title: Addition of 10-Day Decitabine to Fludarabine/Total Body Irradiation Conditioning is Feasible and Induces Tumor-Associated Antigen-Specific T Cell Responses.
abstract: Allogeneic hematopoietic cell transplantation (HCT) offers the possibility of curative therapy for patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics and in patients who cannot tolerate consolidation chemotherapy (eg, due to previous toxicity). We assessed the toxicity and efficacy of 10-day decitabine (Dec), fludarabine (Flu), and 2 Gy total body irradiation (TBI) as a new conditioning regimen for allogeneic HCT in patients with MDS, CMML, or AML. Thirty patients were enrolled, including 11 with MDS, 2 with CMML, and 17 with AML. Patients received 20 mg/m(2)/day Dec on days -11 to -2, 30 mg/m(2)/day Flu on days -4 to -2, and 2 Gy TBI on day -1, followed by infusion of a donor stem cell graft on day 0. Postgrafting immunosuppression consisted of cyclosporin A and mycophenolate mofetil. At a median follow-up of 443 days, the overall survival was 53%, relapse incidence was 27%, and nonrelapse mortality was 27%. The incidence of severe acute (grade III/IV) graft-versus-host disease (GVHD) was 27%, and that of (predominantly mild) chronic GVHD was 60%. Immunomonitoring studies revealed that specific CD8(+) T cell responses against epigenetically silenced tumor-associated antigens (TAAs), including cancer-testis antigens (MAGE-A1/A2/A3 and PRAME) and RHAMM, occurred more frequently in patients who had received Dec/Flu/TBI conditioning (8 of 11 patients) compared with a control group of patients who had received only Flu/TBI conditioning (2 of 9 patients). In summary, Dec/Flu/TBI conditioning proved feasible and effective and enhanced the induction of TAA-reactive CD8(+) T cell responses in vivo, which may contribute to disease control post-transplantation.
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands.
authors: Marjan
authors: M
authors: Cruijsen
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Willemijn
authors: W
authors: Hobo
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands.
authors: Walter J F M
authors: WJFM
authors: van der Velden
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands.
authors: Manita E J
authors: MEJ
authors: Bremmers
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Rob
authors: R
authors: Woestenenk
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands.
authors: Brigitte
authors: B
authors: Bär
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: J H Frederik
authors: JHF
authors: Falkenburg
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Michel
authors: M
authors: Kester
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands.
authors: Nicolaas P M
authors: NPM
authors: Schaap
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Joop
authors: J
authors: Jansen
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands.
authors: Nicole N M
authors: NNM
authors: Blijlevens
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Harry
authors: H
authors: Dolstra
authors: Department of Hematology, Radboudumc, Nijmegen, the Netherlands; Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. Electronic address: gerwin.huls@radboudumc.nl.
authors: Gerwin
authors: G
authors: Huls
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D000077209:Decitabine; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods / Q000401:mortality; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000628:therapy*; D015477:Leukemia, Myelomonocytic, Chronic / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014916:Whole-Body Irradiation
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D014740:Vidarabine; D001374:Azacitidine; C024352:fludarabine
keywords: Decitabine; Hematopoietic cell transplantation; Hypomethylating agents; Nonmyeloablative conditioning; Poor-risk acute myelogenous leukemia/myelodysplastic syndrome