Abstract
Post-transplant cyclophosphamide (PTCy) is being increasingly used as graft-versus-host disease (GVHD) prophylaxis post allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR1). However, results may differ in patients transplanted in CR2. We retrospectively evaluated transplant outcomes of adult AML patients transplanted between 2010–2019 from 9–10/10 human leukocyte antigen (HLA)-matched unrelated donor (UD) in CR2. In total, 127 patients were included (median age 45.5 years, 54% male). Median follow-up was 19.2 months. Conditioning was myeloablative (MAC) in 50.4% and the graft source was peripheral blood in 93.7% of the transplants. Incidence of acute (a)GVHD II-IV and III-IV was 26.2% and 9.2%. Two-year total and extensive chronic (c)GVHD were 34.3% and 13.8 %, respectively. Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 17.2%, 21.1%, 61.7, %, 65.2%, and 49.3%, respectively. Time from diagnosis to transplant (>18 months) was a favorable prognostic factor for RI, LFS, OS, and GRFS while favorable risk cytogenetics was a positive prognostic factor for OS. The patient’s age was a poor prognostic factor for NRM and cGVHD. Finally, the female-to-male combination and reduced intensity conditioning (RIC) were poor and favorable prognostic factors for cGVHD, respectively. We conclude that PTCy is an effective method for GVHD prophylaxis in AML patients undergoing allo-HCT in CR2 from UD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
Professor Mohamad Mohty, and Dr Myriam Labopin from the ALWP will provide the data upon request.
References
Zeiser R, Blazar BR, Acute Graft-versus-Host Disease -. Biologic Process, Prevention, and Therapy. N Engl J Med. 2017;377:2167–79.
Zeiser R, Blazar BR. Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets. N Engl J Med. 2017;377:2565–79.
Tegla C, Choi J, Abdul-Hay M, Cirrone F, Cole K, Al-Homsi AS. Current Status and Future Directions in Graft-Versus-Host Disease Prevention Following Allogeneic Blood and Marrow Transplantation in Adults. Clin Hematol Int. 2020;2:5–12.
Storb R, Deeg HJ, Whitehead J, Cirrone F, Cole K, Al-Homsi AS. 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;314:729–35.
Storb R, Deeg HJ, Pepe M, Appelbaum F, Anasetti C, Beatty P, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 1989;73:1729–1734.9.
Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transpl. 2008;14:641–50. https://doi.org/10.1016/j.bbmt.2008.03.005.
Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai HL, Bolaños-Meade J, et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transpl. 2010;16:482–9. https://doi.org/10.1016/j.bbmt.2009.11.011.
Saliba RM, Majid AA, Pidala J, Arora M, Spellman SR, Hemmer MT, et al. Characteristics of Graft-versus-Host Disease (GvHD) after Post-Transplant Cyclophosphamide versus Conventional GvHD Prophylaxis. Transpl Cell Ther. 2022;16:S2666–636701476-2. https://doi.org/10.1016/j.jtct.2022.07.013.
Mayumi H, Umesue M, Nomoto K. Cyclophosphamide-induced immunological tolerance: an overview. Immunobiology. 1996;195:129–39.
Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Tran. 2013;19:117–22.11.
Jones RJ, Barber JP, Vala MS, Collector MI, Kaufmann SH, Ludeman SM, et al. Assessment of aldehyde dehydrogenase in viable cells. Blood. 1995;85:2742–6.
Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N, et al. NK cell recovery after haploidentical HSCT with pos ttransplant cyclophosphamide: dynamics and clinical implications. Blood. 2018;131:247–62.
Rambaldi B, Kim HT, Reynolds C, Chamling Rai S, Arihara Y, Kubo T, et al. Impaired T- and NK-cell reconstitution after haploidentical HCT with post-transplant cyclophosphamide. Blood Adv. 2021;5:352–64.
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.
Lorentino F, Labopin M, Ciceri F, Vago L, Fleischhauer K, Afanasyev B, et al. Acute Leukemia Working Party (ALWP) and Cellular Therapy and Immunobiology Working Party (CTIWP) of the European Society for Blood and Marrow Transplantation (EBMT). Post-transplantation cyclophosphamide GvHD prophylaxis after hematopoietic stem cell transplantation from 9/10 or 10/10 HLA-matched unrelated donors for acute leukemia. Leukemia. 2021;35:585–94.
Brissot E, Labopin M, Moiseev I, Cornelissen JJ, Meijer E, Van Gorkom G, et al. Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donors. J Hematol Oncol. 2020;13:87.
Battipaglia G, Labopin M, Hamladji RM, Blaise D, Chevallier P, Brissot E, et al. Post-Transplant cyclophosphamide versus antithymocyte globulin patients Acute myeloid Leuk undergoing allogeneic stem cell Transplant HLA-identical sibling donors: A retrospective Anal Acute Leuk Working Part Eur Soc Blood Marrow Transplant Cancer. 2021;127:209–18. 5
Battipaglia G, Galimard JE, Labopin M, Raiola AM, Blaise D, Ruggeri A, et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia WorkingParty of the EBMT. Bone Marrow Transpl. 2022;57:562–71.
Sanz J, Galimard JE, Labopin M, Afanasyev B, Angelucci E, Ciceri F, et al. Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT. J Hematol Oncol. 2020;13:46.
Gilleece MH, Labopin M, Savani BN, Yakoub-Agha I, Socié G, Gedde-Dahl T, et al. Allogeneic haemopoietic transplantation for acute myeloid leukaemia in second complete remission: a registry report by the Acute Leukaemia Working Party of the EBMT. Leukemia. 2020;34:87–99.
Gilleece MH, Shimoni A, Labopin M, Robinson S, Beelen D, Socié G, et al. Measurable residual disease status and outcome of transplant in acute myeloid leukemia in second complete remission: a study by the acute leukemia working party of the EBMT. Blood Cancer J. 2021;11:88.
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl. 2009;15:1628–33.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transpl. 1995;15:825–8.
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;69:204–17.
Kanate AS, Nagler A, Savani B. Summary of scientific and statistical methods, study endpoints and definitions for observational and registry-based studies in hematopoietic cell transplantation. Clin Hematol Int. 2019;2:2–4.
Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transpl. 2016;51:610–1.
R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing; 2020. https://www.R-project.org/
Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest. 2019;129:2357–73.
Rimando JC, McCurdy SR, Luznik. How We Prevent GVHD in High Risk Patients: Post-Transplant Cyclophosphamide and Beyond.L. Blood. 2022 Apr: blood.2021015129. https://doi.org/10.1182/blood.2021015129
Mussetti A, Paviglianiti A, Parody R, Sureda A. Is Post-Transplant Cyclophosphamide the New Methotrexate? A J Clin Med. 2021;10:3548 https://doi.org/10.3390/jcm10163548.
Jentzsch M, Bischof L, Backhaus D, Brauer D, Schulz J, Franke GN, et al. Impact of MRD status in patients with AML undergoing allogeneic stem cell transplantation in the first vs the second remission. Blood Adv. 2022;6(Aug):4570–80.
Shouval R, Fein JA, Labopin M, Kröger N, Duarte RF, Bader P, et al. Outcomes of allogeneic haematopoietic stem cell transplantation from HLA-matched and alternative donors: a European Society for Blood and Marrow Transplantation registry retrospective analysis. Lancet Haematol. 2019;6:e573–e584.
Nagler A, Labopin M, Craddock C, Socié G, Yakoub-Agha I, Gedde-Dahl T, et al. Cytogenetic risk classification maintains its prognostic significance in transplanted FLT3-ITD mutated acute myeloid leukemia patients: On behalf of the acute leukemia working party/European society of blood and marrow transplantation. Am J Hematol. 2022;97(Mar):274–82.
Battipaglia G, Labopin M, Kröger N, Vitek A, Afanasyev B, Hilgendorf I, et al. Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood 2019;134:892–9.
Acknowledgements
We thank all the EBMT centers and national registries for contributing patients to this study (see Appendix S1). We also thank the data managers for their excellent work.
Author information
Authors and Affiliations
Contributions
AN wrote the manuscript, designed the study, and interpreted the data. ML designed the study, performed the statistical analyses, interpreted the data, and edited the manuscript. MM designed the study, interpreted the data, and edited the manuscript. RS helped in writing the manuscript. AK, HLW, MR, DB, JV, IYA, GC, PR, YK, JS and FC reviewed the manuscript and provided clinical data. All authors approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics approval
The scientific boards of the ALWP of the EBMT approved this study.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Nagler, A., Labopin, M., Swoboda, R. et al. Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) in second complete remission (CR2) transplanted from unrelated donors with post-transplant cyclophosphamide (PTCy). A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 58, 552–557 (2023). https://doi.org/10.1038/s41409-023-01940-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41409-023-01940-6