Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes
Open accessAbstract
TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors.
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TP53 mutation burden (high variant allele frequency, concurrent complex karyotype, and/or multihit state) is linked to inferior survival with median overall survival of 6-8 months.
“The TP53 mutation burden (ie, high variant allele frequency [VAF], concurrent complex karyotype, and/or multihit state) is integrally linked to inferior survival with median OS of 6-8 months.8-10,12”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [12]
The prognostic analysis (page unavailable) links higher TP53 VAF, complex karyotype, and two or more TP53 abnormalities to worse survival in patients with MDS. It does not establish the claimed median overall survival of 6–8 months; the shortest median reported for its four modeled prognostic groups is 9.2 months. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHypomethylating agents such as azacitidine and decitabine yield complete remission rates of approximately 15%-20% in patients with either TP53-mutant or wild-type MDS.
“Hypomethylating agents (HMAs), such as azacitidine and decitabine, yield statistically similar complete remission (CR) rates of approximately 15%-20% in patients with either TP53-mutant or wild-type MDS.12-14”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [12]
The section “TP53 mutation VAF and TP53 deletion influence response outcomes with HMA therapy” reports no statistically significant difference in complete remission between TP53-mutant and wild-type MDS. It gives rates of 27% versus 22%, however, rather than approximately 15%–20% for both groups. Page information was not provided in the passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRemissions 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 [12]
The Discussion says TP53 mutations are associated with short response durations, and the HMA-therapy results report shorter response duration in patients with TP53 abnormalities. The survival analysis reports a median OS of 9.2 months for one prognostic subgroup, but it does not establish a 5-to-12-month median OS range for TP53-mutant patients generally; other subgroups had longer survival. Page numbers were not provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredmTP53 patients with high VAF (>20-23%), biallelic state, and/or complex karyotype have particularly poor risk.
“Specifically, mTP53 patients with a high variant allele frequency (VAF; i.e., >20%–23%), biallelic state, and/or complex karyotype (CK) have particularly poor risk.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [5]
The prognostic-subgroups section reports that higher TP53 VAF and complex karyotype are associated with worse prognosis in TP53-mutated MDS, but it does not establish a >20%–23% VAF cutoff. The Discussion says biallelic TP53 mutations require confirmation, so this paper does not establish poor risk specifically for a confirmed biallelic state. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn mTP53 mutant MDS with HMA, the CR rate is ~20% with a median OS of less than 12 months.
“In mTP53 mutant MDS with HMA, the CR rate is ~20% with a median OS of less than 12 months.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [5]
The section on HMA response reports a 27% CR rate for TP53-mutant patients; single-agent HMA CR rates range from 16% to 28%, broadly consistent with the approximate figure. The paper reports median OS of 10.7 months for patients who did not undergo transplantation, but that is not identified as the HMA-treated subgroup, so the claimed OS for that specific group is not established. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Treatment outcomes for patients with TP53 mutations are poor with available therapies.
“Treatment outcomes for patients with TP53 mutations are poor with available therapies.8-12”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [12]
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References 36 · Cited by 133
- Authors
- Montalban-Bravo, G., Kanagal-Shamanna, R., Benton, C. B., Class, C. A., Chien, K. S., Sasaki, K., Naqvi, K., Alvarado, Y., Kadia, T. M., Ravandi, F., Daver, N., Takahashi, K., Jabbour, E., Borthakur, G., Pemmaraju, N., Konopleva, M., Soltysiak, K. A., Pierce, S. R., Bueso-Ramos, C. E., Patel, K. P., Kantarjian, H., & Garcia-Manero, G.
- Affiliations
- Department of Leukemia,
- Department of Hematopathology, and
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Montalban-Bravo, Guillermo
- Kanagal-Shamanna, Rashmi
- Benton, Christopher B.
- Class, Caleb A.
- Chien, Kelly S.
- Sasaki, Koji
- Naqvi, Kiran
- Alvarado, Yesid
- Kadia, Tapan M.
- Ravandi, Farhad
- Daver, Naval
- Takahashi, Koichi
- Jabbour, Elias
- Pemmaraju, Naveen
- Konopleva, Marina
- Soltysiak, Kelly A.
- Bueso-Ramos, Carlos E.
- Patel, Keyur P.
- Kantarjian, Hagop
- Garcia-Manero, Guillermo
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2020-02-06
- Volume
- 4
- Issue
- 3
- Pages
- 482-495
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC7013259
- OpenAlex
- W3005329625
- Cited by
- 133
- References
- 36
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 14 · 2023: 29 · 2022: 20 · 2021: 22 · 2020: 16
- FWCI
- 13.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Blood Advances (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons @ Butler University (Butler University) (submittedVersion)
- Funders
- National Institutes of Health (CA- 016672)
- University of Texas MD Anderson Cancer Center ((CA016672), grant CA016672)
- National Cancer Institute (Grant CA016672, CA 016672, T32CA009666)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- TP53 mutation, myelodysplastic syndrome, variant allele frequency, hypomethylating agents, complex karyotype, prognosis, overall survival, IPSS-R, disease transformation, prognostic model, genomic context
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Gene Frequency, Humans, Middle Aged, Mutation, Myelodysplastic Syndromes, Prognosis, Tumor Suppressor Protein p53, Genomics, Young Adult
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