Doctor and patient

Photo courtesy of NIH

VIENNA—A 2-drug combination can produce complete responses (CRs) in elderly patients with newly diagnosed acute myeloid leukemia (AML), but whether the treatment confers a survival benefit remains to be seen.

The combination consists of the HDAC inhibitor pracinostat and the antineoplastic agent azacitidine.

In a phase 2 study, the treatment produced CRs in nearly a third of AML patients, and follow-up has shown that responses improve over time.

However, the median overall survival has not been reached.

“The combination of pracinostat and azacitidine continues to demonstrate compelling clinical activity in these elderly patients with newly diagnosed AML,” said Daniel P. Gold, PhD, President and Chief Executive Officer of MEI Pharma, the company developing pracinostat.

“While the overall survival trend in this study is encouraging, we believe that longer follow-up is needed to gain an accurate survival estimate. Ultimately, this survival estimate will be critical in determining the development path forward for this combination. We look forward to providing an update when these data mature, which we expect to occur later this year.”

The current data were presented at the 20th Congress of the European Hematology Association (abstract P568*). The trial was sponsored by MEI Pharma.

The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML. Fifty-four percent of patients had intermediate-risk cytogenetics, 42% had high-risk, and 4% were not evaluable.

The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.

To date, half of patients have discontinued treatment, 8% due to death, 36% because of progressive disease, 32% due to adverse events, and 24% for other reasons.

Response and survival

Thus far, 54% of patients (n=27) have achieved the primary endpoint of CR plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).

Thirty-two percent of patients had a CR, 14% had a CRi, 8% achieved MLFS, and 6% had a partial response (PR) or PR with incomplete count recovery (PRi).

Among the 27 patients with intermediate-risk cytogenetics, 63% achieved a CR/CRi/MLFS, and 7% had a PR/PRi. Among the 21 patients with high-risk cytogenetics, 48% achieved a CR/CRi/MLFS, and none had a PR/PRi.

The researchers said these response rates compare favorably with previous studies of azacitidine alone in this patient population. In this trial, most responses occurred within the first 2 cycles of therapy and continued to improve with ongoing therapy.

The median overall survival has not yet been reached. Sixty-four percent of patients (n=32) are still being followed (range, 6-15 months).

The survival rate of patients with intermediate-risk cytogenetics appears greater than that for patients with high-risk cytogenetics, though neither subset of patients has reached median survival.

The 60-day mortality rate was 10% (n=5).

Safety and tolerability

The most common treatment-emergent adverse events (AEs) were nausea (66%), constipation (58%), fatigue (48%), febrile neutropenia (40%), thrombocytopenia (32%), diarrhea (30%), vomiting (28%), decreased appetite (28%), anemia (26%), hypokalemia (26%), neutropenia (24%), pyrexia (24%), dizziness (24%), dyspnea (24%), and rash (20%).

Treatment-emergent AEs led to discontinuation in 8 patients. Two of these patients developed sepsis that proved fatal.

The other events included grade 3 peripheral motor neuropathy (which was resolved), grade 3 parainfluenza (resolved with sequelae), grade 3 prolonged QTc/atrial fibrillation (resolved), grade 2 failure to thrive (not resolved), grade 3 mucositis (not resolved), and grade 2 fatigue (not resolved).

AEs resulting in dose reductions were frequently due to disease, according to the researchers.

The team also noted that nearly half of the patients in this study (n=22) have received pracinostat and azacitidine beyond 6 months, and 5 patients have received it for more than a year, which reflects long-term tolerability.

*Information in the abstract differs from that presented at the meeting.

Jury still out on combo for elderly AML