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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-014-2126-9) contains supplementary material, which is available to authorized users.

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

“…In total 7 patients with MDS or CMML and 2 patients with AML receiving CC‐486 monotherapy in this study attained CR or PR, including, importantly, patients for whom previous DNMTi therapy had failed. While multiple studies have shown injectable azacitidine can improve OS in higher‐risk MDS and AML without requiring CR5, 7, 8, 9, 37; the effect of CC‐486 on OS has not yet been reported and was not captured in this phase 1 study, but is under investigation in an ongoing phase 3 trial of CC‐486 in patients with MDS (NCT01566695).…”

“…Parenteral azacitidine has been extensively evaluated in patients with MDS, chronic myelomonocytic leukemia (CMML), and AML in large randomized clinical trials,5, 6, 7 in regional registry studies,8, 9, 10, 11, 12, 13 and in numerous smaller retrospective analyses of patients treated in community practice 14, 15. These studies show azacitidine reduces cytopenias in select lower‐risk MDS and prolongs overall survival (OS) in higher‐risk MDS and AML,5, 6, 7, 16 may be effective maintenance therapy after induction chemotherapy (IC) or allogeneic hematopoietic stem cell transplant (alloHSCT),17, 18, 19, 20 and can induce responses in patients with relapsed/refractory disease 12, 21.…”

“…Importantly, the study of azacitidine has revealed nuances of treatment with DNMTi therapy not seen with the use of traditional chemotherapy. These include improved OS, which can occur in the absence of a complete remission (CR),7, 8, 22 a need to treat with as many as 6 treatment cycles prior to achieving maximal response, and hematologic toxicities seen during early treatment tend to decrease if patients can remain on treatment 7, 8, 23…”

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

“…The largest azacytidine studies describe either a similar overall survival of MDS patients with CK+/MK+ or CK+/MK− [30] or a worse outcome of AML patients with CK+/MK+ compared to CK+/MK− [31], albeit with limited patient numbers. Our post hoc analysis constitutes the first analysis of a phase III randomized HMA trial in MDS/ AML, but it has similar limitations: when comparing cytogenetic subgroups of DAC-treated patients, the numbers (particularly in the CK+/MK− group, n=9) became too small to allow meaningful comparisons of outcomes.…”

Low Dose Cytosine Arabinoside and Azacitidine Combination in Elderly Patients with Acute Myeloid Leukemia and Refractory Anemia with Excess Blasts (MDS-RAEB2)

“…In this study, 302 patients were evaluated. The overall response rate was 48 %, and the median overall survival was 9.6 months [14].…”