General AML

HMAs may represent a feasible therapeutic option for patients with R/R AML

Maximilian Stahl from Yale University School of Medicine, New Haven, CT, and colleagues conducted a large retrospective study, which investigated the efficacy of hypomethylating agents (HMAs) in relapsed or refractory (R/R) acute myeloid leukemia (AML) and evaluated for predictors of outcomes that can identify patients most likely to benefit from HMAs.

Using an international multicenter retrospective database, 655 patients (median age at diagnosis = 65 years; range, 16–92) with relapsed (n = 290) or refractory (n = 365) AML were included in this study. Patients were administered azacitidine (57%) or decitabine (43%). Among patients treated with azacitidine, 76.5% received a 7-day (7-0) schedule of azacitidine, whereas 17.9% and 2.4% of patients received a 5-day (5-0) and a 7-day schedule with a weekend break (5-2-2), respectively. Among patients treated with decitabine, 72.1%, 1.2%, and 19.9% received a 5-day (5-0), a 7-day (7-0), and a 10-day (10-0) schedule, respectively.

The primary endpoint of the study was overall survival (OS). The secondary endpoints included complete remission (CR) and CR with incomplete count recovery (CRi) rates.

Key findings:
  • CR: 11% (70/655)
  • CRi: 5.3% (34/655)
  • Hematologic improvement: 8.5% (54/655)
  • Presence of ≤ 5% circulating blasts (odds ratio [OR] = 1.87, P = 0.0278) and a 10-day schedule of decitabine (OR = 2.37, P = 0.0374) significantly associated with improved response rates
  • 30-day mortality rate: 6.4% (95% CI, 4.6–8.8)
  • Median OS for all patients: 6.7 months (95% CI, 6.1–7.3)
  • Median OS in patients achieving CR and CRi compared to non-responders: 25.3 vs 14.6 months respectively, P = 0.05
  • Presence of > 5% circulating blasts (HR = 1.29; P = 0 .02) and > 20% blasts in the bone marrow (HR = 1.24; P = 0.04) were significant predictors for inferior OS

This is the largest study of HMAs in R/R AML until date with a significant subset of patients (16%) achieving CR/CRi and a median OS of 21.2 months (95% CI, 16.3–28.6). These findings demonstrate that “outside of a clinical trial, HMAs represent a reasonable therapeutic option for some patients with RR AML”. Some key limitations of this study include its retrospective nature and patient selection bias.

The authors noted that their study “helps to inform the discussion between providers and patients regarding HMAs as a treatment option for R/R AML” and demonstrates “the urgent need for improved therapeutic options.” They also added that their study serves as a “valuable reference in the development of future clinical trial using HMAs as the backbone”.

References
  1. Stahl M. et al. Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort. Blood Advances. 2018 2: 923–932. DOI: 10.1182/bloodadvances.2018016121.
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