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Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia: a comparative study

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Abstract

The role of total body irradiation (TBI) in allogeneic hematopoietic stem cell transplantation (HCT) for adult acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we investigated long-term treatment outcomes of transplanted ALL patients aiming to identify prognostic factors and the impact of conditioning. We enrolled consecutive ALL patients transplanted from 1990 to 2016, following TBI- or busulfan (Bu)-based conditioning regimen. We studied 151 ALL patients transplanted in first complete remission (CR) (60), other CR (33), or relapsed/refractory disease (58) from sibling (87), and HLA-matched (42) or mismatched (17) unrelated and alternative donors (5). High-dose fractionated TBI-based conditioning was administered in 84. No differences were observed in baseline characteristics, except for disease stage at transplant, donor type, and graft source. With a follow-up of 19.0 (0.5–170.5) in TBI and 14.5 (1.2–319.1) months in non-TBI patients, there was no difference in acute (grades II–IV) or chronic GVHD, thrombotic microangiopathy, and bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group. There was no significant difference in the cumulative incidence (CI) of treatment-related or relapse mortality and disease-free or overall survival (OS). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p = 0.024), advanced disease stage (p = 0.007), and female-to-male donor (p = 0.006). Interestingly, TBI patients younger than 40 years had significantly higher OS (55.1%, p = 0.023) and DFS (48.6%, p = 0.020). In conclusion, high-dose TBI is feasible in younger patients providing better survival. The choice between TBI- or Bu-conditioning regimens remains challenging.

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References

  1. Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N, Goodell BW, Hickman RO, Lerner KG, Neiman PE, Sale GE, Sanders JE, Singer J, Stevens M, Storb R, Weiden PL (1977) One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49(4):511–533

    CAS  PubMed  Google Scholar 

  2. Ferry C, Socie G (2003) Busulfan-cyclophosphamide versus total body irradiation-cyclophosphamide as preparative regimen before allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia: what have we learned? Exp Hematol 31(12):1182–1186

    Article  CAS  PubMed  Google Scholar 

  3. Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L et al (1994) 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 83(9):2723–2730

    CAS  PubMed  Google Scholar 

  4. Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S (2003) Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant 32(6):543–548. https://doi.org/10.1038/sj.bmt.1704198

    Article  CAS  PubMed  Google Scholar 

  5. Granados E, de La Camara R, Madero L, Diaz MA, Martin-Regueira P, Steegmann JL et al (2000) Hematopoietic cell transplantation in acute lymphoblastic leukemia: better long term event-free survival with conditioning regimens containing total body irradiation. Haematologica 85(10):1060–1067

    CAS  PubMed  Google Scholar 

  6. Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM (1983) Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309(22):1347–1353. https://doi.org/10.1056/NEJM198312013092202.

    Article  CAS  PubMed  Google Scholar 

  7. Tutschka PJ, Copelan EA, Klein JP (1987) Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70(5):1382–1388

    CAS  PubMed  Google Scholar 

  8. Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W et al (2002) 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 8(9):493–500

    Article  CAS  PubMed  Google Scholar 

  9. Kim SE, Lee JH, Choi SJ, Ryu SG, Lee KH (2005) Morbidity and non-relapse mortality after allogeneic bone marrow transplantation in adult leukemia patients conditioned with busulfan plus cyclophosphamide: a retrospective comparison of oral versus intravenous busulfan. Haematologica 90(2):285–286

    CAS  PubMed  Google Scholar 

  10. Andersson BS, Kashyap A, Gian V, Wingard JR, Fernandez H, Cagnoni PJ, Jones RB, Tarantolo S, Hu WW, Blume KG, Forman SJ, Champlin RE (2002) 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 8(3):145–154

    Article  CAS  PubMed  Google Scholar 

  11. Ljungman P, Hassan M, Bekassy AN, Ringden O, Oberg G (1997) High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. Bone Marrow Transplant 20(11):909–913. https://doi.org/10.1038/sj.bmt.1700994

    Article  CAS  PubMed  Google Scholar 

  12. Shi-Xia X, Xian-Hua T, Hai-Qin X, Bo F, Xiang-Feng T (2010) Total body irradiation plus cyclophosphamide versus busulphan with cyclophosphamide as conditioning regimen for patients with leukemia undergoing allogeneic stem cell transplantation: a meta-analysis. Leuk Lymphoma 51(1):50–60. https://doi.org/10.3109/10428190903419130

    Article  CAS  PubMed  Google Scholar 

  13. Tang W, Wang L, Zhao WL, Chen YB, Shen ZX, Hu J (2011) Intravenous busulfan-cyclophosphamide as a preparative regimen before allogeneic hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 17(10):1555–1561. https://doi.org/10.1016/j.bbmt.2011.04.003.

    Article  CAS  PubMed  Google Scholar 

  14. Mitsuhashi K, Kako S, Shigematsu A, Atsuta Y, Doki N, Fukuda T, Kanamori H, Onizuka M, Takahashi S, Ozawa Y, Kurokawa M, Inoue Y, Nagamura-Inoue T, Morishima Y, Mizuta S, Tanaka J, Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (2016) Comparison of cyclophosphamide combined with total body irradiation, oral busulfan, or intravenous busulfan for allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 22(12):2194–2200. https://doi.org/10.1016/j.bbmt.2016.09.007.

    Article  CAS  PubMed  Google Scholar 

  15. Kebriaei P, Anasetti C, Zhang MJ, Wang HL, Aldoss I, de Lima M, Khoury HJ, Sandmaier BM, Horowitz MM, Artz A, Bejanyan N, Ciurea S, Lazarus HM, Gale RP, Litzow M, Bredeson C, Seftel MD, Pulsipher MA, Boelens JJ, Alvarnas J, Champlin R, Forman S, Pullarkat V, Weisdorf D, Marks DI, Hogan W, Battiwalla M, Copelan E, Hildebrandt G, Ganguly S, Majhail N, Woolfrey A, Nivison-Smith I, Hertzberg M, Diaz MA, Jakubowski A, Ustun C, Yong A, Freytes C, DeFilipp Z, Inamoto Y, Cahn JY, Savani B, Yared J, Bajel A, Bacher U, Uy G, Rizzieri D, Wieduwilt M, Schultz K, Grunwald M, Kamble R, Qayed M, Brammer J, Ballen K, Khera N, Schouten H, Bierings M, Kanakry C, Wood WA, Saad A, Savoie L, Hamilton BK, Aljurf M, Vij R, Pawarode A, Olsson R, Wirk BM, Beitinjaneh A, Seo S, Cerny J, Akpek G, Norkin M, Nishihori T, Lazaryan A, Sabloff M (2017) Intravenous busulfan compared with total body irradiation pretransplant conditioning for adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 24:726–733. https://doi.org/10.1016/j.bbmt.2017.11.025.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Eder S, Canaani J, Beohou E, Labopin M, Sanz J, Arcese W, Or R, Finke J, Cortelezzi A, Beelen D, Passweg J, Socié G, Gurman G, Aljurf M, Stelljes M, Giebel S, Mohty M, Nagler A (2017) Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: a matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Am J Hematol 92(10):997–1003. https://doi.org/10.1002/ajh.24823.

    Article  CAS  PubMed  Google Scholar 

  17. Friend BD, Schiller GJ (2017) Closing the gap: novel therapies in treating acute lymphoblastic leukemia in adolescents and young adults. Blood Rev 32:122–129. https://doi.org/10.1016/j.blre.2017.09.005

    Article  PubMed  Google Scholar 

  18. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828

    CAS  PubMed  Google Scholar 

  19. Flowers ME, Kansu E, Sullivan KM (1999) Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am 13(5):1091–1112 viii-ix

    Article  CAS  PubMed  Google Scholar 

  20. Sakellari I, Batsis I, Bousiou Z, Mallouri D, Constantinou V, Gavriilaki E, Smias C, Yannaki E, Kaloyannidis P, Papaioannou G, Stavroyianni N, Syrigou A, Sotiropoulos D, Fylaktou A, Tsompanakou A, Saloum R, Anagnostopoulos A (2017) The role of low-dose anti-thymocyte globulin as standard prophylaxis in mismatched and matched unrelated hematopoietic peripheral stem cell transplantation for hematologic malignancies. Clin Lymphoma Myeloma Leuk 17(10):658–666. https://doi.org/10.1016/j.clml.2017.06.008

    Article  PubMed  Google Scholar 

  21. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    Article  CAS  PubMed  Google Scholar 

  22. Hartman AR, Williams SF, Dillon JJ (1998) 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 22(5):439–443. https://doi.org/10.1038/sj.bmt.1701334

    Article  CAS  PubMed  Google Scholar 

  23. Hwang YY, Mohty M, Chim CS (2015) Allogeneic hematopoietic stem cell transplantation in Philadelphia-negative adult ALL: myeloablative, non-myeloablative, and beyond. Hematology 20(2):61–71. https://doi.org/10.1179/1607845414Y.0000000175

    Article  CAS  PubMed  Google Scholar 

  24. Giebel S, Labopin M, Socie G, Beelen D, Browne P, Volin L et al (2017) Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 102(1):139–149. https://doi.org/10.3324/haematol.2016.145631

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS et al (2012) Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 119(1):296–307. https://doi.org/10.1182/blood-2011-06-364265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakasone H, Fukuda T, Kanda J, Mori T, Yano S, Kobayashi T et al (2015) Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. Bone Marrow Transplant 50(4):559–565. https://doi.org/10.1038/bmt.2014.293

    Article  CAS  PubMed  Google Scholar 

  27. Cho YH, Lim HA, Lee MH, Kim I, Lee JS, Park S et al (2007) Pharmacokinetics and tolerability of intravenous busulfan in hematopoietic stem cell transplantation. Clin Transpl 21(3):417–422. https://doi.org/10.1111/j.1399-0012.2007.00664.x

    Article  Google Scholar 

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Correspondence to Eleni Gavriilaki.

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Sakellari, I., Gavriilaki, E., Chatziioannou, K. et al. Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia: a comparative study. Ann Hematol 97, 1987–1994 (2018). https://doi.org/10.1007/s00277-018-3383-9

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