Introduction: Inhibition of histone deacetylation and DNA hypermethylation induces re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Pracinostat, a potent oral Class I, II, IV histone deacetylase (HDAC) inhibitor, in combination with azacitadine (AZA) showed promising efficacy in a Phase 2 study in patients ≥65 years with AML not eligible for induction chemotherapy (Garcia Manero, Blood 2016). The overall response rate (all complete/partial remissions) was 64% and the median overall survival was 19.1 months. An evaluation of somatic mutations in this study suggested that continued treatment after achieving a response either lowered the variant allele frequency or cleared residual mutations (Takahashi, JCO 2017). To further explore the benefit of continued treatment we conducted post-hoc analyses to determine the time to first response and assess whether there was a correlation between the duration of treatment and occurrence of a response.

Methods: This was a multicenter, phase 2 study in 50 patients ≥65 years with untreated de novo or secondary AML (ie, > 20% bone marrow blasts) and intermediate/high-risk cytogenetics who were not candidates for intensive therapy due to co-morbidities and/or AML features. Treatment consisted of pracinostat 60 mg orally 3 days/week on alternate days for 3 weeks and AZA 75 mg/m2 either subcutaneously or intravenously daily for 7 days or a 5-2-2 schedule. Cycles were repeated every 28 days until disease progression, lack of response or poor tolerability. Time to marrow complete response (CR) was calculated and logistic regression modeling was used to assess the probability of a CR utilizing ECOG performance status (PS), cytogenetic risk, and duration of treatment as covariates.

Results: The median age was 75 years (range 66-84 years). Most patients were male (28; 65%) with de novo AML (33, 66%), ECOG PS 0-1 (38; 88%) and with intermediate-risk (27; 54%) or high-risk (21; 42%) cytogenetics. Median bone marrow (BM) blasts at entry were 40% (range 20%-89%). The median number of treatment cycles was 6.5 (range 1-27+). While 27 patients (54%) received ≥5 cycles, 13 (26%) received only 1-2 cycles. Median time to BM blasts <5% was 2 cycles (57 days; range 25-243); however, 3 patients (12%) required >6 cycles to respond. Of the 21 patients (42%) achieving a morphologic CR, 15 (71%) achieved this after at least 100 days of therapy. The logistic regression analysis indicated a statistically significant correlation between treatment duration and occurrence of CR.

With a median follow-up of 24.2 months (range 14.7-32.9), 19 patients (38%) discontinued due to progressive disease, 11 (22%) due to patient or investigator decision and 14 (28%) due to adverse events, the majority of which were fatigue, failure to thrive, neutropenia, or thrombocytopenia. Of these, 6 patients discontinued during the first 3 cycles, 2 between cycles 4-6, and the remaining 6 after cycle 6. No unexpected toxicities were observed with the combination of pracinostat and AZA.

Conclusions: A high response rate with pracinostat + AZA has been previously reported in this study of elderly patients with AML. These post-hoc analyses suggest that while marrow remission may be achieved early, prolonged exposure is likely to be beneficial in maximizing clinical response. A phase 3 study of pracinostat in combination with AZA in untreated patients with AML unfit for standard induction chemotherapy is ongoing. In that study it is recommended that patients who have no evidence of disease progression should receive a minimum of 6 cycles of study treatment, if and when possible, to maximize the likelihood of a response to treatment.


Atallah: ADC Therapeutics: Research Funding. Khaled: Daiichi Sankyo, Inc: Other: Travel Support; City of Hope: Research Funding. Spezia: Helsinn: Employment, Patents & Royalties: co-inventor. Palmesino: Helsinn: Employment.

Author notes


Asterisk with author names denotes non-ASH members.