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Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group.

ABSTRACT: The treatment of relapsed acute myeloid leukaemia (AML) remains unsatisfactory. We conducted a phase II randomized trial where patients received intermediate-dose cytarabine for 4 d followed by gemtuzumab ozogamicin on day 5 (Arm A), or combined with liposomal daunorubicin for 3 d (Arm B), or cytarabine given for 5 d combined with cyclophosphamide for 3 d and topotecan by continuous infusion for 5 d (Arm C). Eligible patients had primary refractory AML, a first relapse after a remission of <1 year, or a second or greater relapse. The primary objective of this trial was attainment of a conventional complete remission (CR) or a CR without platelet recovery (CRp) in at least 40% of patients. The CR/CRp rates for the 82 eligible patients were 3/26 (12%) in Arm A, 2/29 (7%) in Arm B, and 1/27 (4%) in Arm C. No patients who had relapsed within 6 months of initial CR or who had suffered multiple relapses responded. More than 95% of patients subsequently died of AML. No unexpected toxicities were encountered. We conclude that none of these three regimens were effective enough in the treatment of high-risk relapsed or refractory AML to warrant further study. This trial was registered at http://www.clinicaltrials.gov as #NCT00005962.

SUBMITTER: Litzow MR

PROVIDER: S-EPMC2809127 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group.

Litzow Mark R MR Othus Megan M Cripe Larry D LD Gore Steven D SD Lazarus Hillard M HM Lee Sandra J SJ Bennett John M JM Paietta Elisabeth M EM Dewald Gordon W GW Rowe Jacob M JM Tallman Martin S MS

British journal of haematology 20091005 2

The treatment of relapsed acute myeloid leukaemia (AML) remains unsatisfactory. We conducted a phase II randomized trial where patients received intermediate-dose cytarabine for 4 d followed by gemtuzumab ozogamicin on day 5 (Arm A), or combined with liposomal daunorubicin for 3 d (Arm B), or cytarabine given for 5 d combined with cyclophosphamide for 3 d and topotecan by continuous infusion for 5 d (Arm C). Eligible patients had primary refractory AML, a first relapse after a remission of <1 ye ...[more]

PMID: 19804455

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Project description:Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat.In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598.38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction.Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned.Chroma Therapeutics.

Dataset Information

Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group.

Publications

Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group.

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