title: Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS.
abstract: Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Thirty-four patients ≥60 years old (median age 70 years; range, 60-83) were randomized to receive tosedostat (120 mg on days 1-21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m2 /d) or decitabine (20 mg/m2 /d) every 35 d. Twenty-nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS-refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3-internal tandem duplication mutations. Median follow-up was 11.2 months (range, 0.5-22.3), and median survival was 11.5 months (95% confidence interval, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3-4 non-haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Raya
authors.initials: R
authors.lastname: Mawad
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Becker
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hendrie
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Bart
authors.initials: B
authors.lastname: Scott
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Laboratory Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Wood
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Dean
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Sandhu
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Hans Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Walter
authors.affiliation: CTI Biopharma Corp, Seattle, WA, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Wang
authors.affiliation: CTI Biopharma Corp, Seattle, WA, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Myint
authors.affiliation: Departments of Medicine, University of Washington, Seattle, WA, USA.|CTI Biopharma Corp, Seattle, WA, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Singer
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Elihu
authors.initials: E
authors.lastname: Estey
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Departments of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D000077209:Decitabine; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D006877:Hydroxamic Acids; D003561:Cytarabine; D000077209:Decitabine; C531970:tosedostat; D001374:Azacitidine; D005998:Glycine
keywords: acute myeloid leukaemia; elderly; myelodysplastic syndrome