Abstract
Malignancy relapse remains a major barrier to treatment success in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) markedly reduces hematologic malignancy relapse risk, but relapses still occur in these patients. Patients (n = 275) with moderate or severe cGVHD were enrolled on the National Cancer Institute (NCI) prospective cross-sectional natural history study (NCT00092235). Subjects were median 36 months after allo-HSCT and were followed subsequently for malignancy relapse and survival. Seventeen patients experienced relapse. In a multivariable model including time-dependent influences on relapse, risk factors associated with increased risk of relapse included shorter time from transplant to cGVHD evaluation (HR 0.279, 95% CI 0.078–0.995) and lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.260, 95% CI 0.094–0.719). In a model excluding time-dependent influences on relapse risk, lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.288, 95% CI 0.103–0.804), lower C4 complement level (HR 0.346, 95% CI 0.129–0.923), and higher body mass index (HR 3.222, 95% CI 1.156–8.974), were all associated with increased relapse risk. Parameters indicating cGVHD severity and activity are associated with risk of malignancy relapse. Classical predictors of relapse after allo-HSCT do not seem to be prognostic.
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References
Singh Anurag K, McGuirk Joseph P. Allogeneic stem cell transplantation: a historical and scientific overview. Cancer Res. 2016;76:6445–51.
Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301:2349–61.
Choi SW, Reddy P. Current and emerging strategies for the prevention of graft-versus-host disease. Nat Rev Clin Oncol. 2014;11:536–47.
Li JM, Giver CR, Lu Y, Hossain MS, Akhtari M, Waller EK. Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Immunotherapy. 2009;1:599–621.
Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21:266–74.
Martin PJ, Counts GW Jr, Appelbaum FR, Lee SJ, Sanders JE, Deeg HJ, et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol. 2010;28:1011–6.
Bishop MR, Alyea EP 3rd, Cairo MS, Falkenburg JHF, June CH, Kroger N, et al. Introduction to the reports from the National Cancer Institute First International Workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16:563–4.
Mo XD, Kong J, Zhao T, Xu LP, Zhang XH, Liu DH, et al. Extramedullary relapse of acute leukemia after haploidentical hematopoietic stem cell transplantation: incidence, risk factors, treatment, and clinical outcomes. Biol Blood Marrow Transplant. 2014;20:2023–8.
Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. 2007;25:4938–45.
Barrett AJ, Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Rev Hematol. 2010;3:429–41.
Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani M, Fagioli F, et al. Chronic GVHD is associated with inferior relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant. 2012;47:1474–8.
Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M, et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia. 2014;28:2235–40.
Gratwohl A, Brand R, Apperley J, van Biezen A, Bandini G, Devergie A, et al. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (CLWP-EBMT). Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood. 2002;100:3877–86.
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;11:945–56.
Mitchell SA, Leidy NK, Mooney KH, Dudley WN, Beck SL, LaStayo PC, et al. Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease. Bone Marrow Transplant. 2010;45:762–9.
Gooley TA, Leisinring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706.
Miflin G, Russell NH, Franklin I, Cook G, Milligan DW, Hutchinson RM, et al. An analysis of the effect of chronic GvHD on relapse and survival following allogeneic PBSC transplantation. Cytotherapy. 2000;2:423–8.
Brunet S, Urbano-Ispizua A, Ojeda E, Ruiz D, Moraleda M, Diaz A, et al. Evidence of graft-versus-tumor (GVT) effect in 136 patients with advanced hematologic malignancies receiving unmanipulated peripheral blood stem cell allografts (allo-PSCT): the Spanish experience. Blood. 1999;94:165a.
Lee SJ, Klein JP, Barrett AJ, Ringden J, Antin JH, Cahn JY, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002;100:406–14.
Preisler HD, Anderson K, Rai K, Cuttner J, Yates J, DuPre E, et al. The frequency of long‐ term remission in patients with acute myelogenous leukaemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years. Br J Haematol. 1989;71:189–94.
Schiffer CA, Dodge R, Larson RA. Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer. 1997;80:2210–4.
Boyiadzis M, Arora M, Klein JP, Hassebroek A, Hemmer M, Urbano-Ispizua A, et al. Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia. Clin Cancer Res. 2015;21:2020–8.
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–78.
Grkovic L, Baird K, Steinberg SM, Williams KM, Pulanic D, Cowen EW, et al. Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity. Leukemia. 2012;26:633–43.
Page KM, Labopin M, Ruggeri A, Michel G, Diaz de Heredia C, O”Brien T, et al. Factors associated with long-term risk of relapse after unrelated cord blood transplantation in children with acute lymphoblastic leukemia in remission. Biol Blood Marrow Transplant. 2017;23:1350–8.
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.
Bader P, Hancock J, Kreyenberg H, Goulden NJ, Niethammer D, Oakhill A, et al. Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. Leukemia. 2002;16:1668–72.
Brunstein CG, Petersdorf EW, DeFor TE, Noreen H, Maurer D, MacMillan ML, et al. Impact of allele-level HLA mismatch on outcomes in recipients of double umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2016;22:487–92.
Kongtim P, Di SA, Rondon G, Chen J, Adekola K, Popat U, et al. Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:713–9.
Pérez-Simón JA, Díez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD, et al. Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol. 2005;130:394–403.
Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Lupo Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361:478–88.
Crucitti L, Crocchiolo R, Toffalori C, Mazzi B, Greco R, Signori A, et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia. 2015;29:1143–52.
Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med. 2019;25:603–11.
Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112:4371–83.
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.
Acknowledgements
The authors would like to thank all patients and their families for participating in the NIH cGVHD natural history study. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, NCI; the National Institute for Dental and Craniofacial Research; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and the National Eye Institute. The views expressed in this work do not represent the official views of the National Institutes of Health or the United States Government.
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Ruben, C.L., Pirsl, F., Steinberg, S.M. et al. Predictors of hematologic malignancy relapse in patients with advanced chronic graft-versus-host disease. Bone Marrow Transplant 56, 1584–1592 (2021). https://doi.org/10.1038/s41409-021-01211-2
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DOI: https://doi.org/10.1038/s41409-021-01211-2