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A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies.
Biol Blood Marrow Transplant. 2017 Dec; 23(12):2088-2095.BB

Abstract

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies.

Authors+Show Affiliations

Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York. Electronic address: spitzerb@mskcc.org.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York.Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York.Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York.Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York.Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28711727

Citation

Spitzer, Barbara, et al. "A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed By Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 23, no. 12, 2017, pp. 2088-2095.
Spitzer B, Jakubowski AA, Papadopoulos EB, et al. A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies. Biol Blood Marrow Transplant. 2017;23(12):2088-2095.
Spitzer, B., Jakubowski, A. A., Papadopoulos, E. B., Fuller, K., Hilden, P. D., Young, J. W., Barker, J. N., Koehne, G., Perales, M. A., Hsu, K. C., van den Brink, M. R., Kernan, N. A., Prockop, S. E., Scaradavou, A., Castro-Malaspina, H., O'Reilly, R. J., & Boulad, F. (2017). A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 23(12), 2088-2095. https://doi.org/10.1016/j.bbmt.2017.07.004
Spitzer B, et al. A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed By Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies. Biol Blood Marrow Transplant. 2017;23(12):2088-2095. PubMed PMID: 28711727.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies. AU - Spitzer,Barbara, AU - Jakubowski,Ann A, AU - Papadopoulos,Esperanza B, AU - Fuller,Kirsten, AU - Hilden,Patrick D, AU - Young,James W, AU - Barker,Juliet N, AU - Koehne,Guenther, AU - Perales,Miguel-Angel, AU - Hsu,Katharine C, AU - van den Brink,Marcel R, AU - Kernan,Nancy A, AU - Prockop,Susan E, AU - Scaradavou,Andromachi, AU - Castro-Malaspina,Hugo, AU - O'Reilly,Richard J, AU - Boulad,Farid, Y1 - 2017/07/12/ PY - 2017/05/05/received PY - 2017/07/07/accepted PY - 2017/7/18/pubmed PY - 2018/8/2/medline PY - 2017/7/17/entrez KW - Chemotherapy-only KW - Hematopoietic stem cell transplantations KW - Myeloid malignancies KW - T-cell depleted SP - 2088 EP - 2095 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 23 IS - 12 N2 - We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/28711727/A_Chemotherapy_Only_Regimen_of_Busulfan_Melphalan_and_Fludarabine_and_Rabbit_Antithymocyte_Globulin_Followed_by_Allogeneic_T_Cell_Depleted_Hematopoietic_Stem_Cell_Transplantations_for_the_Treatment_of_Myeloid_Malignancies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(17)30573-6 DB - PRIME DP - Unbound Medicine ER -