Helsinn and MEI Pharma announced findings from a genetic mutation analysis of patients in a Phase II clinical study of the investigational drug pracinostat and azacitidine in acute myeloid leukemia (AML), including a significant correlation between genetic mutations in the DNA methylation pathway and clinical response.
Available samples from 41 of the 50 patients enrolled in the Phase II study were sequenced to characterize the genetic mutation profile of these patients. The overall mutation profile of the patients in this study appear to be generally typical of an older population with AML and are also common in myelodysplastic syndrome (MDS). The most frequent mutations, occurring in 37% of samples studied (15/41), were found in the DNA methylation pathway, including DNMT3A, IDH1, IDH2 and TET2. Patients with these mutations had a complete response (CR) rate of 60%, a significant improvement (p=0.027) over patients with the wild-type genes (22%).
Notably, the phase II analysis also showed that median overall survival was roughly equivalent in patients with mutations typically associated with de novo AML (18.1 months) and secondary AML (17.7 months). In a recent study, the standard-of-care regimen of cytarabine and daunorubicin (7+3) in patients with secondary AML showed a median overall survival of 5.95 months.
"This mutational analysis enabled us to identify frequently occurring genetic abnormalities that may predict outcomes in older AML patients treated with the combination of pracinostat and azacitidine," Dr. Guillermo Garcia-Manero, MD Anderson Cancer Center, principal investigator of the study said. "In addition, we confirmed that the mutation profile in the Phase II AML study was representative not only of the larger population of older AML patients, but common in MDS patients as well. Finally, longitudinal sequencing analyses showed that continued treatment with pracinostat and azacitidine increases the rate of minimal residual disease clearance. These findings combine to support the upcoming Phase III study of pracinostat plus azacitidine in AML as well as the Phase II dose-optimization study of pracinostat and azacitidine in high and very high MDS."
Results from the Phase II study of pracinostat and azacitidine in elderly patients with AML showed a median overall survival of 19.1 (95%CI: 10.0-26.5) months, one-year survival of 62% and a CR rate of 42%. CR rate and overall survival were consistent across patient subsets. Responses were durable (median CR+CRi 17.2 months), blast clearance was rapid (median 8 weeks) and maximum clinical benefit required prolonged therapy (> 6 months) in some patients. The combination of pracinostat and azacitidine had no unexpected toxicities. The most common grade 3/4 treatment-emergent adverse events reported in >10% of all patients included thrombocytopenia, febrile neutropenia, neutropenia, fatigue and anemia.