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Published in: Annals of Hematology 10/2018

01-10-2018 | Original Article

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

Authors: Ioanna Sakellari, Eleni Gavriilaki, Konstantinos Chatziioannou, Maria Papathanasiou, Despina Mallouri, Ioannis Batsis, Zoi Bousiou, Stella Bouziana, Varnavas Constantinou, Vassiliki Douka, Chrysa Apostolou, Michalis Iskas, Chrysavgi Lalayanni, Anastasia Athanasiadou, Damianos Sotiropoulos, Evangelia Yannaki, Vasilis Gianouzakos, Achilles Anagnostopoulos

Published in: Annals of Hematology | Issue 10/2018

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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.
Literature
1.
go back to reference 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):511–533PubMed 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):511–533PubMed
2.
go back to reference 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):1182–1186CrossRefPubMed 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):1182–1186CrossRefPubMed
3.
go back to reference 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):2723–2730PubMed 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):2723–2730PubMed
4.
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
5.
go back to reference 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):1060–1067PubMed 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):1060–1067PubMed
6.
go back to reference 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. CrossRefPubMed 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/​NEJM198312013092​202.​ CrossRefPubMed
7.
go back to reference Tutschka PJ, Copelan EA, Klein JP (1987) Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70(5):1382–1388PubMed Tutschka PJ, Copelan EA, Klein JP (1987) Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70(5):1382–1388PubMed
8.
go back to reference 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):493–500CrossRefPubMed 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):493–500CrossRefPubMed
9.
go back to reference 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):285–286PubMed 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):285–286PubMed
10.
go back to reference 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):145–154CrossRefPubMed 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):145–154CrossRefPubMed
12.
14.
go back to reference 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. CrossRefPubMed 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.​ CrossRefPubMed
15.
go back to reference 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. CrossRefPubMedPubMedCentral 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.​ CrossRefPubMedPubMedCentral
16.
go back to reference 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. CrossRefPubMed 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.​ CrossRefPubMed
18.
go back to reference 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):825–828PubMed 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):825–828PubMed
19.
go back to reference 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-ixCrossRefPubMed 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-ixCrossRefPubMed
20.
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
24.
Metadata
Title
Long-term outcomes of total body irradiation plus cyclophosphamide versus busulfan plus cyclophosphamide as conditioning regimen for acute lymphoblastic leukemia: a comparative study
Authors
Ioanna Sakellari
Eleni Gavriilaki
Konstantinos Chatziioannou
Maria Papathanasiou
Despina Mallouri
Ioannis Batsis
Zoi Bousiou
Stella Bouziana
Varnavas Constantinou
Vassiliki Douka
Chrysa Apostolou
Michalis Iskas
Chrysavgi Lalayanni
Anastasia Athanasiadou
Damianos Sotiropoulos
Evangelia Yannaki
Vasilis Gianouzakos
Achilles Anagnostopoulos
Publication date
01-10-2018
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 10/2018
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-018-3383-9

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