Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

Adult Bone Marrow Transplant Service Department of Medicine Memorial Sloan Kettering Cancer Center New York USA

CHU Nantes Department of D'Hematologie Nantes France

Department of Bone Marrow and Onco Hematology Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch Gliwice Poland

Department of Haematology and Stem Cell Transplant St István and St László Hospital of Budapest Hungary

Department of Hematology Hôpital Saint Antoine Paris France

Department of Hematology Hospital Clinic Institute of Hematology and Oncology Barcelona Spain

Department of Hematology Reina Sofía University Hospital IMIBIC University of Cordoba Spain

Department of Hematology VU University Medical Center Amsterdam The Netherlands

Department of Internal Medicine Division of Hematology GROW School for Oncology and Developmental Biology Maastricht University Medical Center Maastricht The Netherlands

Dipartimento di Diagnostica per Immagini Radioterapia Oncologica ed Ematologia Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italy

Erasmus MC Cancer Institute University Medical Center Rotterdam The Netherlands

Hematology and Bone Marrow Transplant Department Chaim Sheba Medical Center Tel Hashomer Israel

Hematology Hospital GU Gregorio Marañón Instituto de Investigación Sanitaria Gregorio Marañon Departamento de Medicina UCM Madrid Spain

Institute of Hematology and Blood Transfusion Prague Czech Republic

IRCCS Policlinico San Martino Hospital Genova Italy

Medicana International Bone Marrow Transplant Unit Istanbul Turkey

Programme de Transplantation and Therapie Cellulaire Centre de Recherche en Cancérologie de Marseille Institut Paoli Calmettes Marseille France

RM Gorbacheva Research Institute Pavlov University St Petersburg Russia

S S C 5 D Trapianto di Cellule Staminali A O U Citta della Salute e della Scienza di Torino Italy

Sezione di Ematologia Dipartimento di Scienze Radiologiche ed Ematologiche Università Cattolica del Sacro Cuore Roma Italy

Stem Cell Transplantation and Cellular Therapies Unit Grande Ospedale Metropolitano Bianchi Melacrino Morelli Reggio Calabria Italy

University Hospital Center Zagreb School of Medicine University of Zagreb Croatia

University Hospital Eppendorf Bone Marrow Transplantation Centre Hamburg Germany

University Medical Center Groningen University of Groningen The Netherlands

University Vita Salute San Raffaele Milan Italy

Zobrazit více v PubMed

Versluis J, Cornelissen JJ. Risks and benefits in a personalized application of allogeneic transplantation in patients with AML in first CR. Semin Hematol. 2019;56:164–170. PubMed

Cornelissen JJ, Gratwohl A, Schlenk RF, et al. . The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9:579–590. PubMed

Gratwohl A, Hermans J, Goldman JM, et al. . Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998;352:1087–1092. PubMed

Gratwohl A, Stern M, Brand R, et al. . Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115:4715–4726. PubMed

Sorror ML, Maris MB, Storb R, et al. . Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919. PubMed PMC

Passweg JR, Baldomero H, Bregni M, et al. . Hematopoietic SCT in Europe: data and trends in 2011. Bone Marrow Transplant. 2013;48:1161–1167. PubMed PMC

Versluis J, Labopin M, Niederwieser D, et al. . Prediction of non-relapse mortality in recipients of reduced intensity conditioning allogeneic stem cell transplantation with AML in first complete remission. Leukemia. 2015;29:51–57. PubMed

Barba P, Martino R, Orti G, et al. . Validation of a new integrated prognostic score to predict non-relapse mortality in patients undergoing reduced-intensity conditioning allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2015;50:1371–1374. PubMed

Luznik L, O’Donnell PV, Symons HJ, et al. . HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–650. PubMed PMC

O’Donnell PV, Luznik L, Jones RJ, et al. . Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8:377–386. PubMed

Pasic I, Lipton JH, Kim DD, et al. . Post-transplant cyclophosphamide combined with anti-thymocyte globulin for graft-vs-host disease prophylaxis improves survival and lowers non-relapse mortality in older patients undergoing allogeneic hematopoietic cell transplantation. Ann Hematol. 2020;99:1377–1387. PubMed

Bashey A, Zhang X, Sizemore CA, et al. . T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31:1310–1316. PubMed

Ruggeri A, Sun Y, Labopin M, et al. . Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant. Haematologica. 2017;102:401–410. PubMed PMC

Broers AEC, de Jong CN, Bakunina K, et al. . Posttransplant cyclophosphamide for prevention of graft-versus-host disease: the prospective randomized HOVON-96 trial. Blood Adv. 2022;6:3378–3385. PubMed PMC

Spyridonidis A, Labopin M, Savani BN, et al. . Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020;55:1114–1125. PubMed

Battipaglia G, Labopin M, Kröger N, et al. . Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134:892–899. PubMed

Gagelmann N, Bacigalupo A, Rambaldi A, et al. . Haploidentical stem cell transplantation with posttransplant cyclophosphamide therapy vs other donor transplantations in adults with hematologic cancers: a systematic review and meta-analysis. JAMA Oncol. 2019;5:1739–1748. PubMed PMC

Luznik L, Bolaños-Meade J, Zahurak M, et al. . High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115:3224–3230. PubMed PMC

Kanakry CG, O’Donnell PV, Furlong T, 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;32:3497–3505. PubMed PMC

Mielcarek M, Furlong T, O’Donnell PV, et al. . Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502–1508. PubMed PMC

Bolaños-Meade J, Reshef R, Fraser R, 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:e132–e143. PubMed PMC

Barba P, Piñana JL, Martino R, et al. . Comparison of two pretransplant predictive models and a flexible HCT-CI using different cut off points to determine low-, intermediate-, and high-risk groups: the flexible HCT-CI Is the best predictor of NRM and OS in a population of patients undergoing allo-RIC. Biol Blood Marrow Transplant. 2010;16:413–420. PubMed

Barba P, Martino R, Pérez-Simón JA, et al. . Combination of the hematopoietic cell transplantation comorbidity index and the European Group for Blood and Marrow Transplantation score allows a better stratification of high-risk patients undergoing reduced-toxicity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20:66–72. PubMed

Shouval R, Fein JA, Shouval A, et al. . External validation and comparison of multiple prognostic scores in allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019;3:1881–1890. PubMed PMC

Castagna L, Fürst S, Marchetti N, et al. . Retrospective analysis of common scoring systems and outcome in patients older than 60 years treated with reduced-intensity conditioning regimen and alloSCT. Bone Marrow Transplant. 2010;46:1000–1005. PubMed

Sorror ML, Storer B, Storb RF. Validation of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in single and multiple institutions: limitations and inferences. Biol Blood Marrow Transplant. 2009;15:757–758. PubMed PMC

Shouval R, Fein JA, Cho C, et al. . The Simplified Comorbidity Index (SCI) - a new tool for prediction of non-relapse mortality in allogeneic HCT. Blood Adv. 2022;6:1525–1535. PubMed PMC

Goldberg MA, Antin JH, Guinan EC, et al. . Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood. 1986;68:1114–1118. PubMed

de Jonge ME, Huitema ADR, Rodenhuis S, et al. . Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005;44:1135–1164. PubMed

Iqubal A, Iqubal MK, Sharma S, et al. . Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision. Life Sci. 2019;218:112–131. PubMed

Yeh J, Whited L, Saliba RM, et al. . Cardiac toxicity after matched allogeneic hematopoietic cell transplant in the posttransplant cyclophosphamide era. Blood Adv. 2021;5:5599–5607. PubMed PMC

Duléry R, Mohty R, Labopin M, et al. . Early cardiac toxicity associated with post-transplant cyclophosphamide in allogeneic stem cell transplantation. JACC Cardio Oncol. 2021;3:250–259. PubMed PMC

Hunger SP, Mullighan CG. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood. 2015;125:3977–3987. PubMed PMC

Döhner H, Estey E, Grimwade D, et al. . Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447. PubMed PMC

Dillon R, Hills R, Freeman S, et al. . Molecular MRD status and outcome after transplantation in NPM1-mutated AML. Blood. 2020;135:680–688. PubMed PMC

Venditti A, Piciocchi A, Candoni A, et al. . GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia. Blood. 2019;134:935–945. PubMed

Steyerberg EW, Uno H, Ioannidis JPA, et al. . Poor performance of clinical prediction models: the harm of commonly applied methods. J Clin Epidemiol. 2018;98:133–143. PubMed

Potdar R, Varadi G, Fein J, et al. . Prognostic scoring systems in allogeneic hematopoietic stem cell transplantation: where do we stand? Biol Blood Marrow Transplant. 2017;23:1839–1846. PubMed

Moons KGM, Altman DG, Reitsma JB, et al. . Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): explanation and elaboration. Ann Intern Med. 2015;162:W1–W73. PubMed

Collins GS, Reitsma JB, Altman DG, et al. . Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMJ. 2015;350:g7594. PubMed

Geva M, Pryce A, Shouval R, et al. . High lactate dehydrogenase at time of admission for allogeneic hematopoietic transplantation associates to poor survival in acute myeloid leukemia and non-Hodgkin lymphoma. Bone Marrow Transplant. 2021;56:2690–2696. PubMed

Kataoka K, Nannya Y, Hangaishi A, et al. . Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:195–204. PubMed

Shouval R, de Jong CN, Fein J, et al. . Baseline renal function and albumin are powerful predictors for allogeneic transplantation-related mortality. Biol Blood Marrow Transplant. 2018;24:1685–1691. PubMed

Beije N, Versluis J, Kraan J, et al. . Circulating endothelial cell enumeration demonstrates prolonged endothelial damage in recipients of myeloablative allogeneic stem cell transplantation. Haematologica. 2015;100:e246–e249. PubMed PMC