Background:

Hypomethylating agents combined with venetoclax (HMA+VEN) represent the standard of care treatment for older or unfit patients (pts) with ND-AML. Event-free (EFS) and overall survival (OS) following HMA+VEN can be stratified using the molecular prognostic risk signature (mPRS), based on mutations within four genes at diagnosis (N/KRAS, FLT3-ITD, and TP53) into higher, intermediate, and lower-benefit groups. Pts classified as intermediate-benefit have mutation(s) in active signaling kinases (N/KRAS and FLT3-ITD) that increase resistance to HMA+VEN.

Mutations in PTPN11 (PTPN11+) also impact the RAS-MAPK signaling pathway and correspond with inferior OS following intensive chemotherapy (Fobare et al. 2022, Blood Advances). Whether PTPN11+ imparts resistance like other signaling mutations in pts receiving frontline HMA+VEN is unknown. This retrospective analysis assessed the influence of PTPN11+ on response and survival in pts with ND-AML treated with HMA+VEN.

Methods:

The primary analysis cohort (N=279) included ND-AML pts receiving HMA+VEN at three U.S. academic medical centers. An independent international cohort (N=206; Centre Hospitalier Lyon Sud) was used to support key findings from the primary analysis.

Baseline clinical and molecular demographics and treatment characteristics were collected. Comparisons of categorical and continuous variables utilized the Fisher exact test and Wilcoxon rank-sum or Kruskal-Wallis test as appropriate. Survival was evaluated utilizing the Kaplan-Meier method with Cox proportional hazards modeling for multivariable analysis (MVA). Allogeneic hematopoietic cell transplant (HCT) was considered a time-dependent covariate.

Results:

Two-hundred seventy-two (97%) of 279 pts included in the primary analysis had available NGS results, identifying 22 pts with PTPN11+ (8%). There was no significant difference between pts with vs. without PTPN11+ with respect to age (median 70 vs. 72 years, p: 0.22), sex (female: 45% vs. 41%, p: 0.067), or co-occurring mutations after adjusting for false discovery. Accordingly, there was no significant difference between pts with vs. without PTPN11+ with respect to mPRS risk group assignment (higher-benefit: 45% [N=112] vs. 45% [N=10], intermediate-benefit: 45% [N=78] vs. 31% [N=10], lower-benefit: 9.1% [N=60] vs. 24% [N=2], p: 0.20). A trend towards fewer pts proceeding to HCT was observed for pts with vs. without PTPN11+ (20% vs. 4.5%, p: 0.09).

The overall response rate (ORR: CR+CRi+MLFS+PR) differed significantly between pts with vs. without PTPN11+ (41% [N=9/22] vs. 73% [N=183/250], p: 0.001). Pts with vs. without PTPN11+ had lower CR/CRi rates (36% [N=8] vs. 68% [N=18], p: 0.003), and higher rates of refractory disease (36% [N=8] vs. 12% [N=31], p: 0.006).

After a median follow-up of 28.3 months, median OS in pts with vs. without PTPN11+ was 4.8 vs 12.5 months (HR: 2.0, 95% CI: 1.21-3.32, p: 0.007). Median EFS was also inferior (median: 2.15 vs. 7.96 months, p: 0.023). Compared to pts with mPRS intermediate or lower-benefit group mutations, OS was shorter in pts with PTPN11+ vs. pts with N/KRAS mutations (10.2 months, 95% CI: 4.25-NR) or FLT3-ITD mutations (11.4 months, 95% CI: 8.31-NR), and similar to pts with TP53 mutations (6.5 months, 95% CI: 4.89-9.4).

When evaluating survival across mPRS risk groups, OS was shorter in pts with vs. without PTPN11+ (median: 4.0 vs. 16 months, HR: 3.55, 95% CI: 1.57-7.17, p: 0.0018) within the higher-benefit group. There was no significant OS difference between pts with vs. without PTPN11+ in the intermediate (p: 0.28) or lower-benefit groups (p: 0.17). After MVA modeling inclusive of mPRS risk stratification, HCT, and PTPN11+, PTPN11+ remained independently associated with an increased risk of death (HR: 2.05, 95% CI: 1.23-3.43, p: 0.0062).

Within the confirmatory cohort (N=206), PTPN11+ was identified at a similar frequency (8%, N=16). The CR/CRi rate in pts with vs. without PTPN11+ was 69% (N=11) vs. 71% (N=135). Pts with vs. without PTPN11+ continued to experience shorter OS (median 7.8 vs. 14.3 months, p: 0.003).

Conclusions:

PTPN11+ is associated with shorter OS following frontline HMA+VEN, with outcomes more similar to cases harboring alternative signaling kinase mutations or TP53-mutated AML. Given the associated adverse prognosis, consideration should be given to incorporating PTPN11+ into risk stratification models for frontline HMA+VEN therapy.

Disclosures

Leonard:Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy; Takeda: Consultancy; France Foundation: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, accommodations, and expenses. Maziarz:Orca: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Consultancy, Other: participated in data and safety monitoring boards , Research Funding; Ori-cell Therapeutic: Honoraria; Gilead Sciences: Other: stock or other ownership; Artiva Bio: Other: Leadership Role; stock or other ownership; Athersys: Other: participated in data and safety monitoring boards, Patents & Royalties; Bristol Myers Squibb: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Autolus: Consultancy; Vor BioPharma: Other: participated in data and safety monitoring boards; Century Therapeutics: Other: participated in data and safety monitoring boards. Traer:Servier Laboratories: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Schrödinger: Research Funding; Incyte Corporation: Research Funding; Prelude Therapeutics: Research Funding; AstraZeneca: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Swords:Disc Medicine: Consultancy. Saultz:Ikena: Research Funding; Rigel: Consultancy; Sanofi: Consultancy. Tyner:Incyte: Research Funding; Kronos: Research Funding; Meryx: Research Funding; Constellation: Research Funding; Genentech: Research Funding; Recludix: Membership on an entity's Board of Directors or advisory committees; Ellipses: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Aptos: Research Funding; AstraZeneca: Research Funding; Schrodinger: Research Funding; Tolero: Research Funding. Heiblig:Pfizer: Honoraria; Abbvie: Honoraria; Jazz pharmaceutical: Honoraria; Servier: Honoraria; Astellas: Honoraria. Pollyea:MEI: Honoraria; Karyopharm: Honoraria, Research Funding; Sanofi: Honoraria; Novartis: Honoraria; Rigel: Honoraria; Daiichi Sankyo: Honoraria; Boehringer Ingelheim: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Oncoverity: Honoraria; Aptevo: Honoraria; Syros: Honoraria; Qihan: Honoraria; Seres: Honoraria; Gilead: Honoraria; Syndax: Honoraria; Adicet: Honoraria; Sumitomo: Honoraria; Medivir: Honoraria; Hibercell: Honoraria; LINK: Honoraria; Abbvie: Honoraria, Research Funding; Beigene: Honoraria; Ryvu: Honoraria. Lachowiez:COTA Healthcare: Consultancy; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

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2024
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