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01-06-2023 | Graft-Versus-Host Disease | Review Article

Posttransplant cyclophosphamide beyond haploidentical transplantation

Authors: Leonardo Javier Arcuri, Andreza Alice Feitosa Ribeiro, Nelson Hamerschlak, Mariana Nassif Kerbauy

Published in: Annals of Hematology | Issue 5/2024

Abstract

Posttransplant cyclophosphamide (PTCy) has practically revolutionized haploidentical (Haplo) hematopoietic cell transplantation (HCT). Comparisons between Haplo with PTCy and unrelated donor (URD) with conventional graft-versus-host disease (GVHD) prophylaxis have shown comparable overall survival with lower incidences of GVHD with Haplo/PTCy and led to the following question: is it PTCy so good that can be successfully incorporated into matched related donor (MRD) and URD HCT? In this review, we discuss other ways of doing PTCy, PTCy in peripheral blood haploidentical transplants, PTCy in the context of matched related and matched unrelated donors, PTCy with mismatched unrelated donors, and PTCy following checkpoint inhibitor treatment. PTCy is emerging as a new standard GVHD prophylaxis in haploidentical, HLA-matched, and -mismatched HCT.

Luznik L, O’Donnell PV, Symons HJ et al (2008) HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14:641–650. https://doi.org/10.1016/j.bbmt.2008.03.005CrossRefPubMedPubMedCentral

Arcuri LJ, Aguiar MTM, Ribeiro AAF, Pacheco AGF (2019) Haploidentical transplantation with post-transplant cyclophosphamide versus unrelated donor hematopoietic stem cell transplantation: a systematic review and meta-analysis. Biol Blood Marrow Transplant 25:2422–2430. https://doi.org/10.1016/j.bbmt.2019.07.028CrossRefPubMed

Luznik L, Pasquini MC, Logan B et al (2022) Randomized phase III BMT CTN trial of calcineurin inhibitor–free chronic graft-versus-host disease interventions in myeloablative hematopoietic cell transplantation for hematologic malignancies. JCO 40:356–368. https://doi.org/10.1200/JCO.21.02293CrossRef

Zu Y, Li Z, Gui R et al (2022) Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial. Bone Marrow Transplant 57:1573–1580. https://doi.org/10.1038/s41409-022-01754-yCrossRefPubMedPubMedCentral

Bolaños-Meade J, Reshef R, Fraser R et al (2019) 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 6:e132–e143. https://doi.org/10.1016/S2352-3026(18)30221-7CrossRefPubMedPubMedCentral

Kanakry CG, O’Donnell PV, Furlong T et al (2014) 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. JCO 32:3497–3505. https://doi.org/10.1200/JCO.2013.54.0625CrossRef

Moiseev IS, Pirogova OV, Alyanski AL et al (2016) Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant 22:1037–1042. https://doi.org/10.1016/j.bbmt.2016.03.004CrossRefPubMed

Gooptu M, Romee R, St. Martin A et al (2021) HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis. Blood 138:273–282. https://doi.org/10.1182/blood.2021011281

Brissot E, Labopin M, Moiseev I et al (2020) 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 13:87. https://doi.org/10.1186/s13045-020-00923-0CrossRefPubMedPubMedCentral

10.

Mehta RS, Saliba RM, Rondon G et al (2022) Post-transplantation cyclophosphamide versus tacrolimus and methotrexate graft-versus-host disease prophylaxis for HLA-matched donor transplantation. Transplant Cell Ther 28:695.e1-695.e10. https://doi.org/10.1016/j.jtct.2022.07.021CrossRefPubMed

11.

Berro M, Rivas M, Trucco J et al (2021) Post-transplant cyclophosphamide demonstrates lower non-relapse mortality and better graft-versus-host disease/relapse-free survival compared with antithymocyte globulin in unrelated donor hematopoietic stem cell transplantation. A single-center experience. Bone Marrow Transplant 56:986–988. https://doi.org/10.1038/s41409-020-01146-0CrossRefPubMed

12.

Cooper DL, Manago J, Patel V et al (2021) Incorporation of posttransplant cyclophosphamide as part of standard immunoprophylaxis for all allogeneic transplants: a retrospective, single institution study. Bone Marrow Transplant 56:1099–1105. https://doi.org/10.1038/s41409-020-01144-2CrossRefPubMed

13.

Holtan SG, Hamadani M, Wu J et al (2022) 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 140:LBA-4-LBA-4. https://doi.org/10.1182/blood-2022-171463

14.

Broers AEC, de Jong CN, Bakunina K et al (2022) Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial. Blood Adv 6:3378–3385. https://doi.org/10.1182/bloodadvances.2021005847CrossRefPubMedPubMedCentral

15.

Brissot E, Lpobin M, Labussiere H et al (2021) POST-transplantation cyclophosphamide vs. antithymocyte globulin after ric regimen allo-hct: first analysis of a prospective randomized multicenter trial in recipients of 10/10 matched donors. Bone Marrow Transplant 56:12–13. https://doi.org/10.1038/s41409-021-01341-7CrossRef

16.

Carnevale-Schianca F, Caravelli D, Gallo S et al (2021) Post-transplant cyclophosphamide and tacrolimus—mycophenolate mofetil combination governs GVHD and immunosuppression need, reducing late toxicities in allogeneic peripheral blood hematopoietic cell transplantation from HLA-matched donors. JCM 10:1173. https://doi.org/10.3390/jcm10061173CrossRefPubMedPubMedCentral

17.

Chevallier P, Le Bourgeois A, Garnier A et al (2021) A prospective phase 2 study testing high dose post-transplant cyclophosphamide as sole GHVD prophylaxis after matched allotransplant using Baltimore-based reduced-intensity conditioning regimens and PBSC as source of graft. Blood 138:1812–1812. https://doi.org/10.1182/blood-2021-149534CrossRef

18.

Solomon SR, Sanacore M, Zhang X et al (2014) Calcineurin inhibitor–free graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide and brief-course sirolimus following reduced-intensity peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 20:1828–1834. https://doi.org/10.1016/j.bbmt.2014.07.020CrossRefPubMed

19.

Greco R, Lorentino F, Morelli M et al (2016) Posttransplantation cyclophosphamide and sirolimus for prevention of GVHD after HLA-matched PBSC transplantation. Blood 128:1528–1531. https://doi.org/10.1182/blood-2016-06-723205CrossRefPubMed

20.

Kunacheewa C, Owattanapanish W, Jirabanditsakul C, Issaragrisil S (2020) Post-transplant cyclophosphamide and thymoglobulin, a graft-versus-host disease prophylaxis in matched sibling donor peripheral blood stem cell transplantations. Cell Transplant 29:096368972096590. https://doi.org/10.1177/0963689720965900CrossRef

21.

Spyridonidis A, Labopin M, Brissot E et al (2022) Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. https://doi.org/10.1038/s41409-022-01816-1

22.

Kwon M, Bailén R, Pascual-Cascón MJ et al (2019) Posttransplant cyclophosphamide vs cyclosporin A and methotrexate as GVHD prophylaxis in matched sibling transplantation. Blood Adv 3:3351–3359. https://doi.org/10.1182/bloodadvances.2019000236CrossRefPubMedPubMedCentral

23.

Shaw BE, Jimenez-Jimenez AM, Burns LJ et al (2021) National marrow donor program–sponsored multicenter, phase II trial of HLA-mismatched unrelated donor bone marrow transplantation using post-transplant cyclophosphamide. JCO 39:1971–1982. https://doi.org/10.1200/JCO.20.03502CrossRef

24.

Battipaglia G, Labopin M, Kröger N et al (2019) Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood 134:892–899. https://doi.org/10.1182/blood.2019000487CrossRefPubMed

25.

Jimenez Jimenez A, Komanduri K, Brown S et al (2022) Improved GRFS after posttransplant cyclophosphamide-based vs ATG-based HLA-mismatched unrelated donor transplant. Blood Adv 6:4491–4500. https://doi.org/10.1182/bloodadvances.2022007596CrossRefPubMedPubMedCentral

26.

Modi D, Kondrat K, Kim S et al (2021) Post-transplant cyclophosphamide versus thymoglobulin in hla-mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome. Transplant Cell Ther 27:760–767. https://doi.org/10.1016/j.jtct.2021.06.018CrossRefPubMed

27.

Mehta RS, Saliba RM, Hayase E et al (2022) Mycophenolate mofetil: a friend or a foe with post-transplantation cyclophosphamide and tacrolimus prophylaxis in HLA-matched donors? Transplant Cell Ther 28:500.e1-500.e10. https://doi.org/10.1016/j.jtct.2022.05.039CrossRefPubMed

28.

Koura D, Tzachanis D, Ball ED et al (2021) A randomized phase II trial comparing a calcineurin inhibitor-free graft-versus-host disease prophylaxis regimen with post-transplantation cyclophosphamide and abatacept to standard of care. Blood 138:1816–1816. https://doi.org/10.1182/blood-2021-145824CrossRef

29.

Bejanyan N, Pidala JA, Wang X et al (2021) A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation. Blood Adv 5:1154–1163. https://doi.org/10.1182/bloodadvances.2020003779CrossRefPubMedPubMedCentral

30.

Battipaglia G, Labopin M, Blaise D et al (2022) Impact of the addition of antithymocyte globulin to post-transplantation cyclophosphamide in haploidentical transplantation with peripheral blood compared to post-transplantation cyclophosphamide alone in acute myelogenous leukemia: a retrospective study on behalf of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. Transplant Cell Ther 28:587.e1-587.e7. https://doi.org/10.1016/j.jtct.2022.06.006CrossRefPubMed

31.

Zhang W, Gui R, Zu Y et al (2022) Reduced‐dose post‐transplant cyclophosphamide plus low‐dose post‐transplant anti‐thymocyte globulin as graft‐versus‐host disease prophylaxis with fludarabine–busulfan–cytarabine conditioning in haploidentical peripheral blood stem cell transplantation: a multicentre, randomized controlled clinical trial. Br J Haematol. https://doi.org/10.1111/bjh.18483

32.

Chiusolo P, Bug G, Olivieri A et al (2018) A modified post-transplant cyclophosphamide regimen, for unmanipulated haploidentical marrow transplantation, in acute myeloid leukemia: a multicenter study. Biol Blood Marrow Transplant 24:1243–1249. https://doi.org/10.1016/j.bbmt.2018.01.031CrossRefPubMed

33.

Lazzari L, Balaguer-Roselló A, Montoro J et al (2022) Post-transplant cyclophosphamide and sirolimus based graft-versus-host disease prophylaxis after allogeneic stem cell transplantation for acute myeloid leukemia. Bone Marrow Transplant 57:1389–1398. https://doi.org/10.1038/s41409-022-01725-3CrossRefPubMedPubMedCentral

34.

McAdams MJ, Hyder M, Dimitrova D et al (2021) Phase I/II study of reduced dosing of post-transplantation cyclophosphamide (PTCy) after HLA-haploidentical bone marrow transplantation. Blood 138:101–101. https://doi.org/10.1182/blood-2021-146997CrossRef

35.

Sugita J, Kamimura T, Ishikawa T et al (2021) Reduced dose of posttransplant cyclophosphamide in HLA-haploidentical peripheral blood stem cell transplantation. Bone Marrow Transplant 56:596–604. https://doi.org/10.1038/s41409-020-01065-0CrossRefPubMed

36.

Duléry R, Goudet C, Mannina D et al (2022) Reduced post-transplant cyclophosphamide doses in haploidentical hematopoietic cell transplantation for elderly patients with hematological malignancies. Bone Marrow Transplant. https://doi.org/10.1038/s41409-022-01908-yCrossRefPubMedPubMedCentral

37.

Al-Homsi AS, Roy TS, Cole K et al (2015) Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant 21:604–611. https://doi.org/10.1016/j.bbmt.2014.08.014CrossRefPubMed

38.

Strauss G, Osen W, Debatin K-M (2002) Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs. Clin Exp Immunol 128:255–266. https://doi.org/10.1046/j.1365-2249.2002.01777.xCrossRefPubMedPubMedCentral

39.

Kanakry CG, Ganguly S, Zahurak M et al (2013) Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med 5. https://doi.org/10.1126/scitranslmed.3006960

40.

Kanakry CG, Coffey DG, Towlerton AMH et al (2016) Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight 1. https://doi.org/10.1172/jci.insight.86252

41.

Arcuri LJ, Hamerschlak N, Rocha V et al (2021) Outcomes after haploidentical hematopoietic cell transplantation with post-transplantation cyclophosphamide: a systematic review and meta-analysis comparing myeloablative with reduced-intensity conditioning regimens and bone marrow with peripheral blood stem cell grafts. Transplant Cell Ther 27:782.e1-782.e7. https://doi.org/10.1016/j.jtct.2021.06.011CrossRefPubMed

42.

Salas MQ, Prem S, Remberger M et al (2020) High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis. Leuk Lymphoma 61:3198–3208. https://doi.org/10.1080/10428194.2020.1797010CrossRefPubMed

43.

Kanakry CG, Bolaños-Meade J, Kasamon YL et al (2017) Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide. Blood 129:1389–1393. https://doi.org/10.1182/blood-2016-09-737825CrossRefPubMedPubMedCentral

44.

Holtick U, Chemnitz J-M, Shimabukuro-Vornhagen A et al (2016) OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation. Eur J Haematol 96:27–35. https://doi.org/10.1111/ejh.12541CrossRefPubMed

45.

Salas MQ, Atenafu EG, Law AD et al (2021) Lower dose of ATG combined with post-transplant cyclophosphamide for HLA matched RIC alloHCT is associated with effective control of GVHD and less viral infections. Leuk Lymphoma 62:3373–3383. https://doi.org/10.1080/10428194.2021.1966781CrossRefPubMed

46.

on behalf of Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH), Bailén R, Kwon M et al (2021) Post-transplant cyclophosphamide for GVHD prophylaxis compared to ATG-based prophylaxis in unrelated donor transplantation. Ann Hematol 100:541–553. https://doi.org/10.1007/s00277-020-04317-7

47.

O’Donnell PV, Luznik L, Jones RJ et al (2002) Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 8:377–386. https://doi.org/10.1053/bbmt.2002.v8.pm12171484CrossRefPubMed

48.

Goldsmith SR, Abid MB, Auletta JJ et al (2021) Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood 137:3291–3305. https://doi.org/10.1182/blood.2020009362CrossRefPubMedPubMedCentral

49.

Solán L, Landete E, Bailén R et al (2020) Cytokine release syndrome after allogeneic stem cell transplantation with posttransplant cyclophosphamide. Hematol Oncol 38:597–603. https://doi.org/10.1002/hon.2772CrossRefPubMed

50.

Oltolini C, Greco R, Galli L et al (2020) Infections after allogenic transplant with post-transplant cyclophosphamide: impact of donor HLA matching. Biol Blood Marrow Transplant 26:1179–1188. https://doi.org/10.1016/j.bbmt.2020.01.013CrossRefPubMed

51.

Kumar K, Subash C, Prabhu D et al (2021) Experience of low dose (25mg/Kg) of cyclophosphamide (Chennai-Chezhian-Kishore PTCy Protocol) as post transplant cyclophosphamide (PTCy) dose in haploidentical bone marrow transplant. Blood 138:4867–4867. https://doi.org/10.1182/blood-2021-144784CrossRef

52.

Bobillo S, Nieto JC, Barba P (2021) Use of checkpoint inhibitors in patients with lymphoid malignancies receiving allogeneic cell transplantation: a review. Bone Marrow Transplant 56:1784–1793. https://doi.org/10.1038/s41409-021-01268-zCrossRefPubMed

53.

Schoch LK, Cooke KR, Wagner-Johnston ND et al (2018) Immune checkpoint inhibitors as a bridge to allogeneic transplantation with posttransplant cyclophosphamide. Blood Adv 2:2226–2229. https://doi.org/10.1182/bloodadvances.2018019208CrossRefPubMedPubMedCentral

54.

Paul S, Zahurak M, Luznik L et al (2020) Non-myeloablative allogeneic transplantation with post-transplant cyclophosphamide after immune checkpoint inhibition for classic hodgkin lymphoma: a retrospective cohort study. Biol Blood Marrow Transplant 26:1679–1688. https://doi.org/10.1016/j.bbmt.2020.06.012CrossRefPubMedPubMedCentral

55.

Oran B, Garcia-Manero G, Saliba RM et al (2020) Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors. Cancer 126:2193–2205. https://doi.org/10.1002/cncr.32796CrossRefPubMed

56.

Saberian C, Abdel-Wahab N, Abudayyeh A et al (2021) Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation. J Immunother Cancer 9:e001818. https://doi.org/10.1136/jitc-2020-001818

57.

Nikoloudis A, Buxhofer-Ausch V, Aichinger C et al (2023) Adverse impact of a high CD4 / CD8 ratio in the allograft may be overcome by methotrexate- but not mycophenolate- or post-transplant cyclophosphamide-based graft versus host disease prophylaxis. Eur J Haematol 110:715–724. https://doi.org/10.1111/ejh.13956CrossRefPubMed

58.

Clausen J, Böhm A, Straßl I et al (2017) HLA-C KIR-ligands determine the impact of anti-thymocyte globulin (ATG) on graft versus host and graft versus leukemia effects following hematopoietic stem cell transplantation. Biomedicines 5:13. https://doi.org/10.3390/biomedicines5020013CrossRefPubMedPubMedCentral

Title: Posttransplant cyclophosphamide beyond haploidentical transplantation
Authors: Leonardo Javier Arcuri
Andreza Alice Feitosa Ribeiro
Nelson Hamerschlak
Mariana Nassif Kerbauy
Publication date: 01-06-2023
Publisher: Springer Berlin Heidelberg
Keywords: Graft-Versus-Host Disease
Graft-Versus-Host Disease
Mycophenolate Mofetil
Tacrolimus
Published in: Annals of Hematology / Issue 5/2024
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-023-05300-8

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