Giardini C, et al. Allogeneic bone marrow transplantation for hematological malignancies following therapy with high doses of busulphan and cyclophosphamide. Haematologica. 1989;74:455–61.
Fière D, Lepage E, Sebban C, Boucheix C, Gisselbrecht C, Vernant JP, et al. Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol J Am Soc Clin Oncol. 1993;11:1990–2001.
Eder S, Canaani J, Beohou E, Labopin M, Sanz J, Arcese W, et al. Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: a matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Am J Hematol. 2017;92:997–1003.
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;18:295–304.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl J Am Soc Blood Marrow Transpl. 2015;21:389–401.e1.
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 Transpl J Am Soc Blood Marrow Transpl. 2005;11:945–56.
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 Transpl. 2015;21:984–99.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
Harrell FE, Lee KL, Califf RM, Pryor DB, Rosati RA. Regression modelling strategies for improved prognostic prediction. Stat Med. 1984;3:143–52.
Baron F, Labopin M, Savani BN, Beohou E, Niederwieser D, Eder M, et al. Graft‐versus‐host disease and graft‐versus‐leukaemia effects in secondary acute myeloid leukaemia: a retrospective, multicentre registry analysis from the Acute Leukaemia Working Party of the EBMT. Br J Haematol. 2019. https://doi.org/10.1111/bjh.16185.
Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, The Seattle Marrow Transplant Team. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med. 1981;304:1529–33.
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.
Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C, et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia. 2012;26:2462–8.
MacMillan ML, Robin M, Harris AC, DeFor TE, Martin PJ, Alousi A, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transpl. 2015;21:761–7.
Schlenk RF, Döhner K, Mack S, Stoppel M, Király F, Götze K, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian Trial AMLHD98A. J Clin Oncol. 2010;28:4642–8.
Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N, et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigen–identical siblings versus human leukocyte antigen–allelic–matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006;24:5695–702.
Walter RB, Pagel JM, Gooley TA, Petersdorf EW, Sorror ML, Woolfrey AE, et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia. 2010;24:1276–82.
Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387–94.
Veys P, Wynn RF, Ahn KW, Samarasinghe S, He W, Bonney D, et al. Impact of immune modulation with in vivo T-cell depletion and myleoablative total body irradiation conditioning on outcomes after unrelated donor transplantation for childhood acute lymphoblastic leukemia. Blood. 2012;119:6155–61.
Czerw T, Labopin M, Giebel S, Socié G, Volin L, Fegueux N, et al. Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: an analysis by the Acute Leukemia Wo: ATG in Allo-PBSCT for Ph-Neg ALL. Cancer. 2018;124:2523–33.
Hoegh-Petersen M, Amin MA, Liu Y, Ugarte-Torres A, Williamson TS, Podgorny PJ, et al. Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse. Bone Marrow Transpl. 2013;48:105–14.
Soiffer RJ, LeRademacher J, Ho V, Kan F, Artz A, Champlin RE, et al. Impact of immune modulation with anti–T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood. 2011;117:6963–70.
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;125:1333–8.
Solh M, Zhang X, Connor K, Brown S, Solomon SR, Morris LE, et al. Factors predicting graft-versus-host disease–free, relapse-free survival after allogeneic hematopoietic cell transplantation: multivariable analysis from a single center. Biol Blood Marrow Transpl. 2016;22:1403–9.
Bensinger WI, Clift R, Martin P, Appelbaum FR, Demirer T, Gooley T, et al. Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation. Blood. 1996;88:2794–800.
Schmitz N, Eapen M, Horowitz MM, Zhang M-J, Klein JP, Rizzo JD, et al. Long-term outcome of patients given transplants of mobilized blood or bone marrow: a report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Blood. 2006;108:4288–90.
Champlin RE, Schmitz N, Horowitz MM, Chapuis B, Chopra R, Cornelissen JJ, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT). Blood. 2000;95:3702–9.
Baker M, Wang H, Rowley SD, Cai L, Pecora AL, Skarbnik A, et al. Comparative outcomes after haploidentical or unrelated donor bone marrow or blood stem cell transplantation in adult patients with hematological malignancies. Biol Blood Marrow Transpl J Am Soc Blood Marrow Transpl. 2016;22:2047–55.
Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004;104:3501–6.
Pidala J, Martens M, Anasetti C, Carreras J, Horowitz M, Lee SJ, et al. Factors associated with successful discontinuation of immune suppression after allogeneic hematopoietic cell transplantation. JAMA Oncol. 2019. https://jamanetwork.com/journals/jamaoncology/fullarticle/2751877.
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SP and MR had full access to all of the data in the study and take responsibility for the integrity and the accuracy of the data analysis. Concept and design: SP, GS, and MR. Acquisition, analysis, or interpretation of data: SP and MR. Drafting of the manuscript: SP, MR, and GS. Critical revision of the manuscript for important intellectual content: SP, MR, GS, PHP, ASDG, AB, AX, and ND. Statistical analysis and data interpretation: SP. Final approval of the manuscript: all authors.
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Pagliuca, S., Prata, P.H., Xhaard, A. et al. Long-term outcomes and risk factor analysis of steroid-refractory graft versus host disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 56, 38–49 (2021). https://doi.org/10.1038/s41409-020-0977-3
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DOI: https://doi.org/10.1038/s41409-020-0977-3
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