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 NPM1mut (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 . Prof. Hartmut Döhner (Universitätsklinikum Ulm, Germany) presented previously unpublished survival outcomes for oral azacitidine versus placebo by NPM1/FLT3 mutational status at diagnosis .
The QUAZAR AML-001 trial enrolled 469 patients with de novo or secondary AML, intermediate-risk or poor-risk cytogenetics (NPM1mut n=137; FLT3 mut n=66; NPM1wt 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). NPM1mut 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 NPM1mut (62%) than with NPM1wt (49%). Median OS was 42.2 months for NPM1mut + azacitidine; 15.9 months for NPM1mut + placebo; 19.6 months for NPM1wt + azacitidine; and 14.6 months for NPM1wt + placebo. Median RFS was 23.2 months for NPM1mut + azacitidine; 6.9 months for NPM1mut + placebo; 7.8 months for NPM1wt + azacitidine; and 4.6 months for NPM1wt + 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; FLT3wt + azacitidine 24.7; FLT3wt + placebo 15.2. RFS (in months): FLT3-ITD + azacitidine 23.1; FLT3-ITD + placebo 4.6; FLT3wt + azacitidine 10.2; FLT3wt + placebo 4.9. Evaluation of patients with mutations in both genes also showed markedly longer OS and RFS in azacitidine-treated patients.
In conclusion, NPM1mut and/or FLT3wt 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.
- Papaemmanuil E, et al. N Engl J Med 2016;374:2209–21.NPM1 mutationFL
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- Wei AH, et al. N Eng J Med 2020;383:2526–37.
- 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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Table of Contents: EHA 2021
Letter from the Editor
EHA 2021 Highlights Podcast
Immuno-oncology agents are effective in treating classic Hodgkin’s lymphoma
MATRix with ASCT: best long-term survival for primary CNS lymphoma
Naratuximab emtansine + rituximab safe and effective in diffuse large B-cell lymphoma
The journey ahead for CAR T-cell therapy in r/r follicular lymphoma
ZUMA-5 vs SCHOLAR-5: Axicabtagene ciloleucel significantly improves FL outcome
Promising chemo-free treatment options in r/r DLBCL
Sabatolimab achieved durable responses in patients with high-risk MDS and AML
Final analysis of EURO-SKI: primary endpoints met in chronic myeloid leukaemia
Favourable outcomes with zanubrutinib versus ibrutinib in patients with r/r CLL
Oral azacitidine improves overall survival in patients with acute myeloid leukaemia
Reduced-intensity conditioning ASCT is effective in older patients with AML
ELEVATE-TN: Acalabrutinib shows long-term efficacy in chronic lymphocytic leukaemia
ELEVATE-RR: Acalabrutinib demonstrates similar efficacy and better safety versus ibrutinib
Fixed 12 cycles and MRD-guided venetoclax consolidation effective in CLL
GLOW: Ibrutinib + venetoclax showed superior PFS as first-line CLL treatment
Myeloma and Myelofibrosis
Novel targets in myelofibrosis: overview of emergent therapies
Immune therapy of multiple myeloma
MAIA results confirm superior efficacy of daratumumab with standard-of-care
ANDROMEDA: Addition of daratumumab showed superior efficacy in patients with AL amyloidosis
Thrombotic and Thrombocytopenic Disorders including COVID-19 related
Acquired TTP: new treatments and updated guidelines
Maternal screening to prevent foetal and neonatal alloimmune thrombocytopenia
Fostamatinib effectively increased platelet counts in immune thrombocytopenic purpura
Physiopathology of coagulopathy in haematological malignancies and COVID-19
Haemostatic abnormalities are associated with mortality in COVID-19
Mechanisms of COVID-19 vaccine-induced thrombotic thrombocytopenia
COVID-19 vaccine-induced immune thrombotic thrombocytopenia: discovery and diagnosis
Luspatercept improved anaemia in patients with non-transfusion-dependent β-thalassaemia
Personalising treatment for sickle cell disease
Gene therapy: A promising approach for hereditary haemoglobinopathies
Promising chemo-free treatment options in r/r DLBCL