A Clinically Practicable Approach to Predict <i>TP53</i> Allelic Configurations in Myeloid Neoplasia

Bahaj, Waled; Kewan, Tariq; Gurnari, Carmelo; Durmaz, Arda; Ponvilawan, Ben; Pandit, Ishani; Kubota, Yasuo; Ogbue, Olisaemeka; Aly, Mai; Madanat, Yazan F.; Bat, Taha; Balasubramanian, Suresh Kumar; Mori, Minako; Meggendorfer, Manja; Carraway, Hetty E.; Mukherjee, Sudipto; Sekeres, Mikkael A.; Haferlach, Torsten; Visconte, Valeria; Maciejewski, Jaroslaw P.

doi:10.1182/blood-2022-162913

Cited by 3 publications

(3 citation statements)

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“…Additionally, the TP53 variant allele frequency is tightly consistent with outcomes. In both MDS and AML patients, a VAF of >40% had a strong correlation to inferior survival as those subset of patients had a median OS of 124 days compared to a median OS that was not reached in patients with VAF <20% which was confirmed in a validation dataset with a 20% VAF cutoff representing the optimal cutpoint which has been further confirmed in two follow up publications (optimal VAF cutoff of 23%) [15‒17]. In a large cohort of patients with an average VAF of 39%, an increase in VAF of 1% correlated to a hazard of death increase by 1.02 [18].…”

Section: Tp53 Mutations In Mds and Amlmentioning

confidence: 76%

“…Compared to the TP53 wildtype, patients with monoallelic mutations had a 2-fold increase risk of death with a HR of 2.1, and the patient’s with biallelic mutations had even worse prognosis with the risk of death quadrupling with a HR of 4.0. In further analysis, there was a greater difference in OS between single-hit and double-hit TP53 mutations in MDS (HR = 3.1; 2.43–4.09) when compared to AML (HR = 1.5; 1.2–2) [17]. Complex karyotypes were also a poor prognostic indicator with the median OS at 1.0 years versus 2.1 years ( p < 0.001) in patients with noncomplex karyotypes.…”

Section: Tp53 Mutations In Mds and Amlmentioning

confidence: 99%

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TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

DiGennaro,

Sallman

2023

Acta Haematol

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Background Acute Myeloid Leukemia (AML) is a heterogeneous hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid cells in the bone marrow. The tumor suppressor gene TP53 plays a crucial role in maintaining genomic integrity and preventing the development of cancer. TP53 mutations are frequently observed in AML (~10% of patients) and are associated with aggressive disease behavior, resistance to therapy, and poor prognosis. Summary Recent changes in classification of TP53-mutated myelodysplastic syndrome (MDS) have occurred related to the allelic status of TP53 and more importantly to harmonize MDS/AML patients as a homogeneous hematological malignancy. Current treatment regimens involve hypomethylating agents +/- venetoclax or intensive chemotherapy although unfortunately independent of treatment regimen the overall survival (OS) of this patient cohort is around 6 months with poor long-term outcomes after allogeneic stem cell transplantation. Recent developments geared towards the treatment of TP53-mutated MDS/AML have focused on immunotherapies. Key Messages Notably, there is optimism surrounding these new therapies that could provide breakthroughs with improving outcomes either as monotherapy or combined with established nonimmune therapies. This paper aims to provide an overview of TP53-mutated MDS/AML, including the underlying mechanisms, clinical implications, and emerging therapeutic strategies targeting this hematologic malignancy.

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Section: Tp53 Mutations In Mds and Amlmentioning

confidence: 76%

Section: Tp53 Mutations In Mds and Amlmentioning

confidence: 99%

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

DiGennaro,

Sallman

2023

Acta Haematol

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“…In MDS, multi-hit TP53 disruption (in the subsets of multiple mutations, mutation plus 17p deletion, or mutation plus loss of heterozygosity) frequently presents with a higher rate of additional chromosomal abnormalities compared to monoallelic/single-hit mutation and significantly worse prognosis [115]. Indeed, the detrimental impact of multi-hit TP53 was also shown in AML [112,116,117], in accordance with data on the negative impact of high TP53 variant allele frequency (VAF) [118]. However, this finding was not confirmed in the large analysis by Tazi and colleagues [57], suggesting further research on this issue is needed.…”

Section: Tp53mentioning

confidence: 99%

Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors

Boscaro¹,

Urbino²,

Catania³

et al. 2023

Cancers

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An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML subgroups. In recent years, this rapidly evolving field has made the prognostic evaluation of AML more challenging. Traditional prognostic factors, established in cohorts of patients treated with standard intensive chemotherapy, are becoming less accurate as new effective therapies are emerging. The widespread availability of next-generation sequencing platforms has improved our knowledge of AML biology and, consequently, the recent ELN 2022 recommendations significantly expanded the role of new gene mutations. However, the impact of rare co-mutational patterns remains to be fully disclosed, and large international consortia such as the HARMONY project will hopefully be instrumental to this aim. Moreover, accumulating evidence suggests that clonal architecture plays a significant prognostic role. The integration of clinical, cytogenetic, and molecular factors is essential, but hierarchical methods are reaching their limit. Thus, innovative approaches are being extensively explored, including those based on “knowledge banks”. Indeed, more robust prognostic estimations can be obtained by matching each patient’s genomic and clinical data with the ones derived from very large cohorts, but further improvements are needed.

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Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS)

et al. 2023

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A Clinically Practicable Approach to Predict TP53 Allelic Configurations in Myeloid Neoplasia

Cited by 3 publications

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TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors

Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS)

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