Two lower doses of oral azacytidine (oral-AZA [CC-486]) are safe for patients with lower- and intermediate-risk myelodysplastic syndromes (MDS), according to the results of the phase II/III ASTREON study presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.1
“The results of the ASTREON study indicate that the [200 mg and 300 mg] oral-AZA doses, given on a 14-day schedule, are safe in patients with lower-risk MDS,” study author Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center in Houston, told ASH Clinical News.
The ASTREON trial was designed to address the safety of the prior AZA-MDS-003 trial. That trial tested a 300 mg once-daily dose of oral-AZA given for 21 days of a 28-day cycle in patients age 18 and older with lower-risk (LR) MDS and at least one cytopenia. This treatment significantly improved the rate of red blood cell count transfusion independence versus placebo and led to durable improvements in hematology parameters in patients with LR-MDS. However, the incidence of early death (within the first 56 days) was higher in the oral-AZA arm, due mostly to infections in those patients with MDS and pretreatment neutropenia.2
The primary endpoints in the ASTREON trial were adverse events (AEs) and complete remission (CR) within six cycles per International Working Group 2006 criteria. In the phase II portion, 47 patients were randomized one-to-one to receive a decreased dose schedule of 200 mg or 300 mg of oral-AZA daily for 14 days of a 28-day cycle. Most patients (42 of 47) had received prior therapy for MDS. The median age was 73.5 in the 200 mg arm and 73.0 in the 300 mg arm.
The median duration of treatment was 31.6 weeks in the 200 mg group and 32.7 weeks in the 300 mg group, and the duration of follow-up was a median of 233 and 238 days in each group, respectively.
Patients in both treatment arms experienced similar rates of treatment-emergent AEs (TEAEs): 23 patients (96%) in the 200 mg group and 20 patients (87%) in the 300 mg group had at least one TEAE. Twelve patients (50%) in the 200 mg group and 15 patients (65%) in the 300 mg group had a grade 3-4 TEAE. The most common TEAE, occurring in at least 20% of patients in each treatment arm, was neutropenia followed by constipation, nausea, thrombocytopenia, diarrhea, and vomiting.
Eight patients (33%) in the 200 mg group and six patients (26%) in the 300 mg group discontinued treatment. One patient (4%) in the 200 mg arm and three patients (13%) in the 300 mg arm discontinued treatment due to TEAEs. One death occurred in the 300 mg group, which was considered treatment related. As of January 30, 2024, 16 of 24 patients (67%) in the 200 mg and 17 of 23 patients (74%) in the 300 mg arms remained on treatment.
No patient has achieved a CR thus far on the trial. One patient in each treatment arm achieved a partial remission. Six patients in each dose arm achieved an erythroid response.
Longer follow-up from the trial is needed to better assess the efficacy of these two reduced dosing regimens of oral-AZA.
“These results indicate that we need to continue to work on [safe regimens] for our patients with LR-MDS,” Dr. Garcia-Manero said, but added, “Unfortunately, it seems that the sponsor of the trial is not going to continue to support this trial.”
Any conflicts of interest declared by the authors can be found in the original abstract.
References
- Garcia-Manero G, Yee KWL, Hernandez F, et al. Preliminary safety and efficacy of oral azacitidine in patients (pts) with low-/intermediate (int)-risk myelodysplastic syndromes (MDS): phase 2 results from the ASTREON trial. Abstract 6509. Presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting; June 1, 2024; Chicago, Illinois.
- Garcia-Manero G, Santini V, Almeida A, et al. Phase III, randomized, placebo-controlled trial of cc-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(13):1426-1436.