Background: Older patients with TN-AML who are ineligible for intensive chemotherapy have limited therapeutic options and poor outcomes. Hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) have been the standard of care in this population for more than a decade and were approved in Europe for patients not candidates for intensive chemotherapy or patients not candidates for hematopoietic cell transplant. However, there is no direct efficacy and safety comparative data of AZA and DEC from a prospective large randomzied study. We took advantage of the largest randomized trial for patients with TN-AML who were not eligible for intensive chemotherapy, ASTRAL-1, to compare efficacy and safety of AZA vs DEC in patients randomized to these 2 treatments
Aims: To compare clinical outcomes between AZA and DEC in TN-AML patients not eligible for intensive chemotherapy
Methods: ASTRAL-1 is a global randomized Phase 3 trial which enrolled 815 patients with TN AML who were not eligible for intensive chemotherapy using stringent criteria including age ≥ 75 year or comorbidities including ECOG PS 3. Patients were randomized 1:1 to either Guadecitabine (G), a next generation HMA (60 mg/m2/d SC days 1-5) or a preselected Treatment Choice (TC) of AZA (75 mg/m2/d IV or SC days 1-7), DEC (20 mg/m2/d IV days 1-5), or low dose Ara-C (LDAC) (20 mg SC BID days 1-10). AML diagnosis and responses were assessed by an independent central pathologist blinded to randomization assignment. Responses were recorded using IWG 2003 criteria. Rates of Complete Response (CR) and Overall Survival (OS) were co-primary endpoints.
Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), or LDAC (15%). Of 407 patients randomized to TC, 338 (83%) were treated with either AZA (171 patients) or DEC (167 patients). Baseline variables were well balanced between AZA and DEC patients with no statistically significant differences in baseline characteristics: median age 76 y for both treatments, with poor PS 2-3 in 47.4% vs 53.9%, poor risk cytogenetics 38% vs 33.5%, secondary AML 38% vs 36.5%, BM blasts > 30% in 63.7% vs 71.3%, and TP53 mutations in 12.9% vs 11.3% for AZA vs DEC respectively. Median follow up was 25.5 months and median number of treatment cycles was 6 for AZA (range 1,31), and 5 for DEC (range 1,34). The ITT analyses showed a CR rate of 17.5% vs 19.2% (p= 0.70); and overall CR (CR+CRp+CRi) of 22.2% vs 25.1% (p= 0.53) for AZA vs DEC respectively. Median OS was 8.7 vs 8.2 months for AZA vs DEC respectively with Hazard Ratio of 0.97 (95% CI 0.77, 1.23; log rank p= 0.8). Additional subgroup analyses by baseline characteristics and molecular genetic mutations will be presented at the meeting. There was no statistically significant difference in the incidence of Grade ≥ 3 AEs (88.9% vs 87.4%), serious AEs (81.9% vs 76.0%), or 30-day all-cause mortality (11.7% vs 7.8%) for AZA vs DEC respectively. There was a trend of higher 60-day all-cause mortality on AZA (20.5%) vs DEC (13.2%) (p= 0.07).
Conclusions/Summary: This is the largest comparison of clinical outcomes associated with AZA and DEC for patients with TN AML not eligible for intensive chemotherapy who were treated in the same prospective study. While patients were randomized between G and each of AZA and DEC separately with no direct randomization of AZA vs DEC, the patients’ characteristics were well balanced in patients randomized to the two HMA treatments. There were no significant differences in CR, overall CR, OS, or safety between AZA and DEC.