General AML

Highlights from ASH 2016: Abstract 100 – A Phase 2 Study of Pracinostat and Azacitidine in Elderly Patients with AML Not Eligible for Induction Chemotherapy: Response and Long-Term Survival Benefit

On Saturday 3rd December, at the 58th Annual Meeting & Exposition of the American Society of Hematology (ASH) in San Diego, CA, there was a gripping session focusing on “Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation.”

Guillermo Garcia-Manero, MD, of the Department of Leukemia at The University of Texas M.D. Anderson Cancer Center, Houston, USA, presented the key findings from a phase 2 study of pracinostat and azacitidine. Pracinostat is a potent oral Class I, II, IV Histone Deacetylase (HDAC) inhibitor and azacitidine (AZA) is a novel hypomethylating agent. Garcia-Manero et al. investigated the combination of these agents in 50 older patients (median age 75 years) unable to undergo induction chemotherapy.

The findings were:

  • Complete Response (CR) was achieved in 21 patients
  • CR with incomplete blood count recovery (CRi) in 2 patients
  • Morphologic Leukemia Free status (MLFs) in 3 patients
  • cCR rate of 52%
  • Median duration of cCR was 13.2 months

  • Median Overall Survival (OS) was 19.1 months, 1-year and 2-year OS were 62% and 41%, respectively

  •  OS by cytogenetic risk group, high vs intermediate; 13.5 months vs 24.1 months

  • OS in de novo vs secondary AML, 13.0 months vs 19.6 months

  •  OS in ≥ 75 years vs < 75 years; 13.5 months vs 22.8 months 

  • OS by ECOG Performance Status (PS), PS 0–1 vs PS 2; 19.1 months vs 13.0 months

  • Thrombocytopenia was the most common grade ≥ 3 hematologic adverse event (46%)

The authors concluded that pracinostat + AZA led to a high rate of response in elderly patients with AML. Furthermore, the responses were durable and observed irrespective of age, cytogenetic risk, ECOG performance status, and de novo or secondary AML.

Abstract 100

Background: Pracinostat, a potent oral Class I, II, IV histone deacetylase (HDAC) inhibitor, exhibited modest single-agent activity in relapsed AML. Inhibition of histone deacetylation and DNA hypermethylation induces re-expression of silenced genes in myeloid malignancies in a synergistic fashion. A pilot study of pracinostat with azacitidine (AZA) in myelodysplastic syndromes showed the combination to be active and well tolerated (Blood 2012;120:3821). We conducted a Phase 2 study to evaluate pracinostat + AZA in patients ≥65 years with AML not eligible for induction chemotherapy. Minimum 1-year survival data were reported previously (Blood 2015;126:453). Here we report long-term survival and response analyses.

Methods: Main eligibility: Age ≥65, untreated de novo or secondary AML, ≥20% bone marrow (BM) blasts, not candidate for intensive therapy due to co-morbidities and/or AML features, intermediate or high-risk cytogenetics, and no prior treatment with HDAC inhibitors or hypomethylating agents. Treatment consisted of pracinostat 60 mg orally 3 days/week on alternate days for 3 weeks and AZA 75 mg/m2 subcutaneously or intravenously daily for 7 days, with cycles repeated every 28 days until disease progression, lack of response or poor tolerability. The primary endpoint was a composite complete response rate (cCR) of CR + CRi+ MLFS by IWG criteria. Response was assessed at the end of Cycles 2, 4, 6 and then every 3 cycles or when clinically indicated. Secondary endpoints included overall response rate (cCR + PR), duration of response and overall survival (OS). Study registered under NCT01912274.

Results: Between December 2013 and December 2014, 50 patients were enrolled at 15 U.S. sites. Baseline characteristics: Median age 75 years (range 66-84 years); 33 de novo and 17 secondary AML; 27 intermediate-risk and 21 high-risk cytogenetics and 2 not known; median BM blasts 40% (range 20%-89%), ECOG performance status 0-1 in 84% and 2 in 16%. The median number of treatment cycles was 6.5 (range 1-24+). A CR was achieved in 21 patients (42%), CRi in 2 (4%), and MLFS in 3 (6%) for a cCR rate of 52%. Median time to BM blasts <5% was 57 days (range 25-243 days) and exceeded 168 days (6 cycles) in 3 patients (12%). Median duration of cCR is 13.2 months (95% CI 10.9-21.5 months), with 6 of 26 patients (23%) continuing on therapy for a periods ranging from 20.5 to 29.5 months. With a median follow-up of 21 months, the median OS is 19.1 months (95% CI, 10.0-not reached). One-year and 2-year OS are 62% and 45%. Non-protocol therapies (NPT) were administered in 23 patients (46%). There was no effect on OS after censoring survival duration at the start of NPT. Response and OS by population subsets are summarized in Table 1. Non hematologic adverse events Grade ≥3 reported in >5% of patients: Fatigue 34%; anorexia 10%, cellulitis, pneumonia, asthenia and sepsis in 8%; urinary tract infection, nausea, back pain, hypoxia, hyponatremia, and syncope in 6%. Grade ≥ 3 hematologic toxicities in> 5% of patients: thrombocytopenia 46%; febrile neutropenia 44%; neutropenia 36%; anemia 30%; pancytopenia 6%. The 30-day and 60-day mortality rates were 2% and 10%.

Conclusions: Pracinostat + AZA led to a high rate of responses in elderly patients with AML. Responses were durable and observed irrespective of age, cytogenetics risk, ECOG performance status, and de novo or secondary AML. Marrow remission was typically achieved early, but prolonged exposure was required in some patients to maximize response. The results compare favorably with historical single-agent AZA data in a similar AML population. A phase 3 study of AZA +/- pracinostat in untreated patients with AML unfit for standard induction chemotherapy is starting.

Table 1: Response and Survival According to Baseline Characteristics

  1. Garcia-Manero G. 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. Oral Abstract #100: ASH 58th Annual Meeting and Exposition, San Diego, CA.