Results from a multicenter, placebo-controlled study presented by Guillermo Garcia-Manero, MD, at the ASH annual meeting last month, demonstrated that the oral histone deacetylase (HDAC) inhibitor pracinostat, when added to azacitidine, failed to improve efficacy over azacitidine alone in previously untreated patients with MDS. Treatment with pracinostat was, however, associated with more toxicity –leading to treatment discontinuation in more patients.
Dr. Garcia-Manero, from the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas, and colleagues, enrolled 102 patients ≥18 years old with previously untreated intermediate- or high-risk MDS between June 2013 and August 2014 at 24 U.S. centers.
Patients were randomized to receive:
- Azacitidine 75 mg/m2 on days 1-7 or days 1-5 and 8-9, plus pracinostat 60 mg for 3 days per week for 3 weeks
- Azacitidine 75 mg/m2 on days 1-7 or days 1-5 and 8-9 plus placebo
Patients continued treatment until disease progression, lack of benefit, or intolerance. The study’s primary endpoint was confirmed as complete response (CR) within six cycles. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). The median patient age was 69 years (range = 26-90 years).
After six cycles of treatment, 18 percent of patients in the pracinostat plus azacitidine group had achieved CR, compared with 33 percent in the azacitidine plus placebo group. A summary of response rates is seen in TABLE.
PFS was similar, but slightly higher among patients treated with pracinostat: 10.7 months compared with 9.2 months (hazard ratio [HR]=0.93; p value was non-significant). OS, however, was slightly higher among patients treated with azacitidine alone: 18.8 months and 15.7 months (HR=1.21; p value was non-significant).
When added to azacitidine, pracinostat led to higher rates of adverse events (AEs) than azacitidine alone, including:
- Grade 3 thrombocytopenia: 47% vs. 26%, respectively
- Grade 3 febrile neutropenia: 33% vs. 18%, respectively
- Grade 3 fatigue: 24% vs. 0%, respectively
These AEs were associated with higher rates of treatment discontinuation among pracinostat-treated patients, compared with those treated with azacitidine alone: 26 percent and 10 percent, respectively.
“Pracinostat failed to improve the clinical effectiveness of azacitidine in this population of higher-risk MDS patients,” Dr. Garcia-Manero and colleagues concluded. “This appears related to a higher rate of early study discontinuation in the pracinostat group, primarily due to adverse events.”
The researchers also conducted exploratory analyses in patients who had received four or more treatment cycles to determine if longer treatment duration affected safety and response.
Patients who tolerated treatment with pracinostat plus azacitidine for four or more cycles appear to benefit compared with azacitidine alone, both in terms of OS (HR=0.59) and duration of response (HR=0.48). These results highlight the need to consider alternative doses and schedules with pracinostat, the authors added.
Garcia-Manero G, Berdeja JG, Komrokji RS, et al. A Randomized, Placebo-Controlled, Phase II Study of Pracinostat in Combination with Azacitidine (AZA) in Patients with Previously Untreated Myelodysplastic Syndrome (MDS). Abstract #911. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.
|TABLE. Summary of Response in Patients Treated with Azacitidine Plus Pracinostat or Placebo|
|Pracinostat (n=51)||Placebo (n=51)|
|CR, within 180 days||18%||33%|
|Partial remission (PR)||0%||0%|
|Hematologic improvement (HI)||35%||55%|
|Erythroid response (HI-E)||28%||45%|
|Platelet response (HI-P)||31%||53%|
|Neutrophil response (HI-N)||26%||39%|
|Clinical benefit rate (CR + PR + HI + molecular CR)||53%||63%|