title: Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial.
abstract: Disease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8(+) T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8(+) T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8(+) T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8(+) T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial.
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom. Electronic address: charles.craddock@uhb.nhs.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: Craddock
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Nadira
authors.initials: N
authors.lastname: Jilani
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Shamyla
authors.initials: S
authors.lastname: Siddique
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Christina
authors.initials: C
authors.lastname: Yap
authors.affiliation: Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Josephine
authors.initials: J
authors.lastname: Khan
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nagra
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Janice
authors.initials: J
authors.lastname: Ward
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Ferguson
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Hazlewood
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Buka
authors.affiliation: MRC Molecular Haematology Unit and Department of Haematology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goodyear
authors.affiliation: Department of Clinical Haematology, Manchester Royal Infirmary, Manchester, United Kingdom.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tholouli
authors.affiliation: Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Crawley
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Russell
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Byrne
authors.affiliation: Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom; Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ram
authors.initials: R
authors.lastname: Malladi
authors.affiliation: Department of Haematology, Sheffield Teaching Hospitals NHS Trust and Department of Oncology, University of Sheffield, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Snowden
authors.affiliation: Haematology and Transplant Unit, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Dennis
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods*
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine
keywords: Acute myeloid leukemia; Azacitidine; Relapse; Tumor antigens