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Azacitidine-based combination may improve response rate in chronic myelomonocytic leukemia
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Overall response rate improved with the addition of lenalidomide to azacitidine in patients with chronic myelomonocytic leukemia, according to results from the North American Intergroup Study S1117.
However, the combination of azacitidine (Vidaza, Celgene) and lenalidomide (Revlimid, Celgene) or vorinostat (Zolinza, Merck) did not improve ORR in patients with high-risk myelodysplastic syndrome compared with azacitidine monotherapy.
Data from phase 1 and phase 2 trials showed azacitidine plus lenalidomide conferred 72% ORR among 36 patients, and azacitidine plus vorinostat conferred 70% ORR among 33 patients.
Mikkael A. Sekeres, MD, MS, director of the leukemia program at Cleveland Clinic Taussig Cancer Institute, and colleagues conducted a phase 2 analysis to determine if azacitidine in combination with lenalidomide or vorinostat would improve response rates to warrant an OS analysis of one of the combinations in a phase 3 trial.
The analysis included 277 patients (median age, 70 years; range, 28-93; 31% women) with higher-risk myelodysplastic syndrome or chronic myelomonocytic leukemia (CMML) from 90 clinical centers. Researchers randomly assigned patients 1:1:1 to 75 mg/m2 daily azacitidine on days 1 to 7 of a 28-day cycle (n = 92); azacitidine plus 10 mg/day lenalidomide on days 1 to 21 (n = 93); or azacitidine plus 300 mg vorinostat twice daily on days 3 to 9 (n = 92).
Among the patients, 18 (6%) had treatment-related myelodysplastic syndrome (6%) and 53 (19%) had CMML.
ORR served as the primary endpoint.
Over a median follow-up of 23 months (range, 1-43), patients achieved an ORR of 38% with azacitidine alone, 49% with the lenalidomide combination; and 27% with the vorinostat combination.
Among patients with CMML, those treated with azacitidine plus lenalidomide achieved higher ORR than with azacitidine alone (68% vs. 28%; P = .02).
Researchers observed no differences in ORR across groups for therapy-related myelodysplastic syndrome, IPSS subgroups, transfusion-dependent patients or allogeneic transplantation rates.
Of 113 patients with available mutation data, 103 had at least one mutation (median, 2; range, 0-7). Compared with patients without mutations, the ORR was significantly higher among patients with DNMT3A (67% vs. 34%; P = .025) and numerically higher for patients with BCOR (57% vs. 34%) and NRAS (60% vs. 36%), but lower for patients with SRSF2 (17% vs. 41%) and ASXL1 (23% vs. 43%) mutations. Response duration improved with fewer mutations (HR = 6.86 for two more mutations vs. 0 mutations; P = .01).
All groups demonstrated similar serious adverse events. Patients treated with the vorinostat combination exhibited more grade 3 or higher gastrointestinal toxicities than with azacitidine alone (15% vs. 4%; P = .02). Patients treated with the lenalidomide combination experienced more grade 3 or higher rashes (16% vs. 3%; P = .005).
Patients treated with any combination appeared more likely to undergo nonprotocol-defined dose modifications (P < .001) than patients treated with monotherapy.
Researchers observed an association between lenalidomide dose reduction and worse OS (HR = 1.30; P = .05).
Median OS was 3 to 4 months longer for patients treated with a combination than with monotherapy. In addition, researchers observed a trend for improved OS among patients treated with azacitidine plus vorinostat compared with monotherapy.
Researchers noted underdosing may have compromised outcomes in the combination arms, and that patients with high-risk myelodysplastic syndrome should be treated without dose adjustments for an induction phase in the first 4 months.
“Future studies in higher-risk myelodysplastic syndrome and CMML should be adequately powered to demonstrate an improvement in OS as a primary endpoint, or at minimum, response duration for molecular subtypes between study arms,” the researchers wrote. – by Melinda Stevens
Disclosure: Sekeres reports consultant/advisory roles with Celgene and Millennium. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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