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Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan.
Biol Blood Marrow Transplant. 2015 Aug; 21(8):1495-505.BB

Abstract

This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 10(9)/L on day 11 and platelets > 20 × 10(9)/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status.

Authors+Show Affiliations

Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Department of Biostatistics, Hyogo College of Medicine, Hyogo, Japan.Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan.Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.Department of Hematology/Oncology, Transfusion and Hemapheresis Center, Kurashiki Central Hospital, Kurashiki, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Aichi, Japan.Department of Haematology, Toranomon Hospital, Tokyo, Japan.Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan.Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan. Electronic address: ogawah@hyo-med.ac.jp.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25921715

Citation

Ikegame, Kazuhiro, et al. "Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: a Prospective Multicenter Phase I/II Study in Japan." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 21, no. 8, 2015, pp. 1495-505.
Ikegame K, Yoshida T, Yoshihara S, et al. Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan. Biol Blood Marrow Transplant. 2015;21(8):1495-505.
Ikegame, K., Yoshida, T., Yoshihara, S., Daimon, T., Shimizu, H., Maeda, Y., Ueda, Y., Kaida, K., Ishii, S., Taniguchi, K., Okada, M., Tamaki, H., Okumura, H., Kaya, H., Kurokawa, T., Kodera, Y., Taniguchi, S., Kanda, Y., & Ogawa, H. (2015). Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 21(8), 1495-505. https://doi.org/10.1016/j.bbmt.2015.04.012
Ikegame K, et al. Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: a Prospective Multicenter Phase I/II Study in Japan. Biol Blood Marrow Transplant. 2015;21(8):1495-505. PubMed PMID: 25921715.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Unmanipulated Haploidentical Reduced-Intensity Stem Cell Transplantation Using Fludarabine, Busulfan, Low-Dose Antithymocyte Globulin, and Steroids for Patients in Non-Complete Remission or at High Risk of Relapse: A Prospective Multicenter Phase I/II Study in Japan. AU - Ikegame,Kazuhiro, AU - Yoshida,Takashi, AU - Yoshihara,Satoshi, AU - Daimon,Takashi, AU - Shimizu,Hiroaki, AU - Maeda,Yoshinobu, AU - Ueda,Yasunori, AU - Kaida,Katsuji, AU - Ishii,Shinichi, AU - Taniguchi,Kyoko, AU - Okada,Masaya, AU - Tamaki,Hiroya, AU - Okumura,Hirokazu, AU - Kaya,Hiroyasu, AU - Kurokawa,Toshiro, AU - Kodera,Yoshihisa, AU - Taniguchi,Shuichi, AU - Kanda,Yoshinobu, AU - Ogawa,Hiroyasu, Y1 - 2015/04/25/ PY - 2015/01/25/received PY - 2015/04/08/accepted PY - 2015/4/30/entrez PY - 2015/4/30/pubmed PY - 2016/4/7/medline KW - Anti–T lymphocyte globulin KW - Haploidentical stem cell transplantation KW - Reduced-intensity conditioning KW - Steroid SP - 1495 EP - 505 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 21 IS - 8 N2 - This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 10(9)/L on day 11 and platelets > 20 × 10(9)/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/25921715/Unmanipulated_Haploidentical_Reduced_Intensity_Stem_Cell_Transplantation_Using_Fludarabine_Busulfan_Low_Dose_Antithymocyte_Globulin_and_Steroids_for_Patients_in_Non_Complete_Remission_or_at_High_Risk_of_Relapse:_A_Prospective_Multicenter_Phase_I/II_Study_in_Japan_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(15)00289-X DB - PRIME DP - Unbound Medicine ER -