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Survival Rates with Clofarabine Inferior to Standard Therapy in Older Patients with AML

December 30, 2021

Despite demonstrating clinical activity in older patients with newly diagnosed acute myeloid leukemia (AML) in phase II studies, single-agent clofarabine failed to produce similar rates of overall survival (OS) to those earlier phase studies in a phase III trial, when compared with standard therapy.

For more than two decades, newly diagnosed AML patients who are age 60 or older have been typically treated with induction therapy with daunorubicin and cytarabine, an intensive treatment regimen that has been associated with a high incidence of early mortality, lead author James M. Foran, MD, of the Mayo Clinic Cancer Center in Jacksonville, Florida, explained. However, given the disappointing survival rates with clofarabine seen in this trial, the daunorubicin and cytarabine combination should remain the standard of care.

"We've recognized for a long time that there have been limited advances in survival for older AML patients," Dr. Foran said. "We've also recognized, through our experience and through national databases, that only a minority – a small minority – of patients actually gets to the point of receiving potentially curative intensive therapy."

In this ECOG-ACRIN Cancer Research Group trial, Dr. Foran and colleagues investigated whether single-agent clofarabine could potentially lower induction mortality and achieve similar complete remission (CR) rates and OS as standard therapy in older AML patients.

The phase III trial compared the safety and efficacy of clofarabine as induction and consolidation therapy with standard therapy (daunorubicin and cytarabine) in 727 patients (median age = 68 years; range = 60-86 years). Patients were assigned to receive either:

  • Clofarabine induction (30 mg/m2 for five days and, if indicated, 20 mg/m2 for re-induction) followed by two cycles of consolidation
  • Standard therapy: 1-2 cycles of induction (daunorubicin 60 mg/m2 on days 1 through 3 and cytarabine 100 mg/m2 on days 1 through 7) followed by two cycles of consolidation with cytarabine (1.5g/m2 every 12 hours on days 1 through 6 if age 60-69 years or once-daily if age ≥70 years)

Patients with a human leukocyte antigen-matched donor were eligible for allogeneic hematopoietic cell transplantation after induction, and those completing consolidation were eligible for a secondary randomization to either standard observation or maintenance with low-dose decitabine (20 mg/m2 for three days monthly for one year).

At the time of analysis (December 23, 2014), 686 patients had been randomized; 659 patients had complete treatment information. Of these, 30.4 percent in the standard-therapy group and 40.1 percent in the clofarabine group required two cycles of induction.

With a median follow-up of 7.6 months among the surviving patients, the rates of CR and CR with incomplete marrow recovery (CRi) were similar between both treatment groups (TABLE).

Despite this, patients in the clofarabine group had significantly inferior OS compared with the standard-therapy group: of the 374 patients who died during the study, 174 were receiving standard therapy and 200 were receiving clofarabine (hazard ratio [HR] for OS=1.41 favoring standard therapy; 95% CI 1.12-1.78).

Planned subgroup analyses demonstrated significant differences in OS favoring standard therapy patients:

  • Age 60 to 69 years: HR=1.48 (95% CI 1.99)
  • Age ≥70 years: HR=1.34 (95% CI 0.93-1.93)
  • Intermediate-risk cytogenetics: HR=1.77 (95% CI 1.27-2.47)
  • Unfavorable-risk cytogenetics: HR=0.96 (95% CI 0.65-1.43)
  • No AHD: HR=1.46 (95% CI 1.13-1.89)
  • AHD: HR=1.22 (95% CI 0.74-2.00)

Based on the primary weighted analysis for OS, 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.

"I was surprised that an effort to slightly de-intensify therapy with something we thought was going to be just as efficacious led to an inferior survival," Dr. Foran said. "[These results] taught me that we have to be careful about de-intensifying therapy in this setting because we risk compromising results."


Foran J, Sun Z, Claxton D, 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. Abstract #217. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.

TABLE. Early Treatment Results with Standard Therapy Versus Clofarabine
  Standard therapy (daunorubicin + cytarabine) Clofarabine p Value
CR/CRi 43.8% 42.8% 0.87
30-day mortality 8.5% 7.9% 0.89
60-day mortality 14.9% 13.1% 0.58
Grade 4-5 non-hematologic toxicity (induction) 27% 19% 0.02
Grade 4-5 non-hematologic toxicity (consolidation) 20% 7% 0.001
CR=complete remission; CRi=complete remission with incomplete marrow recovery.


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