Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature
Open accessPublished version of a preprint
Abstract
Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR.
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Remissions in TP53-mutant patients are brief, with a median overall survival ranging from 5 to 12 months.
“However, remissions in TP53-mutant patients are brief with a median overall survival (OS) ranging from 5 to 12 months,8,9,12,13,15-17”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [17]
The Statistical analysis section (page unavailable) reports that TP53 mutations were associated with reduced overall survival, supporting the claim of poor survival. It does not give a TP53-specific median OS of 5–12 months or establish that remissions in TP53-mutant patients were brief; reduced response duration is reported for ASXL1 and ETV6 mutations instead. (LLM, conf=0.85)
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Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes
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- Authors
- Craddock, C. F., Houlton, A. E., Quek, L. S., Ferguson, P., Gbandi, E., Roberts, C., Metzner, M., Garcia-Martin, N., Kennedy, A., Hamblin, A., Raghavan, M., Nagra, S., Dudley, L., Wheatley, K., McMullin, M. F., Pillai, S. P., Kelly, R. J., Siddique, S., Dennis, M., Cavenagh, J. D., & Vyas, P.
- Affiliations
- Queen Elizabeth Hospital Birmingham (GB)
- Cancer Research UK Clinical Trials Unit (GB)
- University of Oxford (GB)
- Queen's University Belfast (GB)
- University Hospitals of North Midlands NHS Trust (GB)
- Leeds Teaching Hospitals NHS Trust (GB)
- The Christie NHS Foundation Trust (GB)
- St Bartholomew's Hospital (GB)
- Corresponding author
- Vyas, Paresh
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2017-10-31
- Volume
- 23
- Issue
- 21
- Pages
- 6430-6440
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2739796560
- Cited by
- 88
- References
- 33
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 4 · 2023: 11 · 2022: 12 · 2021: 16 · 2020: 12 · 2019: 14 · 2018: 9
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (acceptedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Celgene
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- Cancer Research UK (C22436/A15958, 16895, 15958)
- National Institute for Health and Care Research
- Medical Research Council (MC_UU_12009/11, G1000729, MR/L008963/1, MC_UU_12009)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- azacitidine, vorinostat, acute myeloid leukemia, histone deacetylase inhibitors, combination therapy, CDKN2A mutation, IDH1 mutation, TP53 mutation, cell cycle arrest, overall survival, myelodysplastic syndrome, relapsed AML
- MeSH terms
- Vorinostat, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Combined Modality Therapy, Drug Administration Schedule, Female, Humans, Hydroxamic Acids, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Treatment Outcome, Disease-Free Survival, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p18, Histone Deacetylase Inhibitors
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