Adding Clofarabine to AML Induction Shows No Survival Benefit

The addition of clofarabine to standard induction therapy for newly diagnosed acute myeloid leukemia (AML) reduced the probability of relapse but increased toxicity and had no effect on survival, according to the results of a study published in Blood.

“Based on the results of the study there can be little doubt that clofarabine is an active anti-AML therapeutic drug,” wrote researcher Bob Löwenberg, MD, PhD, of the Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues. “The results of the study show the additive antileukemic effect of clofarabine on top of an anthracycline/cytarabine-based remission induction program: more early complete remissions were accomplished and the probability of relapse was substantially reduced.”

According to the study, standard treatment with cytarabine and an anthracycline results in high rates of complete remissions in patients with AML, but with a high frequency of subsequent relapse; specifically, adults aged younger than 65 years have a 50% probability of relapse.

Löwenberg and colleagues conducted this study to see if the addition of clofarabine, a second-generation nucleoside analog that is active in older adults with AML, would be active in younger and middle-aged adults. The phase III study compared two remission induction regimens in patients aged 18 to 65 years: idarubicine/cytarabine and amsacrine/cytarabine with (n = 393) or without (n = 402) clofarabine. Event-free survival was the primary endpoint.

At the end of the study period, complete remission rates did not differ between the two treatment arms. However, patients assigned to clofarabine attained remission faster, with 75% attaining remission after cycle 1 compared with 66% for patients not assigned to the drug.

At a median follow-up of 36 months, there were no differences in overall survival or event-free survival between the two arms. Patients assigned to clofarabine did have an improved relapse rate (35% vs 44%) compared with patients not assigned to the drug. However, the cumulative 4-year probabilities for the competing risk of death were greater in patients assigned clofarabine (22% vs 15%).

The researchers also conducted subgroup analyses and found that clofarabine improved both overall survival (50% vs 29%; P < .001) and event-free survival (40% vs 26%; P = .002) for patients with AML with a European LeukemiaNet 2010 intermediate-I prognostic risk. This effect depended in part on the favorable effect of clofarabine seen in patients with intermediate-risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications.

“None of the individual gene mutations for which we tested were associated with a therapeutic benefit for the clofarabine treatment but it should be noted that the statistical power of these biomarker analyses was limited due to the fact that only moderate numbers were included in many of these subsets,” the researchers wrote.

They also noted that patients assigned clofarabine with a performance status of 0 had significantly reduced relapse probability and reduced relapse at 4 years. Finally, there was no difference noted in the benefit of the clofarabine schedule according to patient subsets of different ages, ie, younger than 45 years vs 45 to 60 years vs 61 to 65 years.

Treatment with clofarabine resulted in added grade 3/4 toxicities and delayed hematologic recovery.

“Overall the disadvantages of the enhanced toxicities offset the advantages of a reduction of relapse so that ultimately there is no overall net benefit in survival in the broad population of patients with AML,” the researchers wrote. “Exploiting the potential therapeutic advantage of clofarabine in the first line of treatment in AML in an optimized way and exploring a less toxic scheduling of the drug will require additional study.”