Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

Abstract

Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n = 302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20-30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53-10.7) months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.

Fig. 1

Kaplan–Meier curves of baseline factors that did not affect overall survival (OS). a Effect of bone marrow blast count on OS (total cohort). b Effect of bone marrow blast count on OS (AZA first line). c Effect of age on OS. d Effect of WHO-AML type on OS. e Effect of white blood cell (WBC) count on OS. f Effect of WBC </≥15 G/l on OS. g Effect of achievement of EMA/FDA-target dose on OS. h Effect of azacitidine (AZA) schedule: 5 vs. 7 days of azacitidine per cycle on OS

Fig. 2

Forrest plot of factors significantly influencing overall survival of azacitidine-treated AML patients (n = 302) in multivariate analysis

Fig. 3

Kaplan–Meier curves of baseline factors that significantly affected overall survival (OS) in multivariate analysis. a Effect of monosomal karyotype (MK) on OS. b Effect of MK in comparison to complex karyotype on OS. c Effect of prior disease-modifying treatment (i.e., azacitidine first-line no vs. yes) on OS. d Effect of hematologic improvement (HI) on OS. e Effect of response deepening (i.e., achievement of BM blast reduction in terms of mCR/CR/PR after HI) on OS. f Overall survival by best response