ORLANDO FLSingle-agent clofarabine is inferior to standard therapy with daunorubicin and cytarabine in older patients with newly diagnosed acute myeloid leukemia (AML) who are fit for intensive therapy, results of a phase 3 trial presented at the 57th American Society of Hematology (ASH) Annual Meeting have shown.1

The daunorubicin and cytarabine 7&3 induction “remains the standard of care for older adults being treated with ‘curative intent,’” said James M. Foran, MD, of the Mayo Clinic Cancer Center in Jacksonville, FL.

These results “suggest the importance of maintaining intensive therapy strategies in older AML patients 60 years or older whenever possible and appropriate,” he added.

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Based on the primary weighted analysis for overall survival, on February 23, 2015, the trial’s data safety monitoring committee recommended suspension of new accrual and all active patients on clofarabine were transitioned to the daunorubicin and cytarabine arm, he reported.

Grade 4 and 5 nonhematologic toxicities were significantly higher in the clofarabine arm compared with daunorubicin and cytarabine, both in the induction (P = .01) and consolidation phases (P = .0005).

Previous phase 2 trials had suggested that induction and consolidation therapy with clofarabine offered lower induction mortality as well as similar rates of complete remission and overall survival. This study was conducted to determine if a non-cytarabine regimen “could achieve similar or superior efficacy with lower mortality,” Dr. Foran said.

As of February 23, 2015, the study had randomly assigned 727 patients 60 and older with newly diagnosed AML to receive either clofarabine 30 mg/m2 x 5 days induction, 20 mg/m2 re-induction (if indicated) plus 2 cycles of consolidation or standard therapy with daunorubicin 60 mg/m2 days 1 to 3 plus cytarabine 100 mg/m2 days 1 to 7 induction for 1 to 2 cycles plus 2 cycles consolidation with cytarabine 1.5 g/m2 every 12 hours days 1 to 6 (age 60-69 years; once daily if age 70 years or older).

Randomization was stratified by age (60-69 vs 70+ years), therapy-related AML, and antecedent hematological disorder. Patients with an HLA-matched donor were eligible for allogeneic transplantation after induction; those completing consolidation were eligible for randomization to maintenance decitabine 20 mg/m2 x 3 days, monthly for 1 year vs observation.

Median age was 68 years (range, 60-86 years); 56.9% were male, and 38.2% were 70 or older; 30.8% had unfavorable cytogenetics.

Median follow-up of surviving patients was 8.2 months.

A total of 380 patients have died, 177 in the daunorubicin plus cytarabine arm and 203 in the clofarabine arm.

Significantly inferior overall survival was observed for clofarabine vs daunorubicin plus cytarabine [hazard ratio (HR) 1.41; 95% CI: 1.12-1.77; P = .003), Dr. Foran reported. Overall survival was 13.8 months (95% CI: 11.7-16.5) in the standard arm compared with 9.99 months (95% CI: 8.35-12.0) in the clofarabine arm.

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Planned subgroup analyses demonstrated significant differences in overall survival for clofarabine among patients aged 60 to 69 years (449 patients; HR 1.46; P = .01) with intermediate-risk cytogenetics (P = .001), and de novo AML (P = .0001); however, not for older patients (278 patients; HR 1.36; P = .11); those with unfavorable cytogenetics (P = .78) or therapy-related AML (P = .73).

Patients in the second randomization and allogeneic transplantation arms are continuing on the trial.


  1. Foran JM, Sun Z, Claxton DF, et al. North American Leukemia‚ Intergroup phase III randomized trial of single agent clofarabine as induction and post-remission therapy‚ and decitabine as maintenance therapy in newly-diagnosed acute myeloid leukemia in older adults (age ≥60 years): a trial of the ECOG-ACRIN Cancer Research Group (E2906). Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting; December 6, 2016, Orlando, FL.