The Confirmation of Safety for the Intensified Conditioning Regimens: A Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Non-Remission Hematological Malignant Diseases
AbstractBackground: The prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) for non-remission hematological malignant diseases is usually unfavorable. The most uncontrollable factor is residual disease or relapse. To overcome this problem, intensified conditioning regimens- sequential and/or additional chemotherapy to the standard regimen- could be effective. However, increasing the intensity of conditioning might also lead to more complications.Materials and Methods: We retrospectively analyzed 81 patients with non-remission disease who received allogeneic HSCT in our institution between 2007 and 2011.Results: 55.6% in 36 myeloablative conditioning patients and 46.7% in 45 reduced-intensity conditioning patients received intensified conditioning. The 5-year probability of overall survival was 35.0% and 17.1% in the standard and intensified group, respectively (p=0.027). Relapse mortality was 30% in the standard regimen group and 36.6% in the intensified regimen group (p=0.54). Transplant-related mortality (TRM) at 30 and 100 days was 5%, 17.1% (p=0.086) and 27.5%, 34.2% (p=0.52) in the standard and intensified group, respectively. There was no difference in TRM between the 2 groups at 30 days and 100 days.Conclusion: The results of the study confirm the safety of the intensified conditioning regimen. Meanwhile, it could be considered as one of the few methods available to reduce the tumor burden before HSCT for refractory malignant diseases.
Gratwohl A, Brand R, Frassoni F, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005; 36(9):757-69.
Ringden O, Labopin M, Schmid C, et al. Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT. Br J Haematol. 2017; 176(3):431-39.
Ferguson P, Hills RK, Grech A, et al. An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation. Haematologica. 2016; 101(11):1351-8.
Chang C, Storer BE, Scott BL, et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood. 2007; 110(4):1379-87.
Avivi I, Canals C, Vernant JP, et al. Matched unrelated donor allogeneic transplantation provides comparable long-term outcome to HLA-identical sibling transplantation in relapsed diffuse large B-cell lymphoma. Bone Marrow Transplant. 2014; 49(5):671-8.
Hishizawa M, Kanda J, Utsunomiya A, et al. Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study. Blood. 2010; 116(8):1369-76.
Andersson BS, Valdez BC and Jones RB: Pharmacologic Basis for High-dose Chemotherapy (ed 5th). Thomas’ hematopoietic cell transplantation 5th ed. Blackwell science, 2016:211-22.
Bensinger WI: High-dose Preparatory regimens (ed 5th). Thomas’ hematopoietic cell transplantation 5th ed. Blackwell science, 2016:223-31
Giralt SA, LeMaistre CF, Vriesendorp HM, et al. Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. J Clin Oncol. 1994; 12(9):1923-30.
Hirabayashi N, Goto S, Ishii M, et al. Busulfan, cyclophosphamide and total body irradiation as conditioning for allogeneic bone marrow transplantation for acute and chronic myeloid leukemia. Bone Marrow Transplant. 1998; 21(11):1079-83.
Kanda Y, Sakamaki H, Sao H, et al. Effect of conditioning regimen on the outcome of bone marrow transplantation from an unrelated donor. Biol Blood Marrow Transplant 2005; 11(11):881-9.
Mengarelli A, Iori A, Guglielmi C, et al. Standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. Haematologica. 2002; 87(1):52-8.
Inamoto Y, Nishida T, Suzuki R, et al. Significance of additional high-dose cytarabine in combination with cyclophosphamide plus total body irradiation regimen for allogeneic stem cell transplantation. Bone Marrow Transplant. 2007; 39(1):25-30.
Shigematsu A, Kondo T, Yamamoto S, et al. Excellent outcome of allogeneic hematopoietic stem cell transplantation using a conditioning regimen with medium-dose VP-16, cyclophosphamide and total-body irradiation for adult patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2008; 14(5):568-75.
Mori T, Aisa Y, Kato J, et al. Safety and efficacy of total body irradiation, cyclophosphamide, and cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Am J Hematol. 2012; 87(4):349-53.
Kroger N, Zabelina T, Sonnenberg S, et al. Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia. Bone Marrow Transplant. 2000; 26(7):711-6.
Li QB, Li L, You Y, et al. A comparative study of outcomes of idarubicin- and etoposide-intensified conditioning regimens for allogeneic peripheral blood stem cell transplantation in patients with high-risk acute leukemia. Acta Pharmacol Sin. 2009; 30(10):1471-8.
Arita K, Kondo T, Sugita J, et al. Sequential chemotherapy and myeloablative allogeneic hematopoietic stem cell transplantation for refractory acute lymphoblastic leukemia. Int J Hematol. 2011; 94(3):291-5.
Hong M, Wu Q, Hu C, et al. Idarubicin-intensified BUCY2 regimens may lower relapse rate and improve survival in patients undergoing allo-SCT for high-risk hematological malignancies: a retrospective analysis. Bone Marrow Transplant. 2012; 47(2):196-202.
Liu QF, Fan ZP, Zhang Y, et al. Sequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia. Biol Blood Marrow Transplant. 2009; 15(11):1376-85.
Pfeiffer T, Schleuning M, Mayer J, et al. Influence of molecular subgroups on outcome of acute myeloid leukemia with normal karyotype in 141 patients undergoing salvage allogeneic stem cell transplantation in primary induction failure or beyond first relapse. Haematologica. 2013; 98(4):518-25.
Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005; 106(8):2912-9.
Morishima Y, Morishita Y, Tanimoto M, et al. Low incidence of acute graft-versus-host disease by the administration of methotrexate and cyclosporine in Japanese leukemia patients after bone marrow transplantation from human leukocyte antigen compatible siblings; possible role of genetic homogeneity. The Nagoya Bone Marrow Transplantation Group. Blood. 1989; 74(6):2252-6.
Terakura S, Wake A, Inamoto Y, et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transplant. 2017; 52(3):423-30.
Yamada Y, Tomonaga M, Fukuda H, et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol. 2001; 113(2):375-82.
Taguchi H, Kinoshita KI, Takatsuki K, et al. An intensive chemotherapy of adult T-cell leukemia/lymphoma: CHOP followed by etoposide, vindesine, ranimustine, and mitoxantrone with granulocyte colony-stimulating factor support. J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 12(2):182-6.
Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013; 48(3):452-58.
Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15(6):825-8.
Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin radiat oncol. 2003; 13(3):176-81.
Koh H, Nakamae H, Hagihara K, et al. Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation. J Exp Clin Cancer Res. 2011; 30:36.
Yamamoto H, Uchida N, Yuasa M, et al. A Novel Reduced-Toxicity Myeloablative Conditioning Regimen Using Full-Dose Busulfan, Fludarabine, and Melphalan for Single Cord Blood Transplantation Provides Durable Engraftment and Remission in Nonremission Myeloid Malignancies. Biol Blood Marrow Transplant. 2016; 22(10):1844-50.
Mori T, Aisa Y, Watanabe R, et al. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for de novo acute myelogenous leukemia with a conditioning regimen of total body irradiation and granulocyte colony-stimulating factor-combined high-dose cytarabine. Biol Blood Marrow Transplant. 2008; 14(6):651-7.
Mehta RS, Di Stasi A, Andersson BS, et al. The development of a myeloablative, reduced-toxicity, conditioning regimen for cord blood transplantation. Clin Lymphoma Myeloma Leuk. 2014; 14(1):e1-5.
Sakellari I, Mallouri D, Gavriilaki E, et al. Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2017; 23(3):445-51
Tsirigotis P, Byrne M, Schmid C, et al. Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant. 2016; 51:1431-8.
Schroeder T, Rachlis E, Bug G, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015; 21(4):653-60.
Ogawa H, Ikegame K, Yoshihara S, et al. Unmanipulated HLA 2-3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2006; 12(10):1073-84.
Kasamon YL, Luznik L, Leffell MS, et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant. 2010; 16(4):482-9.
Woo J, Deeg HJ, Storer B, et al. Factors Determining Responses to Azacitidine in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia with Early Post-Transplantation Relapse: A Prospective Trial. Biol Blood Marrow Transplant.2017; 23(1):176-9.
Ruutu T, de Wreede LC, van Biezen A, et al. Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplant. 2015; 50(12):1542-50.
Orti G, Sanz J, Bermudez A, et al. Outcome of Second Allogeneic Hematopoietic Cell Transplantation after Relapse of Myeloid Malignancies following Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort on Behalf of the Grupo Espanol de Trasplante Hematopoyetico. Biol Blood Marrow Transplant. 2016; 22(3):584-8.
Miyakoshi S, Yuji K, Kami M, et al. Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clin Cancer Res. 2004; 10(11):3586-92.