Azacitidine alone comparable to AZA combos for most MDS patients
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
