Oral azacitidine improves overall survival in patients with acute myeloid leukaemia

Updated results of the QUAZAR AML-001 trial showed an overall survival (OS) benefit of treatment with oral azacitidine compared with placebo in acute myeloid leukaemia (AML). This improvement was irrespective of the patients’ mutational status, however, NPM1 and FLT3 mutations were prognostic and predictive of a survival benefit.

Characterisation of NPM1^mut (23–30%) with and without concomitant internal tandem duplications in FLT3 (FLT3-ITD) (approximately 25%) are used to ascribe risk categories in patients with AML [1,2]. In the multicentre, placebo-controlled, randomised, phase 3 QUAZAR AML-001 trial (NCT01757535), oral azacitidine (CC-486) maintenance therapy significantly prolonged OS and relapse-free survival (RFS) compared with placebo [3]. Prof. Hartmut Döhner (Universitätsklinikum Ulm, Germany) presented previously unpublished survival outcomes for oral azacitidine versus placebo by NPM1/FLT3 mutational status at diagnosis [4].

The QUAZAR AML-001 trial enrolled 469 patients with de novo or secondary AML, intermediate-risk or poor-risk cytogenetics (NPM1^mut n=137; FLT3 ^mut n=66; NPM1^wt n=332; FLT3 ^wt n=403), and not eligible for haematopoietic stem cell transplantation. Participants received either oral 300 mg azacitidine or placebo once daily for a 14/28-day treatment cycle. Primary endpoints were OS and RFS.

In a multivariate OS analysis of azacitidine (n=234) versus placebo (n=233), azacitidine significantly improved OS independent of mutation status (P=0.00297). NPM1^mut at AML diagnosis was favourably prognostic for OS (P≤0.032) and RFS (P≤0.011), and predictive of a survival benefit for patients treated with oral azacitidine versus placebo (OS P≤0.038; RFS P=0.005). Measurable residual disease-negativity at baseline was more common in patients with NPM1^mut (62%) than with NPM1^wt (49%). Median OS was 42.2 months for NPM1^mut + azacitidine; 15.9 months for NPM1^mut + placebo; 19.6 months for NPM1^wt + azacitidine; and 14.6 months for NPM1^wt + placebo. Median RFS was 23.2 months for NPM1^mut + azacitidine; 6.9 months for NPM1^mut + placebo; 7.8 months for NPM1^wt + azacitidine; and 4.6 months for NPM1^wt + placebo.

Median OS and RFS in patients with FLT3-ITD were statistically significantly (P≤0.032) prolonged in the oral azacitidine arm versus placebo. OS (in months): FLT3-ITD + azacitidine 28.2; FLT3-ITD + placebo 9.7; FLT3^wt + azacitidine 24.7; FLT3^wt + placebo 15.2. RFS (in months): FLT3-ITD + azacitidine 23.1; FLT3-ITD + placebo 4.6; FLT3^wt + azacitidine 10.2; FLT3^wt + placebo 4.9. Evaluation of patients with mutations in both genes also showed markedly longer OS and RFS in azacitidine-treated patients.

In conclusion, NPM1^mut and/or FLT3^wt was predictive for survival benefit in patients in remission treated with oral azacitidine in QUAZAR AML-001. Multivariate analyses confirmed the independent prognostic influence of NPM1 and FLT3 mutations, and oral azacitidine showed improvement in OS independent of these mutations.

1. 1. Papaemmanuil E, et al. N Engl J Med 2016;374:2209–21.NPM1 mutationFL
   2. Tiede C, et al. Blood 2002;99(12):4326–35.
   3. Wei AH, et al. N Eng J Med 2020;383:2526–37.
   4. Döhner H, et al. Survival outcomes from the QUAZAR AML-001 trial with oral azacitidine for patients with acute myeloid leukemia in remission by disease subtype, cytogenetic risk, and NPM1 mutation status at diagnosis. S131, EHA 2021 Virtual Congress, 9–17 June.

 

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Posted on 5 August, 2021