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Conditioning Regimens

Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT

Abstract

Haploidentical SCT (HaploSCT) has been most commonly performed using a myeloablative, TBI-based preparative regimen; however, the toxicity with this approach remains very high. We studied the feasibility of a reduced-intensity conditioning regimen in a phase II clinical trial using fludarabine, melphalan and thiotepa and antithymocyte globulin (ATG) for patients with advanced hematological malignancies undergoing T-cell depleted HaploSCT. Twenty-eight patients were entered in the study. Engraftment with donor-derived hematopoiesis was achieved in 78% of patients after a median of 13 days. Six patients experienced primary graft failure, three out of four tested patients had donor-specific anti-HLA antibodies (DSA) (P=0.001). Toxicity included mostly infections. A total of 21 out of 22 patients with AML/myelodysplastic syndrome (MDS) achieved remission after transplant (16 with relapsed/refractory AML). Five out of the 12 patients (42%) with AML/MDS with <15% BM blasts survived long term as compared with none with more advanced disease (P=0.03). HaploSCT with this fludarabine, melphalan and thiotepa and ATG RIC is an effective, well-tolerated conditioning regimen for patients with AML/MDS with low disease burden at the time of transplant and allowed a high rate of engraftment in patients without DSA. Patients with overt relapse fared poorly and require novel treatment strategies.

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References

  1. Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977; 49: 1511–1533.

    Google Scholar 

  2. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    CAS  PubMed  Google Scholar 

  3. Beatty PG, Mori M, Milford E . Impact of racial genetic polymorphism on the probability of finding an HLA-matched donor. Transplantation 1995; 60: 778–783.

    Article  CAS  PubMed  Google Scholar 

  4. Schipper RF, D’Amaro J, Bakker JT, Bakker J, van Rood JJ, Oudshoorn M . HLA gene haplotype frequencies in bone marrow donors worldwide registries. Hum Immunol 1997; 52: 54–71.

    Article  CAS  PubMed  Google Scholar 

  5. Powles RL, Morgenstern GR, Kay HE, McElwain TJ, Clink HM, Dady PJ et al. Mismatched family donors for bone marrow transplantation as treatment for acute leukemia. Lancet 1983; 8325: 612–615.

    Article  Google Scholar 

  6. Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, Champlin RE et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.

    CAS  PubMed  Google Scholar 

  7. Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Cunningham-Rundles S, Dupont B et al. Transplantation for severe combined immunodeficiency with HLA-A, B, D, DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood 1983; 61: 341–348.

    CAS  PubMed  Google Scholar 

  8. Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Giannoni C et al. Successful engraftment of T-cell-depleted haploidentical ‘three-loci’ incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 1994; 84: 3948–3955.

    CAS  PubMed  Google Scholar 

  9. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA Haplotype. N Engl J Med 1998; 339: 1186–1193.

    Article  CAS  PubMed  Google Scholar 

  10. Aversa F, Terenzi A, Felicini R, Carotti A, Falcinelli F, Tabilio A et al. Haploidentical stem cell transplantation for acute leukemia. Int J Hematol 2002; 76: 165–168.

    Article  PubMed  Google Scholar 

  11. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447–3454.

    Article  PubMed  Google Scholar 

  12. Champlin R, Hesdorffer C, Lowenberg B, Martelli MF, Martelsmann RH, Reisner Y et al. Haploidentical ‘megadose’ stem cell transplantation in acute leukemia: recommendations for a protocol agreed upon at the Perugia and Chicago meetings. Leukemia 2002; 16: 427–428.

    Article  CAS  PubMed  Google Scholar 

  13. O’Reilly RJ . T-cell depletion and allogeneic bone marrow transplantation. Semin Hematol 1992; 29: 20–26.

    PubMed  Google Scholar 

  14. Handgretinger R, Klingebiel T, Lang P, Schumm M, Neu S, Geiselhart A et al. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 2001; 27: 777–783.

    Article  CAS  PubMed  Google Scholar 

  15. Szydlo R, Goldman JM, Klein JP, Gale RP, Ash RC, Bach FH et al. Results of allogeneic bone marrow transplant for leukemia using donors other then HLA-identical sibling. J Clin Oncol 1997; 15: 1767–1777.

    Article  CAS  PubMed  Google Scholar 

  16. Kato S, Yabe H, Yasui M, Kawa K, Yoshida T, Watanabe A et al. Allogeneic hematopoietic transplantation of CD34+ selected cells from an HLA haploidentical related donor. Along-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood. Bone Marrow Transplant 2000; 26: 1281–1290.

    Article  CAS  PubMed  Google Scholar 

  17. Dobyski WR, Klein J, Flomenberg N, Pietryga D, Vesole DH, Margolis DA et al. Superior survival associated with transplantation of matched unrelated versus on-antigen mismatched unrelated or highly human-leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts. Blood 2002; 99: 806–814.

    Article  Google Scholar 

  18. Kanda Y, Chiba S, Hirai H, Sakamaki H, Iseki T, Kodera Y et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991–2000). Blood 2003; 102: 1541–1547.

    Article  CAS  PubMed  Google Scholar 

  19. Mehta J, Singhal S, Gee AP, Chiang KY, Godder K, Rhee Fv F et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant 2004; 33: 389–396.

    Article  CAS  PubMed  Google Scholar 

  20. Koh LP, Rizzieri DA, Chao NJ . Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors. Biol Blood Marrow Transplant 2007; 13: 1249–1267.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Spitzer TR, McAfee SL, Dey BR, Colby C, Hope J, Grossberg H et al. Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation 2003; 75: 1448–1751.

    Article  Google Scholar 

  23. Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol 2007; 25: 690–697.

    Article  CAS  PubMed  Google Scholar 

  24. Miltenyi S . Isolation of CD34+ Hematopoietic Progenitor Cells By High-Gradient Magnetic Cell Sorting (MACS). In: Wunder E (ed). Hematopoietic Stem Cells: The Mullhouse Manual. AlphaMed Press: Dayton, OH, 1994, 201–213.

    Google Scholar 

  25. Thiede C, Florek M, Bornhauser M, Ritter M, Mohr B, Brendel C et al. Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transplant 1999; 23: 1055–1060.

    Article  CAS  PubMed  Google Scholar 

  26. Przepiorka D, Martin P, Klingmann HG, Beatty P, Hows J, Thomas ED . 1994 Consensus Conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  27. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  28. Common Toxicity Criteria Version 3 0 Available at http://ctep.info.nih.gov/reporting/ctc.html.

  29. Kaplan EL, Meier P . Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  30. Prentice RL, Kalbfleisch JD, Peterson Jr AV, Flournoy N, Farewell VT, Breslow NE . The analysis of failure times in the presence of competing risks. Biometrics 1978; 34: 541–554.

    Article  CAS  PubMed  Google Scholar 

  31. Cox DR . Regression models and life tables [with discussion]. J R Stat Soc B 1972; 34: 187–202.

    Google Scholar 

  32. Ruggeri L, Capanni M, Tosti A, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

    Article  CAS  PubMed  Google Scholar 

  33. Cooley S, Trachtenberg E, Bergemann TL, Saeteurn K, Klein J, Le CT et al. Donors with group B KiR haplotypes improve relapse-free survival after unrelated hematopoietic stem cell transplantation for acute myelogenous leukemia. Blood 2009; 113: 726–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van Rood JJ, Loberiza Jr FR, Zhang MJ, Oudshoorn M, Claas F, Cairo MS et al. Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or and HLA-haploidentical sibling. Blood 2002; 99: 1572–1577.

    Article  PubMed  Google Scholar 

  35. Lacerda JF, Martins C, Carmo JA, Lourenço F, Juncal C, Rodrigues A et al. Haploidentical stem cell transplantation with purified CD34+ cells after a chemotherapy-alone conditioning regimen. Biol Blood Marrow Transplant 2003; 9: 633–642.

    Article  CAS  PubMed  Google Scholar 

  36. Bethge WA, Haegele M, Faul C, Lang P, Schumm M, Bornhauser M et al. Haploidentical allogeneic stem cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol 2006; 34: 1746–1752.

    Article  CAS  PubMed  Google Scholar 

  37. Handgretinger R, Chen X, Pfeiffer M, Mueller I, Feuchtinger T, Hale GA et al. Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 2007; 1106: 279–289.

    Article  CAS  PubMed  Google Scholar 

  38. Ciceri F, Lobopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood 2008; 112: 3574–3581.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all our pharmacists, transplant coordinators and nursing staff for their dedication to patient care; research nurses, technicians and laboratory personnel who contributed to the collection, recording and reporting of the data.

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Correspondence to S O Ciurea.

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Ciurea, S., Saliba, R., Rondon, G. et al. Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT. Bone Marrow Transplant 45, 429–436 (2010). https://doi.org/10.1038/bmt.2009.189

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