Prevention of Acute Graft-Versus-Host Reaction after Allogeneic Unrelated Hematopoietic Stem Cell Transplantation: Comparison of Effectiveness of Treatment Regimens Based on Anti-Thymocyte Globulin and Cyclophosphamide

BONE MARROW TRANSPLANTATION , , , ,

OV Pirogova, IS Moiseev, EV Babenko, OA Slesarchuk, OV Paina, SN Bondarenko, EV Morozova, AL Alyanskii, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Ol’ga Vladislavovna Pirogova, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)338-62-65; e-mail: dr.pirogova@gmail.com

For citation: Pirogova OV, Moiseev IS, Babenko EV, et al. Prevention of Acute Graft-Versus-Host Reaction after Allogeneic Unrelated Hematopoietic Stem Cell Transplantation: Comparison of Effectiveness of Treatment Regimens Based on Anti-Thymocyte Globulin and Cyclophosphamide. Clinical oncohematology. 2016;9(4):391–97 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-391-397

ABSTRACT

Background & Aims. So far there is no data presented on the effectiveness of prevention of the graft-versus-host reaction (GVH) using post-transplant cyclophosphamide (PTCy) prescribed after unrelated donor allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of this study is to evaluate the incidence of acute and chronic GVH, the transplantation-associated mortality rate, the event-free and overall survival rates, as well as the toxicity profile and the incidence of infectious complications in the study group using cyclophosphamide for GVH prevention; the other aim is to carry out a comparative analysis of the obtained results with the historical control group.

Methods. 110 adult patients were enrolled in a clinical study to evaluate the effectiveness of GVH prevention, using PTCy (No. NCT02294552). In order to prevent GVH, the study group (PTCy group) received cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF). The historical control group (ATG group) consisted of 160 patients prescribed with a GVH prevention regimen including anti-thymocyte globulin (ATG), calcineurin inhibitors, and methotrexate or MMF. Peripheral blood stem cells were used as a source of the transplant.

Results. The cumulative incidence of II–IV degree acute GVH (18.2 % vs. 40.4 %, respectively; p < 0.0001), III–IV degree GVH (4.5 % vs. 22.5 %, respectively; p < 0.0001), and chronic GVH (21.7 % vs. 40.6 %, respectively; p < 0.0001) was significantly lower in the PTCy group than in the ATG group. Prevention of GVH based on PTCy was associated with the reduction in transplant-associated mortality (12.7 % vs. 33.7 %, respectively; p = 0.003), increased overall survival (70.9 % vs. 44.4 %, respectively; p < 0.001), event-free survival (68.2 % vs. 38.1 %, respectively; p < 0.001) and GVH- and relapse-free survival rates (59.1 % vs. 16.3 %, respectively; p = 0.001). Prevention of GVH using PTCy (as compared to ATG) was less toxic, accompanied by a reduction in the incidence veno-occlusive disease (2.7 % vs. 10.9 %, respectively; p = 0.016), severe mucositis (69.5 % vs. 87.6 %, respectively; p < 0.001), and invasive mycosis (7.2 % vs. 29 %, respectively; p < 0.001).

Conclusion. A combination of cyclophosphamide with tacrolimus and MMF is an effective regimen for GVH prevention in patients after allo-HSCT from an unrelated donor.

Keywords: graft-versus-host reaction, GVH prevention, allo-HCST, cyclophosphamide, anti-thymocyte globulin.

Received: March 30, 2016

Accepted: May 4, 2016

Read in PDF (RUS) pdficon

REFERENCES

  1. Thomas’ Hematopoietic Cell Transplantation. 3rd edition. Malden, MA: Blackwell Science Publishers; 2004. pp. 130–77. doi: 10.1002/9780470987070.
  2. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol. 1997;15(5):1767–77.
  3. Di Stasi A, Milton DR, Poon LM, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant. 2014;20(12):1975–81. doi: 10.1016/j.bbmt.2014.08.013.
  4. Zuckerman T, Rowe JM. Alternative donor transplantation in acute myeloid leukemia: which source and when? Curr Opin Hematol. 2007;14(2):152–61. doi: 1097/moh.0b013e328017f64d.
  5. Tolar J, Sodani P, Symons H, et al. Alternative donor transplant of benign primary hematologic disorders. Bone Marrow Transplant. 2015;50(5):619–27. doi: 10.1038/bmt.2015.1.
  6. Anasetti C, Beatty PG, Storb R, et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990;29(2):79–91. doi: 10.1016/0198-8859(90)90071-v.
  7. Kanda Y, Chiba S, Hirai H, et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991–2000). Blood. 2003;102(4):1541–7. doi: 10.1182/blood-2003-02-0430.
  8. Ruutu T, Gratwohl A, de Witte T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49(2):168–73. doi: 10.1038/bmt.2013.107.
  9. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. 2011;117(11):3214–9. doi: 10.1182/blood-2010-08-302109.
  10. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855–64. doi: 10.1016/S1470-2045(09)70225-6.
  11. Soiffer RJ, LeRademacher J, Ho V, et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. 2011;117(25):6963–70. doi: 10.1182/blood-2011-01-332007.
  12. O’Donnell MR, Long GD, Parker PM, et al. Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia. J Clin Oncol. 1995;13(12):2973–9.
  13. Lehnert S, Rybka WB. Amplification of the graft-versus-host reaction by cyclophosphamide: dependence on timing of drug administration. Bone Marrow Transplant. 1994;13(4):473–7. doi: 10.1097/00007890-198606000-00002.
  14. Mayumi H, Himeno K, Tanaka K, et al. Drug-induced tolerance to allografts in mice: Xii. The relationships between tolerance, chimerism, and graft-versus-host disease. Transplantation. 1987;44(2):286–90. doi: 10.1097/00007890-19870800-00021.
  15. Luznik L, Jalla S, Engstrom LW, et al. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98(12):3456–64. doi: 10.1182/blood.v98.12.3456.
  16. Santos GW, Owens AH Jr. A comparison of the effects of selected cytotoxic agents on allogeneic skin graft survival in rats. Bull Johns Hopkins Hosp. 1965;116:327–40.
  17. Berenbaum MC. Prolongation of homograft survival in mice with single doses of cyclophosphamide. 1963;200(4901):84. doi: 10.1038/200084a0.
  18. Owens AH Jr, Santos GW. The effect of cytotoxic drugs on graft-versus-host disease in mice. Transplantation. 1971;11(4):378–82. doi: 10.1097/00007890-197104000-00004.
  19. 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(6):641–50. doi: 10.1016/j.bbmt.2008.03.005.
  20. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825–8.
  21. Filipovich AH, Weisdorf D, Pavletic S, 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(12):945–56. doi: 1016/j.bbmt.2005.09.004.
  22. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637. doi: 10.1007/s00134-012-2769-8.
  23. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21. doi: 10.1086/588660.
  24. Luznik L, Bolanos-Meade J, Zahuraket M, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. 2010;115(16):3224–30. doi: 10.1182/blood-2009-11-251595.
  25. Kanakry CG, Tsai HL, Bolanos-Meade J, et al. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS. 2014;124(25):3817–27. doi: 10.1182/blood-2014-07-587477.
  26. Bradstock KF, Bilmon I, Kwan J, et al. Single-Agent High-Dose Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Human Leukocyte Antigen-Matched Reduced-Intensity Peripheral Blood Stem Cell Transplantation Results in an Unacceptably High Rate of Severe Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2015;21(5):941–4. doi: 10.1016/j.bbmt.2015.01.020.
  27. Holtick U, Chemnitz JM, Shimabukuro-Vornhagen A, et al. 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. 2015;96(1):27–35. doi: 10.1111/ejh.12541.
  28. Solomon SR, Sanacore M, Zhang X, et al. 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. 2014;20(11):1828–34. doi: 10.1016/j.bbmt.2014.07.020.