Reduced dose of posttransplant cyclophosphamide in HLA-haploidentical peripheral blood stem cell transplantation

Abstract

Posttransplant cyclophosphamide (PTCy:100 mg/kg) has been increasingly used in allogeneic hematopoietic stem cell transplantation, however, few studies compared different doses of PTCy. We conducted two consecutive prospective multicenter phase II studies to evaluate the safety and efficacy of 80 mg/kg of PTCy in 137 patients who underwent HLA-haploidentical peripheral blood stem cell transplantation (haploPBSCT) following reduced-intensity conditioning (RIC). GVHD prophylaxis consisted of PTCy at a dose of 40 mg/kg/day on days 3 and 4, tacrolimus, and mycophenolate mofetil. Neutrophil engraftment was achieved in 97% and 96% in the first and second studies, respectively. The incidences of grades II–IV acute GVHD, III–IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 26%, 5%, 35%, and 18% in the first study, and 23%, 1%, 28%, and 15% in the second study, respectively. Overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) at 2 years were 51%, 42%, and 18% in the first study, and 58%, 48%, and 16% in the second study, respectively. The rates of off-immunosuppressants in patients who survived without relapse at 2 years were 83 and 76%. Our results suggest that 80 mg/kg of PTCy is a valid option in haploPBSCT following RIC.

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Fig. 1: Time course of body temperature during the cytokine release syndrome early after haploPBSCT.
Fig. 2: Acute and Chronic GVHD.
Fig. 3: NRM.
Fig. 4: OS stratified by refined DRI.
Fig. 5: Systemic immunosuppression discontinuation.

References

  1. 1.

    McCurdy SR, Luznik L. How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide. Blood. 2019;134:1802–10.

    Article  CAS  Google Scholar 

  2. 2.

    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.

    Article  CAS  Google Scholar 

  3. 3.

    Sugita J, Kawashima N, Fujisaki T, Kakihana K, Ota S, Matsuo K, et al. HLA-haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide after busulfan-containing reduced-intensity conditioning. Biol Blood Marrow Transpl. 2015;21:1646–52.

    Article  Google Scholar 

  4. 4.

    Sugita J, Kagaya Y, Miyamoto T, Shibasaki Y, Nagafuji K, Ota S, et al. Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide. Bone Marrow Transpl. 2019;54:432–41.

    Article  CAS  Google Scholar 

  5. 5.

    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.

    CAS  Google Scholar 

  6. 6.

    Filipovich AH, Weisdorf D, Pavletic S, Socié 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.

    Article  Google Scholar 

  7. 7.

    Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–9.

    Article  CAS  Google Scholar 

  8. 8.

    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.

    Article  CAS  Google Scholar 

  9. 9.

    Bhamidipati PK, DiPersio JF, Stokerl-Goldstein K, Rashidi A, Gao F, Uy GL, et al. Haploidentical transplantation using G-CSF-mobilized T-cell replete PBSCs and post-transplantation CY after non-myeloablative conditioning is safe and is associated with favorable outcomes. Bone Marrow Transpl. 2014;49:1124–6.

    Article  CAS  Google Scholar 

  10. 10.

    Raj K, Pagliuca A, Bradstock K, Noriega V, Potter V, Streetly M, et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant. 2014;20:890–5.

    Article  Google Scholar 

  11. 11.

    Castagna L, Crocchiolo R, Fürst S, Bramanti S, Cheikh El J, Sarina B, et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide. Biol Blood Marrow Transpl. 2014;20:724–9.

    Article  Google Scholar 

  12. 12.

    Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, et al. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol. 2016;91:E284–92.

    Article  Google Scholar 

  13. 13.

    Gooley TA, Leisenring 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.

    Article  CAS  Google Scholar 

  14. 14.

    RJ G. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.

    Article  Google Scholar 

  15. 15.

    Kanda Y. Investigation of the freely available easy-to-use soft- ware ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  16. 16.

    Solomon SR, St Martin A, Shah NN, Fatobene G, Malki Al MM, Ballen KK, et al. Myeloablative vs reduced intensity T-cell-replete haploidentical transplantation for hematologic malignancy. Blood Adv. 2019;3:2836–44.

    Article  Google Scholar 

  17. 17.

    Im A, Rashidi A, Wang T, Hemmer M, MacMillan ML, Pidala J, et al. Risk factors for graft-versus-host disease in haploidentical hematopoietic cell transplantation using post-transplant cyclophosphamide. Biol Blood Marrow Transpl. 2020;26:1459–68.

    Article  CAS  Google Scholar 

  18. 18.

    McCurdy SR, Kanakry CG, Tsai H-L, Kasamon YL, Showel MM, Bolaños-Meade J, et al. Grade II acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after HLA-haploidentical transplant with post-transplant cyclophosphamide. Biol Blood Marrow Transpl. 2018;24:343–52.

    Article  CAS  Google Scholar 

  19. 19.

    McCurdy SR, Kanakry CG, Tsai H-L, Gojo I, Smith BD, Gladstone DE, et al. Development of grade II acute graft-versus-host disease is associated with improved survival after myeloablative HLA-matched bone marrow transplantation using single-agent post-transplant cyclophosphamide. Biol Blood Marrow Transpl. 2019;25:1128–35.

    Article  CAS  Google Scholar 

  20. 20.

    Gorgeis J, Zhang X, Connor K, Brown S, Solomon SR, Morris LE, et al. T cell-replete HLA haploidentical donor transplantation with post-transplant cyclophosphamide is an effective salvage for patients relapsing after an HLA-matched related or matched unrelated donor transplantation. Biol Blood Marrow Transpl. 2016;22:1861–6.

    Article  Google Scholar 

  21. 21.

    Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C, et al. Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation. Bone Marrow Transpl. 2014;49:895–901.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the grant from Regional Medicine Research Foundation (Tochigi, Japan), North Japan Hematology Study Group (NJHSG), and Japan Agency for Medical Research and Development (AMED, 19ek0510025h0002).

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Correspondence to Takanori Teshima.

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Sugita, J., Kamimura, T., Ishikawa, T. et al. Reduced dose of posttransplant cyclophosphamide in HLA-haploidentical peripheral blood stem cell transplantation. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-01065-0

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