SAN DIEGO — Adding pevonedistat to azacitidine demonstrated durable remissions and notable response rates with limited additional toxicity beyond what is typically expected with using azacitidine alone in elderly patients with acute myeloid leukemia, according to findings presented at the ASH Annual Meeting and Exposition.
The combination therapy was also well tolerated, according to the study results.
Ronan T. Swords
Ronan T. Swords, MD, PhD, FRCPI, FRCPath, co-leader of the leukemia/lymphoma/myeloma site disease group at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and colleagues conducted a phase 1 study of 61 adults (median age 75 years) to assess the safety and tolerability of pevonedistat (MLN4924, Takeda) plus azacitidine (Vidaza, Celgene) for the treatment of AML.
Additional objectives included defining the maximum tolerated dose, and the assessment of disease response and pharmacokinetics.
Patients received pevonedistat at either 20 or 30 mg/m2 intravenously on days 1, 3 and 5 plus fixed dose azacitidine at 75 mg/m2 either intravenously or subcutaneously on days 1-5, 8 and 9, and every 28 days until disease progression or unacceptable toxicity.
The researchers assessed adverse events per the NCI-CTCAE v4.03.
Participants received a median of four cycles and 38% of patients received six or more cycles of the combinations therapy.
The most common adverse events were constipation (46%), nausea (44%), fatigue (43%) and anemia (39%). Fifty patients reported grade 3 or greater adverse events – the most frequent of which included anemia (28%), febrile neutropenia (28%), thrombocytopenia (21%) and neutropenia (18%).
Sixty-seven percent of patients experienced serious adverse events which most commonly included febrile neutropenia (25%), neutropenia (25%) and pneumonia (11%).
Two patients discontinued therapy due to pevonedistat-related toxicities.
The overall response rate in 52 evaluable patients was 60% with a median duration of remission of 8.3 months. Eight patients reached partial remission, 18 reached complete remission and five reached complete remission with incomplete blood count recovery.
Sixty-one percent of responses occurred within the first two cycles.
After a median follow-up of 16.4 months, 6-month survival was 52%. Patients receiving the maximum tolerated dose of pevonedistat 20 mg/m2 had a median OS of 7 months. Patients aged 65 to 74 years had a median OS of 16.1 months compared with patients aged 75 years or older who had a median OS of 5.3 months.
“This is a combination that overall is very well tolerated and most patients [received] four courses of therapy which, I think, is an important point to make considering the addition of another agent adds to toxicity and causes patients to drop off early,” Swords said during the presentation. “With azacitidine it usually takes at least four to six cycles to work. By keeping more patients on the study getting continuous therapy with relatively [good] safety data and overall response rates with a trend toward improved survival in secondary AML … we hope to be able to draw more conclusions.” – by Ryan McDonald
Swords RT, et al. Abstract 98. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Swords reports receiving research funding from Takeda. Please see the full study for a list of all other relevant financial disclosures.