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Extended decitabine schedule does not benefit older patients with AML
A 5-day schedule of decitabine appeared as safe and effective as a 10-day schedule among older adults with newly diagnosed acute myeloid leukemia, according to results of a randomized phase 2 trial published in Lancet Oncology.
“Despite modest single-agent activity, decitabine is widely used as a backbone drug for combination approaches in older patients with acute myeloid leukemia,” Nicholas J. Short, MD, assistant professor in department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “Although evidence suggests that 10-day schedules of decitabine are superior to 5-day schedules, no randomized head-to-head comparison between these regimens has been reported.”
The single-center, open-label phase 2 trial included 71 patients aged 60 years and older with AML who were not eligible for intensive chemotherapy. Researchers also included patients aged younger than 60 years if they were not eligible for intensive chemotherapy with an anthracycline plus cytarabine.
Researchers used computer-generated block randomization to assign the first 40 patients equally to the 5-day and 10-day treatment schedules. They assigned the rest with a Bayesian response-adaptive randomization algorithm, which used all previous patients’ treatment and response data to determine allocation of each new patient, favoring the group with a better response.
Patients received 20 mg/m² IV decitabine as induction therapy for either 5 consecutive days (n = 28; median age, 77 years) or 10 consecutive days (n = 43; median age, 78 years) every 4 to 8 weeks for as many as three cycles. Patients who responded could continue to receive decitabine on a 5-day schedule for up to 24 cycles.
The two treatment groups had comparable baseline characteristics. Seven patients in the 5-day group and seven in the 10-day group had TP53 mutation at baseline.
A composite of complete remission, complete remission with incomplete platelet recovery, and complete remission with incomplete hematological recovery, attained at any point and evaluated by intention to treat, served as the primary endpoint.
Results showed similar proportions of the two treatment groups attained the primary endpoint (43% of 5-day group vs. 40% of 10-day group; difference 3 percentage points; 95% credible interval, -21 to 27).
After total follow-up of 38.2 months (median, 5.3 months), researchers observed median OS of 5.5 months (interquartile range [IQR], 2.1 to 11.7) in the 5-day schedule group and 6 months (IQR, 1.9 to 11.7) in the 10-day group, with 1-year OS of 25% in both groups. Eight patients (29%) in the 5-day group and 13 patients (30%) in the 10-day group achieved complete remission.
Stratification by cytogenetics, de-novo vs. secondary or treatment-related AML, or TP53 mutation status showed no difference in the primary endpoint measures or OS between groups.
The most prevalent grade 4 adverse events included neutropenic fever (25% of 5-day group vs. 33% of 10-day group) and infection (18% vs. 37%). One patient in the 5-day group died of sepsis and six patients in the 10-day group died of infection. The two groups had comparable rates of early mortality.
The researchers noted several study limitations, including a lack of large randomized trials comparing decitabine with azacitidine in older patients, and uncertainty as to whether the results could be applied to patients with relapsed or refractory AML.
In a related editorial, Amanda F. Cashen, MD, associate professor in the division of bone marrow transplantation and leukemia at Washington University School of Medicine in St. Louis, wrote that because the longer dosing schedule showed no particular benefit, patients similar to those analyzed in the current study should receive decitabine on a 5-day schedule.
"Give then OS remains short for most older patients with AML, future investigations are needed to clarify the disease characteristics, especially the mutational profile or profiles, that will predict response to decitabine given alone,” Cashen wrote. “For most patients, who are unlikely to have durable responses to decitabine alone, combination therapies with targeted agents should be investigated.” – by Jennifer Byrne
Disclosures: The researchers report no relevant financial disclosures. Cashen reports no relevant financial disclosures.