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Durable Response Observed With Pracinostat and Azacitidine for Older Patients With AML

December 30, 2021

The inhibition of both histone deacetylation (HDAC) and DNA hypermethylation induces re-expression of silenced genes in vitro in cell lines and in primary cells from patients with myeloid malignancies. The DNA hypomethylating agents (HMAs) azacitidine and decitabine are U.S. Food and Drug Administration-approved for myelodysplastic syndromes (MDS), though it is unclear just how these drugs exert their clinical effects in patients. A previous study demonstrated that pracinostat – an HDAC inhibitor – exhibited modest single-agent activity in patients with relapsed acute myeloid leukemia (AML).

In an open-label, phase II study presented at the 2016 ASH Annual Meeting, pracinostat plus azacitidine led to a composite complete response rate (cCRR; primary endpoint, including complete response with or without hematopoietic recovery, as well as morphologic leukemia-free state) of 52 percent. "Pracinostat plus azacitidine led to a high rate of responses in elderly patients with AML … that were durable," the authors noted.

Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors enrolled 50 older patients (median age = 75 years; range = 66-84 years) with AML who were ineligible for induction chemotherapy from 15 U.S. centers between December 2013 and December 2014. Patients were eligible if they had untreated de novo or secondary AML, ≥20 percent bone marrow (BM) blasts, were not a candidate for intensive therapy because of comorbidities or were unlikely to respond favorably to intensive therapy because of adverse AML features such as high-risk cytogenetics, and had not received prior treatment with HDAC inhibitors or HMAs.

A majority of patients (n=33) had de novo AML, while 17 had secondary AML, and the median BM blast was 40 percent (range = 20-89%). Twenty-seven patients had intermediate-risk cytogenetics, 21 had high-risk cytogenetics, and two were unknown. Most patients (84%) had an Eastern Cooperative Oncology Group performance status of 0-1.

Patients received pracinostat 60 mg orally three times per week for three weeks together with azacitidine 75 mg/m2 administered via subcutaneous injection or intravenous infusion daily for the first seven days of each 28-day cycle. Patients received a median of 6.5 treatment cycles (range = 1-24+ cycles).

Twenty-one patients (42%) achieved complete remission (CR), while two (4%) achieved CR with incomplete hematologic recovery, and three (6%) achieved a morphologic leukemia-free state (per International Working Group criteria). Median time to BM blasts <5 percent was 57 days (range = 25-243 days) and exceeded 168 days (6 cycles) in three patients (12%). Median duration of cCR was 13.2 months (95% CI 10.9-21.5), with 23 percent of patients (n=6/26) continuing therapy for a period ranging from 20.5 to 29.5 months.

After a median follow-up of 21 months, the median overall survival (OS) was 19.1 months (95% CI 10.0-not reached). One- and two-year OS rates were 62 percent and 45 percent, respectively. See TABLE for survival outcomes based on baseline characteristics.

Grade ≥3 non-hematologic adverse events (AEs; reported in >5% of patients) included fatigue (34%), anorexia (10%), cellulitis (8%), pneumonia (8%), asthenia (8%), sepsis (8%), urinary tract infection (6%), nausea (6%), back pain (6%), hypoxia (6%), hyponatremia (6%), and syncope (6%). Grade ≥3 hematologic AEs included thrombocytopenia (46%), febrile neutropenia (44%), neutropenia (36%), anemia (30%), and pancytopenia (6%). Thirty- and 60-day mortality rates were 2 percent and 10 percent, respectively.

The authors noted that a phase III study of pracinostat plus azacitidine in untreated patients with AML who are ineligible for standard induction chemotherapy is underway. A randomized study of this combination in previously untreated patients with MDS was reported in 2015 and did not show benefit for the combination compared with azacitidine alone.


Garcia-Manero G, Atallah E, Khaled SK, et al. A phase 2 study of pracinostat and azacitidine in elderly patients with acute myeloid leukemia (AML) not eligible for induction chemotherapy: response and long-term survival benefit. Abstract #100. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.

TABLE. Response and Survival According to Baseline Characteristics
CR Rate cCR Rate Survival
Overall population (n=50) 42% 52% 19.4 months

(95% CI 10-not reached)











Not reached (95% CI 10.7-not reached)

13.5 (95% CI 2.4-not reached)


≥75 years (n=26)

66-74 years (n=24)








13.5 (95% CI 9.0-21.5)

26.5 (95% CI 8.0-26.5)

Type of AML

 De novo (n=33)

Secondary (n=17)








13.02 (95% CI 5.7-26.5)

Not reached (95% CI 16.4-not reached)

ECOG Performance Status

0-1 (n=42)

2 (n=8)








19.08 (95% CI 10.0-19.1)

13.0 (95% CI 8.0-26.5)

CR = complete remission; cCR = composite complete response rate (CR+CR with incomplete count recovery+morphologic leukemia-free state); AML = acute myeloid leukemia; ECOG = Eastern Cooperative Oncology Group


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