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Hypomethylating agents safe, effective for lower-risk myelodysplastic syndrome
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Hypomethylating agents used at a low dose appeared effective and safe for patients with lower-risk myelodysplastic syndrome, according to results of a randomized phase 2 clinical trial.
Further, decitabine induced higher response rates than azacitidine in this patient population.
Hypomethylating agents — decitabine and azacitidine — improve survival among patients with higher-risk myelodysplastic syndrome, but their efficacy for lower-risk disease is less known. Strategies for patients with lower-risk disease — a fraction of whom have a poor prognosis — have focused on improving transfusion requirements, or are only effective for a few patients.
“The treatment of these patients with lower-risk myelodysplastic syndrome remains an unmet medical need, Elias Jabbour, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “A larger confirmatory study is ongoing and may help to clarify whether low-dose hypomethylating agent therapy [among] patients with lower-risk myelodysplastic syndrome can alter the natural history of this disease.”
It has been suggested that low doses of these agents administered in shorter treatment schedules may be active in lower-risk disease.
Thus, Jabbour and colleagues assessed response rates and EFS among 113 patients (median age, 70 years) with lower-risk myelodysplastic syndrome patients treated with low-dose hypomethylating agents.
Most patients (81%) had intermediate-1 risk disease, 18% had therapy-related disease, 14% had chronic myelomonocytic leukemia, and 5% had overlapped myelodysplastic syndrome/myeloproliferative neoplasm other than chronic myelomonocytic leukemia. Fifty-two percent of patients were transfusion dependent.
Researchers used a Bayesian adaptive design to randomly assign patients to 20 mg/m2 IV decitabine (n = 73) daily for 3 consecutive days or 75 mg/m2 IV azacitidine (n = 40) daily, for 28-day cycles. Patients could receive lower doses of decitabine (15 mg/m2 and 10 mg/m2) and azacitidine (50 mg/m2 and 25 mg/m2) if they experienced grade 3 and grade 4 toxicities.
Overall response rate served as the primary endpoint.
Median follow-up was 20 months (range, 2-43).
Treatment occurred for a median of nine cycles. Most patients (96%) received at least two cycles of hypomethylating agents and were evaluable for response.
Researchers reported an ORR for the entire cohort of 62%, and 37% of patients achieved a complete response. Nine percent of patients had a marrow complete response and 18% demonstrated hematologic improvement. Overall, 25% of patients (n = 15 of 59) became transfusion independent.
A higher proportion of patients treated with decitabine achieved overall response (70% vs. 49%;
P = .03), but the complete response rates appeared similar between the arms (37% vs. 36%). Cytogenetic response rates included 61% in the decitabine group and 25% in the azacitidine group (P = .02).
More patients treated with decitabine than azacitidine became transfusion independent (32% vs. 16%).
Researchers reported a median EFS of 18 months (95% CI, 14-22) for the whole population, 20 months among patients treated with decitabine and 13 months among patients treated with azacitidine.
Median OS had not been reached.
Univariate analysis for OS showed transfusion dependence before enrollment (HR = 2.3; 95% CI, 1.1-4.9) and presence of two or more cytopenias (HR = 2.2; 95% CI, 1-4.9) appeared associated with unfavorable survival, whereas complete response favorably affected survival (HR = 0.38; 95% CI, 0.2-0.9).
Grade 3 and higher nonhematologic adverse events appeared rare. Infection or neutropenic fever occurred among 7% of patients treated with decitabine and 5% of patients treated with azacitidine.
“Our study indicates that the use of hypomethylating agents at low dose is relatively safe, as no treatment-related early deaths or high grade adverse events were encountered,” the researchers wrote. “Low-dose hypomethylating agent therapy was effective in this patient population, with more than half of the patients benefiting, a third achieving a complete response and the vast majority being alive and event-free at 1-year landmark.
“Whether early intervention with low-dose hypomethylating agent therapy will impact the outcome of these patients remains to be confirmed,” the researchers added. “Even though promising responses were seen in these lower-risk patients, it is unknown whether this translates to meaningful changes in survival or quality of life, compared to intervening when patients have higher-risk disease.”
Although decitabine appeared associated with a higher ORR, researchers noted they did not use equivalent doses for the two drugs studied.
“Decitabine was used at two-thirds of the approved dose while azacitidine was being used at lower doses (approximately 45% of the original dose of 75 mg/m2 daily for 7 days),” Jabbour and colleagues wrote. “As such, the underperformance of azacitidine could be due to the lower dose used. A 5-day regimen may improve its efficacy, mainly in patients with higher-disease burden.” – by Melinda Stevens
Disclosures: The authors report no relevant financial disclosures.
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