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Conditioning

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS

Abstract

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m2/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19–74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2–4 and grade 3–4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).

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References

  1. Thomas ED, Buckner CD, Clift RA, Fefer A, Johnson FL, Neiman PE et al. Marrow transplant for acute nonlymphoblastic leukemia in first remission. N Engl J Med 1979; 301: 597–599.

    Article  CAS  PubMed  Google Scholar 

  2. Santos GW, Tutscka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB et al. Marrow transplant for acute nonlymphoblastic leucemia alter treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309: 1347–1353.

    Article  CAS  PubMed  Google Scholar 

  3. Tutscka PJ, Copeland EA, Klein JP . Bone marrow transplant for leukemia following a new busulfan and cyclophosphamide regimen. Blood 1987; 70: 1382–1388.

    Google Scholar 

  4. Copelan EA, Biggs JC, Thompson JM, Crilley P, Szer J, Klein JP et al. Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2. Blood 1991; 78: 838–843.

    CAS  PubMed  Google Scholar 

  5. Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse. Blood 1992; 79: 2578–2582.

    CAS  PubMed  Google Scholar 

  6. Ringdén O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindeløv L et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 1994; 83: 2723–2730.

    PubMed  Google Scholar 

  7. Hartman AR, Williams SF, Dillon JJ . Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis. Bone Marrow Transplant 1998; 22: 439–443.

    Article  CAS  PubMed  Google Scholar 

  8. Socié G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood 2001; 98: 3569–3574.

    Article  PubMed  Google Scholar 

  9. Andersson BS, Madden T, Tran HT, Tran HT, Hu WW, Blume KG et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant 2000; 6: 548–554.

    Article  CAS  PubMed  Google Scholar 

  10. Andersson BS, Kashyap A, Gian V, Gian V, Wingard JR, Fernandez H et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant 2002; 8: 145–154.

    Article  CAS  PubMed  Google Scholar 

  11. Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 2002; 8: 493–500.

    Article  CAS  PubMed  Google Scholar 

  12. Nagler A, Rocha V, Labopin M, Unal A, Ben Othman T, Campos A et al. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol 2013; 31: 3549–3556.

    Article  CAS  PubMed  Google Scholar 

  13. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X et al. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood 2013; 122: 3863–3870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Parimon T, Au DH, Martin PJ, Chien JW . A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med 2006; 144: 407–414.

    Article  PubMed  Google Scholar 

  15. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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 

  17. Sayer HG, Kröger M, Beyer J, Kiehl M, Klein SA, Schaefer-Eckart K et al. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant 2003; 31: 1089–1095.

    Article  CAS  PubMed  Google Scholar 

  18. Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J et al. Myelodysplastic Syndrome subcommittee of the Chronic Leukemia Working Party of the European Blood and Marrow Transplantation Group. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; 108: 836–846.

    Article  CAS  PubMed  Google Scholar 

  19. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant 2002; 8: 468–476.

    Article  CAS  PubMed  Google Scholar 

  20. de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004; 104: 857–864.

    Article  CAS  PubMed  Google Scholar 

  21. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M et al. Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant 2008; 14: 672–684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Alatrash G, de Lima M, Hamerschlak N, Pelosini M, Wang X, Xiao L et al. Myeloablative reduced-toxicity i.v. busulfan-fludarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life. Biol Blood Marrow Transplant 2011; 17: 1490–1496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Luger SM, Ringdén O, Zhang MJ, Pérez WS, Bishop MR, Bornhauser M et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2012; 47: 203–211.

    Article  CAS  PubMed  Google Scholar 

  24. Madden T, de Lima M, Thapar N, Nguyen J, Roberson S, Couriel D et al. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant 2007; 13: 56–64.

    Article  CAS  PubMed  Google Scholar 

  25. Röllig C, Bornhäuser M, Thiede C, Taube F, Kramer M, Mohr B et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European Leukemia Net recommendations: evaluation of the proposed reporting system. J Clin Oncol 2011; 29: 2758–2765.

    Article  PubMed  Google Scholar 

  26. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  27. Armand P, Gibson CJ, Cutler C, Ho VT, Koreth J, Alyea EP et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 2012; 120: 905–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sorror ML, Giralt S, Sandmaier BM, De Lima M, Shahjahan M, Maloney DG et al. Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences. Blood 2007; 110: 4606–4613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  PubMed  Google Scholar 

  30. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783.

    Article  CAS  PubMed  Google Scholar 

  31. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of HLA-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  32. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  33. Shulman HM, Sullivan KM, Weiden PI, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  PubMed  Google Scholar 

  34. 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  PubMed  Google Scholar 

  35. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist 1988; 16: 1141–1154.

    Article  Google Scholar 

  36. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Statist Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  37. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  38. Cox DR . Regression models and life tables (with discussion). J R Stat Soc B 1972; 34: 187–220.

    Google Scholar 

  39. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Statist Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  40. Team RDC. R A Language and Environment for Statistical Computing. 2012. Available at http://www.R-project.org.

  41. Russell JA, Duan Q, Chaudhry MA, Savoie ML, Balogh A, Turner AR et al. Transplantation from matched siblings using once-daily intravenous busulfan/fludarabine with thymoglobulin: a myeloablative regimen with low nonrelapse mortality in all but older patients with high-risk disease. Biol Blood Marrow Transplant 2008; 14: 888–895.

    Article  CAS  PubMed  Google Scholar 

  42. Carreras E, Díaz-Beyá M, Rosiñol L, Martínez C, Fernández-Avilés F, Rovira M . The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant 2011; 17: 1713–1720.

    Article  PubMed  Google Scholar 

  43. Carreras E . How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol 2015; 168: 481–491.

    Article  PubMed  Google Scholar 

  44. Nagler A, Labopin M, Berger R, Bunjes D, Campos A, Socié G et al. Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome. Bone Marrow Transplant 2014; 49: 628–633.

    Article  CAS  PubMed  Google Scholar 

  45. Iravani M, Evazi MR, Mousavi SA, Shamshiri AR, Tavakoli M, Ashouri A et al. Fludarabine and busulfan as a myeloablative conditioning regimen for allogeneic stem cell transplantation in high- and standard-risk leukemic patients. Bone Marrow Transplant 2007; 40: 105–110.

    Article  CAS  PubMed  Google Scholar 

  46. Patel P, Sweiss K, Nimmagadda S, Gao W, Rondelli D . Comorbidity index does not predict outcome in allogeneic myeloablative transplants conditioned with fludarabine/i.v. busulfan (FluBu4). Bone Marrow Transplant 2011; 46: 1326–1330.

    Article  CAS  PubMed  Google Scholar 

  47. Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014; 124: 1372–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kanakry CG, O'Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M et al. 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. J Clin Oncol 2014; 32: 3497–3505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bredeson C, LeRademacher J, Kato K, Dipersio JF, Agura E, Devine SM et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood 2013; 122: 3871–3878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW et al. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol 2013; 31: 701–709.

    Article  CAS  PubMed  Google Scholar 

  51. Liu H, Zhai X, Song Z, Sun J, Xiao Y, Nie D et al. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol 2013; 6: 15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2015; 16: 1525–1536.

    Article  CAS  PubMed  Google Scholar 

  53. Oudin C, Chevallier P, Furst S, Guillaume T, El Cheikh J, Delaunay J et al. Reduced-toxicity conditioning prior to allogeneic stem cell transplantation improves outcome in patients with myeloid malignancies. Haematologica 2014; 99: 1762–1768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Valcárcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577–584.

    Article  PubMed  Google Scholar 

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Acknowledgements

We greatly appreciate the participation of all the patients and their families. We are indebted to the contributing members of the GETH at the participating institutions, and nurses, data managers and physicians of the HCT teams at contributing sites. We specially thank Mr Luis Benlloch, GETH Data Manager, for data collection and database assembly. We also thank Dr Gregory Morley for editorial assistance. This clinical trial was funded in part by an educational grant from Pierre-Fabre Iberica Pharmaceutical. This company was not involved in the design and running of the trial, nor in the collection and analysis of the clinical data, and the final manuscript.

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De La Serna, J., Sanz, J., Bermúdez, A. et al. Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS. Bone Marrow Transplant 51, 961–966 (2016). https://doi.org/10.1038/bmt.2016.42

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