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Graft Source

Bone marrow graft as a source of allogeneic hematopoietic stem cells in patients undergoing a reduced intensity conditioning regimen

Abstract

In an attempt to reduce the incidence of chronic GVHD (cGVHD) after reduced-intensity conditioning (RIC), we used BM instead of PBSC and added melphalan 100 mg/m2 to the classical association of fludarabine, 30 mg/m2/day for 3 days and TBI, 200 cGy (FLUIM regimen). Between 2000 and 2012, 51 patients received BM with the FLUIM regimen (group A), and 124 received BM (n=22) or PBSC (n=102) with another RIC regimen (group B). Donors were siblings (n=123) or HLA-matched 10/10 unrelated (n=52). Full donor-type chimerism at day 100 was more often recorded in group A (86%) than in group B (62%); P<0.001. There was no difference between the two groups in terms of OS and EFS, acute GVHD, relapse and non-relapse mortality incidence. cGVHD occurred more often in group B (41%) than in group A (23%); P=0.021. In multivariate analysis, the two risk factors associated with the development of cGVHD were conditioning in group B (hazard ratio (HR)=2.871, 95% confidence interval (CI) (1.372–6.006); P=0.005) and CD34+ count (HR=1.009, 95% CI (1.006–1.011); P<0.001). In conclusion, the FLUIM regimen followed by BM leads to more frequent full-donor chimerism and a reduced incidence of cGVHD without compromising relapse and survival.

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References

  1. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  2. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  3. Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620–1629.

    Article  CAS  PubMed  Google Scholar 

  4. Saito T, Kanda Y, Kami M, Kato K, Shoji N, Kanai S et al. Therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antithymocyte globulin against advanced/refractory acute leukemia/lymphoma. Clin Cancer Res 2002; 8: 1014–1020.

    CAS  PubMed  Google Scholar 

  5. Kassim AA, Chinratanalab W, Ferrara JL, Mineishi S . Reduced-intensity allogeneic hematopoietic stem cell transplantation for acute leukemias: 'what is the best recipe? Bone Marrow Transplant 2005; 36: 565–574.

    Article  CAS  PubMed  Google Scholar 

  6. McSweeney PA, Storb R . Mixed chimerism: preclinical studies and clinical applications. Biol Blood Marrow Transplant 1999; 5: 192–203.

    Article  CAS  PubMed  Google Scholar 

  7. Storb R, Yu C, Barnett T, Wagner JL, Deeg HJ, Nash RA et al. Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation. Blood 1999; 94: 1131–1136.

    CAS  PubMed  Google Scholar 

  8. Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.

    CAS  PubMed  Google Scholar 

  9. Baron F, Little MT, Storb R . Kinetics of engraftment following allogeneic hematopoietic cell transplantation with reduced-intensity or nonmyeloablative conditioning. Blood Rev 2005; 19: 153–164.

    Article  PubMed  Google Scholar 

  10. Dreger P, Haferlach T, Eckstein V, Jacobs S, Suttorp M, Loffler H et al. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safety, kinetics of mobilization, and composition of the graft. Br J Haematol 1994; 87: 609–613.

    Article  CAS  PubMed  Google Scholar 

  11. Diez-Campelo M, Perez-Simon JA, Ocio EM, Castilla C, Gonzalez-Porras JR, Sanchez-Guijo FM et al. CD34+cell dose and outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation. Leuk Lymphoma 2005; 46: 177–183.

    Article  CAS  PubMed  Google Scholar 

  12. Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 2009; 27: 4570–4577.

    Article  PubMed  Google Scholar 

  13. Vigorito AC, Azevedo WM, Marques JF, Azevedo AM, Eid KA, Aranha FJ et al. A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant 1998; 22: 1145–1151.

    Article  CAS  PubMed  Google Scholar 

  14. Blaise D, Kuentz M, Fortanier C, Bourhis JH, Milpied N, Sutton L et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 2000; 18: 537–546.

    Article  CAS  PubMed  Google Scholar 

  15. Morton J, Hutchins C, Durrant S . Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood 2001; 98: 3186–3191.

    Article  CAS  PubMed  Google Scholar 

  16. Group SCTC. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005; 23: 5074–5087.

  17. Mohty M, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood 2002; 100: 3128–3134.

    Article  CAS  PubMed  Google Scholar 

  18. Sarosy G, Leyland-Jones B, Soochan P, Cheson BD . The systemic administration of intravenous melphalan. J Clin Oncol 1988; 6: 1768–1782.

    Article  CAS  PubMed  Google Scholar 

  19. Singhal S, Powles R, Treleaven J, Horton C, Swansbury GJ, Mehta J . Melphalan alone prior to allogeneic bone marrow transplantation from HLA-identical sibling donors for hematologic malignancies: alloengraftment with potential preservation of fertility in women. Bone Marrow Transplant 1996; 18: 1049–1055.

    CAS  PubMed  Google Scholar 

  20. Gandhi V, Plunkett W . Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 2002; 41: 93–103.

    Article  CAS  PubMed  Google Scholar 

  21. Rubio MT, Charbonnier A, de Berranger E, Gandemer V, Magro L, Maury S et al. [Vaccination post hematopoietic stem cell transplantation: which vaccines and when and, how to vaccinate? An SFGM-TC report]. Pathol Biol (Paris) 2013; 61: 139–143.

    Article  Google Scholar 

  22. Rohrlich PS, Kerautret K, Bancillon N, Vauzelle K, Bertrand-Letort M, Ruiz M et al. [Social connection: a report of the SFGM-TC on the maintaining social and family connections during Hematopoietic Stem Cell Transplantation]. Pathol Biol (Paris) 2013; 61: 160–163.

    Article  CAS  Google Scholar 

  23. Dulery R, Giraud C, Beaumont JL, Bilger K, Borel C, Dhedin N et al. [How to handle unexpected biological abnormalities observed in the pre-donation workup for hematopoietic stem cell transplantation: an SFGM-TC report on pre-transplant cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii, or syphilis IgM positive serology test]. Pathol Biol (Paris) 2013; 61: 155–157.

    Article  CAS  Google Scholar 

  24. Deconinck E, Dalle JH, Berceanu A, Chevallier P, Dulery R, Garnier A et al. How I manage respiratory syncytial virus, human herpesvirus 6 and adenovirus reactivation or infection after allogeneic stem cell transplantation: a report of the SFGM-TC. Pathol Biol (Paris) 2013; 61: 149–151.

    Article  CAS  Google Scholar 

  25. Cornillon J, Vantyghem MC, Couturier MA, de Berranger E, Francois S, Hermete E et al. Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on adrenal insufficiency and osteoporosis. Pathol Biol (Paris) 2013; 61: 171–173.

    Article  CAS  Google Scholar 

  26. Cornillon J, Vantyghem MC, Couturier MA, de Berranger E, Francois S, Hermet E et al. Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on dyslipidemia and thyroid disorders. Pathol Biol (Paris) 2013; 61: 168–170.

    Article  CAS  Google Scholar 

  27. Cornillon J, Decanter C, Couturier MA, de Berranger E, Francois S, Hermet E et al. Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility. Pathol Biol (Paris) 2013; 61: 164–167.

    Article  CAS  Google Scholar 

  28. Bay JO, Peffault de Latour R, Bruno B, Coiteux V, Guillaume T, Hicheri Y et al. Diagnosis and treatment of CMV and EBV reactivation as well as post-transplant lymphoproliferative disorders following allogeneic stem cell transplantation: an SFGM-TC report. Pathol Biol (Paris) 2013; 61: 152–154.

    Article  Google Scholar 

  29. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    Google Scholar 

  30. Filipovich AH, Weisdorf D, Pavletic S, Socie 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: 945–956.

    Article  PubMed  Google Scholar 

  31. Zhang X, Zhang MJ, Fine J . A proportional hazards regression model for the subdistribution with right-censored and left-truncated competing risks data. Stat Med 2011; 30: 1933–1951.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mahmoud H, Fahmy O, Kamel A, Kamel M, El-Haddad A, El-Kadi D . Peripheral blood vs bone marrow as a source for allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 1999; 24: 355–358.

    Article  CAS  PubMed  Google Scholar 

  33. Powles R, Mehta J, Kulkarni S, Treleaven J, Millar B, Marsden J et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000; 355: 1231–1237.

    Article  CAS  PubMed  Google Scholar 

  34. Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. New Engl J Med 2001; 344: 175–181.

    Article  CAS  PubMed  Google Scholar 

  35. Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, Howson-Jan K et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 2002; 100: 1525–1531.

    Article  CAS  PubMed  Google Scholar 

  36. Nagler A, Labopin M, Shimoni A, Mufti GJ, Cornelissen JJ, Blaise D et al. Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission: a retrospective analysis from the Acute Leukemia Working Party of EBMT. Eur J Haematol 2012; 89: 206–213.

    Article  PubMed  Google Scholar 

  37. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.

    Article  CAS  PubMed  Google Scholar 

  38. Gahrton G, Iacobelli S, Bandini G, Bjorkstrand B, Corradini P, Crawley C et al. Peripheral blood or bone marrow cells in reduced-intensity or myeloablative conditioning allogeneic HLA identical sibling donor transplantation for multiple myeloma. Haematologica 2007; 92: 1513–1518.

    Article  PubMed  Google Scholar 

  39. Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant 2006; 12: 560–565.

    Article  PubMed  Google Scholar 

  40. Mohty M, Labopin M, Balere ML, Socie G, Milpied N, Tabrizi R et al. Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Leukemia 2010; 24: 1867–1874.

    Article  CAS  PubMed  Google Scholar 

  41. Dulery R, Mohty M, Duhamel A, Robin M, Beguin Y, Michallet M et al. Antithymocyte globulin before allogeneic stem cell transplantation for progressive myelodysplastic syndrome: a study from the French Society of Bone Marrow Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 2014; 20: 646–654.

    Article  CAS  PubMed  Google Scholar 

  42. Yakoub-Agha I, de La Salmoniere P, Ribaud P, Sutton L, Wattel E, Kuentz M et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol 2000; 18: 963–971.

    Article  CAS  PubMed  Google Scholar 

  43. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. New Engl J Med 2007; 356: 1110–1120.

    Article  CAS  PubMed  Google Scholar 

  44. Weisdorf D, Hakke R, Blazar B, Miller W, McGlave P, Ramsay N et al. Risk factors for acute graft-versus-host disease in histocompatible donor bone marrow transplantation. Transplantation 1991; 51: 1197–1203.

    Article  CAS  PubMed  Google Scholar 

  45. Hersh MR, Ludden TM, Kuhn JG, Knight WA 3rd . Pharmacokinetics of high dose melphalan. Invest New Drugs 1983; 1: 331–334.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all of the team members and nursing staff for providing our patients with high-quality care. We are also grateful to the association Capucine for their help in our research.

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Correspondence to I Yakoub-Agha.

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This study was partly presented at the European Bone Marrow Transplantation Congresses, April 2010, Vienna, Austria, and April 2011, Paris, France, and at the Société Française de Greffe de Moelle et de Thérapie Cellulaire annual meeting, September 2010, Paris, France.

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Gomez, E., Duléry, R., Langlois, C. et al. Bone marrow graft as a source of allogeneic hematopoietic stem cells in patients undergoing a reduced intensity conditioning regimen. Bone Marrow Transplant 49, 1492–1497 (2014). https://doi.org/10.1038/bmt.2014.193

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