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ORLANDO, Fla.—The combination of 5-azacitidine and vorinostat is safe and active in patients with newly diagnosed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) ineligible for clinical trials because of poor performance status or the presence of other comorbidities, results of an ongoing study have found.
Current evaluation of patients not yet evaluable for survival (<60 days since initiation of therapy) indicate a likelihood the study will pass both survival and response stopping rules. These results, which suggest levels of activity and safety similar to those observed in populations eligible for clinical trials, support treatment in this poor prognosis population and call into question current eligibility criteria for inclusion in phase 1/2 clinical trials, Guillermo Garcia-Manero, MD, of MD Anderson Cancer Center, Houston, Texas, said in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.
Standard eligibility criteria for most clinical trials in patients with MDS and AML include acceptable performance status, renal and hepatic functions, and lack of other comorbidities, including concomitant malignancies or infection with HIV. Dr. Garcia-Manero and colleagues noted that in their experience, survival in this group of patients is very poor (<60 days) without therapy. Therefore, they developed a phase 2 trial using 5-azacitidine and vorinostat, which are known to be safe when given in combination and have significant activity in MDS and AML, to treat this population in a systematic fashion.
Eligibility for the study included patients ≥18 years of age with previously untreated MDS (int-1 or above) or AML plus creatinine or bilirubin >2 mg/dL or ECOG performance status (PS) >2, or ineligibility for any other protocol. Those with HIV disease or concomitant malignancies were also eligible. Excluded were patients with cerebral blood flow abnormalities.
Patients received 5-azacitidine 75 mg/m2 IV daily x 5 every 3 to 6 weeks and vorinostat 200 mg orally 3 times a day on days 1 to 5 with 5-azacitidine. The trial was designed to stop if expectations for survival at 60 days and/or achievement of complete remission (CR) rates were not achieved based on historical experience at MD Anderson. The study was halted if the number of patients alive at >60 days is < 0/3, 2/6, 3/9, 5/12, 6/15, 8/18, 10/21, 11/24, or 13/27 evaluable or if the number of patients without a CR is >6/6, 11/12, 16/18, 21/24, 26/30. If none of the stopping rules were met, a maximum of 30 patients were to be treated. Operating characteristics targeted a 20% improvement in response and survival. Global and gene-specific hypomethylation, induction of histone acetylation, autophagy, and ROS signaling were evaluated as pharmacodynamic end points.
To date, 30 patients have been treated. Median age was 69 years (range, 44-83 years). Median WBC was 14 x109/L (range 1.4-123 x109/L); median percentage of bone marrow blasts was 20% (range 2-62%).
Treatment has been well tolerated, Dr. Garcia-Manero, said, with only 5 patients (17%) developing severe nonhematologic toxicity: nausea and vomiting. Median follow-up time was 3.6 months (range 1-11 months). Median number of cycles administered is 2+ (range, 1+ – 9+ cycles). Fifteen patients were evaluable for survival at 60 days, 7 (47%) achieved CR, with an overall response of 46%. Based upon these results, Dr. Garcia-Manero states that he “significant clinical activity was witnessed, which leads us to question the current clinical trial eligibility for this patient population.”
