Clinical Relevance of Subgrouping in TP53 mutated Myelodysplastic Neoplasms: Insights from ICC and Who Classifications

Background

Myelodysplastic neoplasms (MDS) with TP53 mutations are associated with poor outcomes. In 2022, the classification of MDS was updated, leading to differences from the 4^th edition of WHO classification, resulting in new names and diagnostic criteria for certain entities, including TP53-mutated MDS. Slightly different from the 5^th edition of WHO, the International Consensus Classifications (ICC) categorizes TP53 mutated myelodysplastic diseases into MDS, MDS/AML and AML with TP53 mutations using modified diagnostic criteria. This study investigates the differences in classification methods and the prognostic implications of subgrouping within TP53-mutated MDS as outlined by WHO and ICC (PMIDs: 35767897 and 35732831).

Methods

We performed a retrospective analysis of 330 cases of TP53-mutated MDS from 2016 to 2023, using the 4th and 5th editions of WHO and ICC criteria for classification. This study received approval from the Institutional Review Board (IRB). Key variables analyzed included karyotype, types of TP53 mutations, disease progression, overall survival (OS), treatment response, and clinical outcomes. Patients were categorized into monoallelic (n=46) and biallelic (n=174) TP53-mutated cases, as well as therapy-related (n=90) and non-therapy-related (n=220) cases. We noted differences in ICC-defined MDS with TP53 mutation, which does not align with WHO criteria as ICC allows for complex karyotypes as a surrogate marker for multi-hit in the TP53 gene-an allowance not present in WHO criteria. We defined bona fide biallelic TP53-mutated cases as those meeting both WHO and ICC MDS diagnostic criteria, with a variant allele frequency cutoff of >10%. Furthermore, we compared ICC-defined MDS/AML with TP53 mutations (10%-19% blasts) (n=88) to other biallelic cases (n=99), and also assessed WHO-defined MDS with low blasts (MDS-LB) (n=34), which the ICC classifies as TP53-mutated MDS primarily due to complex karyotype without a clear second hit. Finally, we analyzed outcomes for patients who underwent hematopoietic stem cell transplantation (HSCT) (n=31) versus those who did not (n=151) within the bona fide biallelic cohort.

Results

Among the analyzed cohort, the median age was 71 years (female/male: 116/214). The median OS for monoallelic cases was 22 months, compared to 12 months for biallelic TP53 mutated cases (p = 0.0006). Therapy-related cases had a median survival of 10 months compared to 14 months for non-therapy-related cases (p = 0.02). When comparing ICC-defined MDS with TP53 mutation based on complex karyotype to bona fide biallelic TP53 mutated cases, there was a trend towards longer survival, but it was not statistically significant (13 months versus 12 months, p = 0.07). The survival difference between WHO-defined MDS-LB with monoallelic TP53 mutation, lacking a complex karyotype, and bona fide biallelic TP53 mutated cases was also not significant (p = 0.31). Similarly, the survival difference between ICC-defined MDS/AML with TP53 mutations and other biallelic cases was not significant (p = 0.33). Notably, patients who received HSCT had a median survival of 21 months, compared to 10 months for those who did not (p < 0.0001).

Conclusion

Our findings suggest that the distinct categorization of TP53 mutated MDS by the ICC may not be necessary, advocating for harmonization with WHO classification. MDS with low blasts, as defined by the 5th edition of WHO but classified as TP53-mutated MDS by the ICC, shows similarly poor outcomes compared to bona fide cases, implying that ICC criteria may be more suitable for these cases. Finally, HSCT appears to be a promising therapy, significantly improving survival in bona fide biallelic TP53 mutated cases.

Komrokji:PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Keros: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; Taiho: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lancet:Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board; Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board. Sallman:Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding.