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Elacytarabine failed to improve outcomes in relapsed/refractory AML
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Neither the novel agent elacytarabine nor seven other commonly used salvage regimens provided clinically meaningful benefit to patients with relapsed/refractory acute myeloid leukemia, according to results of a phase 3 study.
“The data from our work sadly reaffirm, on a global basis, the dismal prognosis of patients with relapsed/refractory AML,” Gail J. Roboz, MD, director of the leukemia program and associate professor of medicine at Weill Cornell Medical College and New York-Presbyterian Hospital, and colleagues wrote. “There is no effective standard of care, and patients with this disease should be treated on clinical trials whenever feasible.”
Gail J. Roboz
The international, multicenter study included 381 patients in 13 countries.
Roboz and colleagues compared elacytarabine (Clavis Pharma) — a novel elaidic acid ester of cytarabine — with investigator’s choice of AML salvage regimen. The regimens included hydroxyurea, hypomethylating agents, high-dose cytarabine, multiagent chemotherapy and supportive care.
OS served as the primary outcome measure.
Results showed no significant difference in OS (3.5 months vs. 3.3 months), response rate (23% vs. 21%) and RFS (5.1 months vs. 3.7 months) between the elacytarabine arm and the control arm.
“OS in both study arms and for all treatments was extremely poor,” Roboz and colleagues wrote. “Novel agents, novel clinical trial designs and novel strategies of drug development are all desperately needed for this patient population.”
Disclosure: The researchers report research funding and honoraria from, employment/leadership positions with, consultant or advisory roles with, and stock ownership in Clavis Pharma. They also report consultant or advisory roles with Astellas, Celgene, Incyte and Teva.
Perspective
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Michael J. Mauro, MD
The trial presented by Roboz and international collaborators from the CLAVELLA trial, using elacytarabine — a lipid conjugated derivative of cytarabine, designed to overcome resistance related to decreased transport cellular uptake — is a large and important negative trial.Comparing this agent to investigator’s choice of alternative regimens in the setting of relapsed/resistant acute myeloid leukemia ranging from alternate induction regimens to supportive care, there were no differences noted in outcome by all measures. The prognosis for this large (n=381) heterogeneous relapsed/resistant AML population was unwavering, irrespective of therapy offered.
The authors rightly conclude that we may lose twice with such approaches, halting further investigation of novel agents based on failure to detect a “signal” in highly resistant patients, and again in broad application of novel therapies in unselected patients with heterogeneous mechanisms of resistance and disease biology despite their common heading of AML.
This study, as others before it, points us directly toward molecular characterization of AML, directed testing of novel agents based on identified targets and — whenever possible — application of therapy prior to acquisition of multiclonal resistant disease.
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