Prognostic Discrimination within a Heterogeneous Population of TP53-Aberrant Myelodysplastic Syndromes and Acute Myeloid Leukemia

Background:TP53-aberrant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) constitute the highest risk molecular subgroup of myeloid neoplasms, and there are currently no FDA-approved targeted therapies for this subset of patients. We have recently explored the reasons for these distinctly adverse outcomes using clonal dynamic modeling. However, prognostic discrimination within this heterogeneous group of patients has not been validated in large-scale efforts. More recently, efforts to gain clarity on this disease subset include the IPSS-M model for MDS, the European LeukemiaNet (ELN) 2022 classification for AML, and the 2022 International Consensus Classification (ICC) for both MDS and AML. For example, the IPSS-M model has shown an adjusted hazard ratio of 3.27 (95% CI 2.38 - 4.48) for multi-hit TP53 aberration; the ELN 2022 classification now includes a new category termed "AML with mutated TP53" for patients with TP53 variant allele frequency (VAF) ≥ 10%; and the 2022 ICC has designated categories for MDS and AML with TP53 mutation. However, these systems do not discern among the subtypes of TP53 genomic aberrations with regard to clinical outcomes.

Methods: Identification of patients from the UMass Chan Leukemia Registry was performed via UMass Clarity, a Microsoft SQL Server database comprised of 23,000 tables, in conjunction with the main reporting environment in EPIC. The Registry identified patients harboring one or more aberrations in TP53 and with ICD-10 code of either D46.9 (MDS, including its subentities) or C92.00 (AML, including its subentities) between 2011-2022. A total of 63 patients were identified. Patients with TP53-aberrant MDS or AML were stratified by the presence or absence of multi-hit status and/or TP53 VAF >50%. Multi-hit status was defined as per the 2022 ICC: two or more distinct TP53 mutations with VAF ≥ 10%, or a single TP53 mutation plus one of the following abnormalities: (1) del(17p13.1), (2) TP53 VAF >50%, (3) copy-neutral loss-of-heterozygosity, or (4) any complex karyotype. Monoallelic status was defined as non-multi-hit. Kaplan-Meier survival with log rank p value analysis was performed on subgroups based on the TP53 genomic state.

Results: Median age of the UMass cohort (n = 63) was 69.8 ± 11.3 years. There were 35 patients (55.6%) with AML. We identified 58 patients who met the 2022 ICC definition for myeloid neoplasm with mutated TP53 (after exclusion of 5 patients with VAF < 10%) then stratified patients based on hit status and VAF. Median overall survival (OS) was similar among patients with monoallelic TP53-mutant MDS, multi-hit TP53-mutant MDS, and monoallelic TP53-mutant AML (median OS 440 days vs. 437 days vs. 440 days, respectively) (Panel A). In contrast, patients with multi-hit TP53-mutant AML had distinctly shorter survival (median 46 days) (Panel A). For patients with multi-hit status MDS or AML per the 2022 ICC (n = 41), we sub-stratified patients based on TP53 VAF. OS for patients with MDS with VAF ≤ 50% and VAF > 50% was similar (median 376 days vs. 435 days, respectively) (Panel B). Patients with AML with TP53 VAF > 50% had significantly inferior OS (median 43 days) (Panel B). Twelve (19.0%) of 63 patients underwent allogeneic hematopoietic cell transplant (allo-HCT) (2 had VAF >50%). Allo-HCT significantly improved median OS (732 days with allo-HCT vs. 161 days for n = 51 without allo-HCT; p = 0.0033) (data not shown). Only 3 (25%) of the 12 allo-HCT recipients achieved MRD-free remission lasting beyond 1000 days; VAF was ≤ 10% in all of these long-term survivors with TP53-mutant MDS or AML.

Conclusion:TP53-aberrant MDS and AML comprise a prognostically heterogeneous group of patients with inferior clinical outcomes, though the highest risk subgroup appears to be AML with multi-hit TP53 status or AML with TP53 VAF > 50%. There is high value in determining the allelic state and hit status at the time of diagnosis to help prognosticate and develop a long-term management plan. Allo-HCT improves median OS, though durable MRD-negative remission is rare. Our data suggest that there may be a limited window of VAF ≤ 10% for the success of allo-HCT for TP53-aberrant myeloid neoplasm. We acknowledge that there is a selection bias for proceeding with allo-HCT. Large-scale systematic studies are needed to comprehensively profile patients classified as myeloid neoplasm with mutated TP53 such that risk-adapted management strategies can implemented.

Patel:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cerny:Sorrento Therapeutics: Current equity holder in private company; Mustang Bio: Current equity holder in private company; Novavax: Current equity holder in private company; Gamida Cell: Current equity holder in private company; Dynavax Technologies: Current equity holder in private company; aTyr Pharma: Current equity holder in private company; Miragen Therapeutics: Current equity holder in private company; TG Therapeutics: Current equity holder in private company; Ovid Therapeutics: Current equity holder in private company; Vaxart: Current equity holder in private company; Veru: Current equity holder in private company; Bluebird Bio/2Seventy: Current equity holder in private company; Actinium Pharmaceuticals: Current equity holder in private company; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmazeuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ramanathan:sanofi: Current holder of stock options in a privately-held company; novartis: Current holder of stock options in a privately-held company; J and J: Current holder of stock options in a privately-held company; moderna: Current holder of stock options in a privately-held company; vertex pharma: Current holder of stock options in a privately-held company; pfizer: Current holder of stock options in a privately-held company; gilead: Current holder of stock options in a privately-held company. Gerber:US Patent and Trademark Office: Patents & Royalties: US Patent No. 9,012,215; US Patent and Trademark Office: Patents & Royalties: US Patent No. 10,222,376; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; US Patent and Trademark Office: Patents & Royalties: US Patent No. 11,209,435.