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A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis.
Biol Blood Marrow Transplant. 2018 08; 24(8):1733-1740.BB

Abstract

With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n = 158) or CyTBI (n = 229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age <55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P = .036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.

Authors+Show Affiliations

Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address: Mahasweta_gooptu@dfci.harvard.edu.Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

29555313

Citation

Gooptu, Mahasweta, et al. "A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan With Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: a Cohort Analysis." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 24, no. 8, 2018, pp. 1733-1740.
Gooptu M, Kim HT, Ho VT, et al. A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis. Biol Blood Marrow Transplant. 2018;24(8):1733-1740.
Gooptu, M., Kim, H. T., Ho, V. T., Alyea, E. P., Koreth, J., Armand, P., Ritz, J., Nikiforow, S., Glotzbecker, B. E., Nageshwar, P., Soiffer, R. J., Antin, J. H., & Cutler, C. S. (2018). A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 24(8), 1733-1740. https://doi.org/10.1016/j.bbmt.2018.03.011
Gooptu M, et al. A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan With Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: a Cohort Analysis. Biol Blood Marrow Transplant. 2018;24(8):1733-1740. PubMed PMID: 29555313.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis. AU - Gooptu,Mahasweta, AU - Kim,Haesook T, AU - Ho,Vincent T, AU - Alyea,Edwin P, AU - Koreth,John, AU - Armand,Philippe, AU - Ritz,Jerome, AU - Nikiforow,Sarah, AU - Glotzbecker,Brett E, AU - Nageshwar,Prashant, AU - Soiffer,Robert J, AU - Antin,Joseph H, AU - Cutler,Corey S, Y1 - 2018/03/16/ PY - 2017/11/13/received PY - 2018/03/11/accepted PY - 2018/3/21/pubmed PY - 2019/7/11/medline PY - 2018/3/21/entrez KW - Allogeneic transplant KW - Fludarabine KW - Graft-versus-host disease KW - Myeloablative KW - Reduced toxicity SP - 1733 EP - 1740 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 24 IS - 8 N2 - With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n = 158) or CyTBI (n = 229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age <55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P = .036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/29555313/A_Comparison_of_the_Myeloablative_Conditioning_Regimen_Fludarabine/Busulfan_with_Cyclophosphamide/Total_Body_Irradiation_for_Allogeneic_Stem_Cell_Transplantation_in_the_Modern_Era:_A_Cohort_Analysis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(18)30124-1 DB - PRIME DP - Unbound Medicine ER -