SpringerLink
Log in

Post-transplant cyclophosphamide compared to sirolimus/tacrolimus in reduced intensity conditioning transplants for patients with lymphoid malignancies

  • Article
  • Published:
Bone Marrow Transplantation Submit manuscript

Abstract

Despite novel cellular and immunomodulatory therapies, allogeneic hematopoietic stem cell transplantation (HSCT) remains a treatment option for lymphoid malignancies. Post-transplant cyclophosphamide (PTCY) is increasingly employed for graft vs. host disease (GVHD) prophylaxis. This study aims to evaluate the safety and efficacy of PTCY in reduce intensity (RIC) HSCT for patients with lymphoid neoplasms compared to sirolimus with tacrolimus (SIR/TAC). The primary endpoint was to compare grade III-IV acute GVHD, severe chronic GVHD, and relapse-free survival (GRFS) between the two GVHD prophylaxis strategies. This study, conducted from January 2012 to December 2020, included 171 consecutive patients (82 in the PTCY and 89 in the SIR/TAC group). Results revealed a significantly decreased incidence of moderate and severe forms of chronic GVHD in PTCY cohort (5.8% [95% CI, 1.8 to 13.1]) versus the SIR/TAC cohort (39.6% [95% CI, 29.3 to 49.7] (p < 0.001)). Other outcomes, including GRFS (PTCY [45.9% (95% CI, 35.8–58.7)] and SIR/TAC groups [36.8% (95% CI, 28–48.4)], (p = 0.72)), non-relapse mortality (NRM), relapse and overall survival (OS) were similar in both groups. Interestingly, the failure to achieve GRFS was mainly attributed to GVHD in the SIR/TAC group, while disease relapse was the primary reason in the PTCY cohort.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Cummulative incidence of GVHD, NRM and relapse in PTCY vs SIR/TAC groups.
Fig. 2: DFS, OS and GRFS in PTCY vs SIR/TAC groups.
Fig. 3: Events responsible for GRFS failure in PTCY vs SIR/TAC groups.

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Snowden JA, Sánchez-ortega I, Corbacioglu S, Basak GW, Chabannon C, Camara R, et al. Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2022. 2022;(May).

  2. Cieri N, Maurer K, Wu CJ. 60 years young: The evolving role of allogeneic hematopoietic stem cell transplantation in cancer immunotherapy. Cancer Res. 2021;81:4373–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Perez-Simón JA, Martino R, Parody R, Cabrero M, Lopez-Corral L, Valcarcel D, et al. The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate. Haematologica. 2013;98:526–32.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bailén R, Kwon M, Pascual-Cascón MJ, Ferrà C, Sanz J, Gallardo-Morillo A, et al. Post-transplant cyclophosphamide for GVHD prophylaxis compared to ATG-based prophylaxis in unrelated donor transplantation. Ann Hematol. 2021;100:541–53. http://springer.longhoe.net/10.1007/s00277-020-04317-7.

  5. Mehta RohteshS, Saliba RimaM, Chen Julianne, Rondon Gabriela, Hammerstrom AimeeE, Alousi Amin, et al. Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. Br J Haematol. 2016;173:444–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Maurer K, Ho VT, Inyang E, Cutler CS, Koreth J, Shapiro RM, et al. Posttransplant cyclophosphamide vs tacrolimus-based GVHD prophylaxis: lower incidence of relapse and chronic GVHD. Blood Adv. 2023;7:3903–15. https://doi.org/10.1182/bloodadvances.2023009791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McCurdy SR, Luznik L. Relapse after allogeneic transplantation with post-transplant cyclophosphamide: Shattering myths and evolving insight. Blood Rev. 2023:101093. https://doi.org/10.1016/j.blre.2023.101093

  8. Mussetti A, Kanate AS, Wang T, He M, Hamadani M, Finel H, et al. Haploidentical versus matched unrelated donor transplants using post-transplantation cyclophosphamide for lymphomas. Transpl Cell Ther. 2023;29:184.e1–184.e9.

    Article  CAS  Google Scholar 

  9. Bolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N. Engl J Med. 2023;388:2338–48.

    Article  PubMed  PubMed Central  Google Scholar 

  10. García-Cadenas I, Esquirol A, Bosch-Vilaseca A, Awol R, Novelli S, Saavedra S, et al. Patterns of infection and infectious-related mortality in patients receiving post-transplant high dose cyclophosphamide as graft-versus-host-disease prophylaxis: impact of HLA donor matching. Bone Marrow Transpl. 2021;56:818–27. https://doi.org/10.1038/s41409-020-01092-x.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Jagasia MH, Greinix HT, Arora M, Williams KM, Cheng G, Kerr H, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease. Biol Blood Marrow Transpl. 2015;21:389–401.

    Article  Google Scholar 

  13. Copelan E, Casper JT, Carter SL, van Burik JAH, 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 Transpl. 2007;13:1469–76.

    Article  Google Scholar 

  14. Sathish N, Wu CA. Let’s flip: an approach to understand median follow-up by the reverse Kaplan-Meier estimator from a statistical programmer’s perspective. PharmaSUG. 2019;1:5.

    Google Scholar 

  15. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34:3661–79.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res. 2011;46:399–424.

    Article  Google Scholar 

  17. Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014;124:1372–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ho VT, Aldridge J, Kim HT, Cutler C, Koreth J, Antin JH, et al. Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transpl. 2009;15:844–50.

    Article  CAS  Google Scholar 

  19. Khimani F, Kim J, Chen L, Dean E, Rizk V, Betts B, et al. Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention. Bone Marrow Transpl. 2017;52:1003–9. https://doi.org/10.1038/bmt.2017.63.

    Article  CAS  Google Scholar 

  20. Kanakry CG, O’Donnell 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;32:3497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Broers AEC, de Jong CN, Bakunina K, Hazenberg MD, van Marwijk Kooy M, de Groot MR, et al. Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv. 2022;6:3378–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mehta RS, Saliba RM, Rondon G, Al-Atrash G, Bashir Q, Hosing CM, et al. Post-transplantation cyclophosphamide versus tacrolimus and methotrexate graft-versus-host disease prophylaxis for HLA-matched donor transplantation. Transpl Cell Ther. 2022;28:695.e1–695.e10. https://doi.org/10.1016/j.jtct.2022.07.021.

    Article  CAS  Google Scholar 

  23. Holtan SG, Hamadani M, WU J, AL Malki MM, Runaas L, Elmariah H, et al. Post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil as the new standard for graft-versus-host disease (GVHD) prophylaxis in reduced intensity conditioning: results from phase III BMT CTN 1703. Blood. 2022;140:LBA-4–LBA-4. https://doi.org/10.1182/blood-2022-171463.

    Article  Google Scholar 

  24. García-Cadenas I, Redondo S, Esquirol A, Portos JM, Novelli S, Saavedra S, et al. Successful outcome in patients with myelofibrosis undergoing allogeneic donor hematopoietic cell transplantation using reduced doses of post-transplantation cyclophosphamide: challenges and review of the literature. Transpl Cell Ther. 2023;29:1–6.

    Article  Google Scholar 

  25. McAdams MJ, Hyder M, Dimitrova D, Sadler JL, McKeown C, Steinberg SM, et al. Phase I/II study of reduced dosing of post-transplantation cyclophosphamide (PTCy) after HLA-haploidentical bone marrow transplantation. Blood. 2021;138:101–101.

    Article  Google Scholar 

  26. García-Cadenas I, Awol R, Esquirol A, Saavedra S, Bosch-Vilaseca A, Novelli S, et al. Incorporating posttransplant cyclophosphamide-based prophylaxis as standard-of-care outside the haploidentical setting: challenges and review of the literature. Bone Marrow Transpl. 2020;55:1041–9. https://doi.org/10.1038/s41409-019-0771-2.

    Article  CAS  Google Scholar 

  27. 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 Transpl. 2020;26:1179–88.

    Article  Google Scholar 

  28. Mehta RS, Saliba RM, Ghanem S, Alousi AM, Rondon G, Anderlini P, et al. Haploidentical versus matched unrelated versus matched sibling donor hematopoietic cell transplantation with post-transplantation cyclophosphamide. Transpl Cell Ther. 2022;28:395.e1–395.e11. https://doi.org/10.1016/j.jtct.2022.04.020.

    Article  CAS  Google Scholar 

  29. Mikulska M, Bartalucci C, Raiola AM, Oltolini C. Does PTCY increase the risk of infections? Blood Rev. 2023:101092. https://doi.org/10.1016/j.blre.2023.101092.

  30. McCurdy SR, Luznik L. Immune reconstitution after T-cell replete HLA-haploidentical transplantation. Semin Hematol. 2019;56:221–6.

  31. Aldiwani M, Tharakan T, Al-Hassani A, Gibbons N, Pavlu J, Hrouda D. BK Virus Associated Haemorrhagic Cystitis. A systematic review of current prevention and treatment strategies. Int J Surg. 2019;63:34–42. https://doi.org/10.1016/j.ijsu.2019.01.019.

    Article  CAS  PubMed  Google Scholar 

  32. Salas MQ, Prem S, Atenafu EG, Datt Law A, Lam W, Al-Shaibani Z, et al. Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD. Bone Marrow Transpl. 2020;55:1773–83. https://doi.org/10.1038/s41409-020-0813-9.

    Article  CAS  Google Scholar 

  33. Mohyuddin GR, Roller J, Shune L, Lin T, Dias A, Ganguly S, et al. Epstein-Barr viremia and post-transplant lymphoproliferative disorders in patients undergoing haploidentical stem cell transplantation with post-transplant cyclophosphamide. Hematol Oncol Stem Cell Ther. 2019;12:171–3. https://doi.org/10.1016/j.hemonc.2018.11.002.

    Article  PubMed  Google Scholar 

  34. Imus PH, Tsai HL, DeZern AE, Jerde K, Swinnen LJ, Bolaños-Meade J, et al. Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. Biol Blood Marrow Transpl. 2020;26:2306–10.

    Article  CAS  Google Scholar 

  35. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M.L.F. is PhD candidate at Universidad Autònoma de Barcelona. This work is submitted in partial fulfillment of the requirement for the PhD.

Author information

Author notes

  1. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Department of Hematology, Vall d’Hebron University Hospital, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus; Departament of Medicine, Universidat Autònoma de Barcelona (UAB), Bellaterra, Spain

    Maria Laura Fox, Guillermo Ortí, Olga Salamero, Ana Pérez González, Pere Barba, Francesc Bosch & David Valcárcel

  2. Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Irene García-Cadenas, Albert Esquirol & Rodrigo Martino

  3. Universidat Autònoma de Barcelona (UAB), Bellaterra, Spain

    Irene García-Cadenas, Albert Esquirol & Rodrigo Martino

  4. Oncology Data Science (ODysSey) Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Victor Navarro

  5. Hematology Department, Hospital Clínico Universitario, Valencia, Spain

    Ariadna Pérez Martínez & Carlos Solano

  6. Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain

    Meriem Kara, Alberto Mussetti & Carlos Solano

  7. Hematology Department, Hospital Regional Universitario de Málaga, Málaga, Spain

    Irene Sánchez Bazán, Alberto Mussetti & Carlos Solano

  8. Hematology Department, Hospital Germans Trias i Pujol, Barcelona, Spain. Universitat de Vic - Universitat Central de Catalunya, Vic, Spain

    Christelle Ferra Coll, Alberto Mussetti & Carlos Solano

  9. Department of Hematology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón Universidad Complutense de Madrid, Madrid, Spain

    Rebeca Bailén, Alberto Mussetti, Mi Kwon & Carlos Solano

  10. Hematology Department, Hospital Universitario Son Espases,IdISBa, Palma de Mallorca, Spain

    Leyre Bento, Alberto Mussetti & Carlos Solano

  11. Clinical Hematology Department, Institut Català d’Oncologia-Hospitalet, Barcelona, Spain

    Rocío Parody, Alberto Mussetti & Carlos Solano

  12. Department of Medicine, University of Valencia, Valencia, Spain

    Carlos Solano

Authors
  1. Maria Laura Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene García-Cadenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ariadna Pérez Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meriem Kara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Irene Sánchez Bazán
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christelle Ferra Coll
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rebeca Bailén
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Leyre Bento
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rocío Parody
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Albert Esquirol
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guillermo Ortí
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alberto Mussetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Olga Salamero
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rodrigo Martino
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ana Pérez González
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Pere Barba
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mi Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Carlos Solano
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Francesc Bosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. David Valcárcel
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH-TC)

  • Maria Laura Fox
  • , Irene García-Cadenas
  • , Ariadna Pérez Martínez
  • , Irene Sánchez Bazán
  • , Christelle Ferra Coll
  • , Rebeca Bailén
  • , Leyre Bento
  • , Rocío Parody
  • , Albert Esquirol
  • , Guillermo Ortí
  • , Alberto Mussetti
  • , Olga Salamero
  • , Rodrigo Martino
  • , Ana Pérez González
  • , Pere Barba
  • , Mi Kwon
  • , Carlos Solano
  •  & David Valcárcel

Contributions

M.L.F. designed the research, analyzed results, made the figures and wrote the paper. I.G. C., P.B and D.V. designed the research; V.N. performed statistical analysis and made the figures; K.M., A.P.M., I.S.B., C.F.C, L.B.M., R.B., E.R., R. P.P, A.E. and A.G.M., collected data. And all authors contributed to the manuscript review and approved the final version for submission.

Corresponding author

Correspondence to Maria Laura Fox.

Ethics declarations

Competing interests

R.B.A.: Speaker: Pfizer, Gilead. Travel: Jazz, Pfizer, Gilead, AstraZeneca. Funding: Jazz. M.K. Gilead, Novartis, BMS and Pfizer. All other authors declare no competing financial interests. The current affiliation for CF is Division of Hematology, Hospital del Mar, Barcelona, Spain.

Consent to participate

All transplantation centers are required to obtain written informed consent from all patients before data registration with the EBMT in accordance with the 1975 Helsinki Declaration.

Ethical approval

Institutional Review and Privacy Board of University Hospital Vall d´Hebron granted approval for this retrospective review (reference code HEM-TIO-2017-01).

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fox, M.L., García-Cadenas, I., Navarro, V. et al. Post-transplant cyclophosphamide compared to sirolimus/tacrolimus in reduced intensity conditioning transplants for patients with lymphoid malignancies. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02322-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41409-024-02322-2

  • Springer Nature Limited

Search

Navigation