Immunophenotypic Markers CD7 and CD56 Improve Risk Stratification of Frontline Hypomethylating Agents + Venetoclax in Newly Diagnosed AML

Background:

The molecular prognostication risk signature (mPRS) stratifies patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated with hypomethylating agent (HMA)+venetoclax (VEN) therapy (Bataller et. al. Blood Adv. 2023). However, significant variability in overall survival (OS) remains across risk groups. Surface CD7 expression (Islam et. al. JCO Clin . Cancer Inform. 2022; Jen et. al. BJH 2024) and CD56 expression (Sasca et. al. Blood 2019. Saultz et. al. ASH 2023) correspond to inferior OS in patients with AML treated with HMA+VEN. Whether incorporating key immunophenotypic markers improves risk stratification in addition to the mPRS remains unknown.

Methods

Patients with ND-AML treated with frontline HMA+VEN combinations at Oregon Health & Science University (N=135), University of Colorado (N=109), and the University of North Carolina (N=35) with available baseline clinical, cytogenetic, molecular, and immunophenotypic data were included. Risk groups were developed using mPRS criteria (higher-benefit: wild-type N/KRAS, FLT3-ITD, and TP53; intermediate-benefit: mutated N/KRAS or FLT3-ITD, wild-type TP53; lower-benefit: mutated TP53). Surface CD7 and CD56 expression was considered positive (+) if present at any reported value (i.e. dim, partial, bright) on institutionally performed multiparameter flow cytometry.

Comparisons of categorical and continuous variables utilized the Fisher exact test and Wilcoxon rank-sum or Kruskal-Wallis test as appropriate. Time to event endpoints were evaluated utilizing the Kaplan-Meier method with cox proportional hazards modeling for multivariable analysis (MVA). Allogeneic hematopoietic cell transplant (HCT) was considered as a time-dependent covariate.

Results

Median patient age across the entire cohort (N=279) was 72 years (range: 20-89). Most patients were adverse-risk by European LeukemiaNet 2022 criteria (favorable: 14% [N=39], intermediate: 15% [N=43], adverse: 68% [N=189], unknown: 2.9% [N=8]), however were considered within the higher-benefit group by mPRS risk (higher: 45% [N=121] intermediate: 32% [N=88], lower: 23% [N=62], unknown: 2.9% [N=8]). Thirty-three percent (N=52) of patients received HCT.

Surface CD7+ and CD56+ was observed in 29% (N=78) and 33% (N=89) of cases, respectively, with CD7+/CD56+ in 11% (N=31). CD56+ was enriched in the mPRS lower-benefit group (higher: 30% vs. intermediate: 27% vs. lower: 48%, p= 0.014). No significant difference in surface CD7+ was observed across mPRS groups. Patients with mutated vs. wild-type IDH1/2 were less likely to have surface CD7+ (13% vs. 35%, p=0.0003), or CD56+ (18% vs. 38%, p=0.003). Patients with a complex karyotype were more likely to have surface CD7+ (50% vs. 38%, p=0.001) or CD56+ (40% vs. 27%, p=0.05), with CD56+ also enriched in TP53 mutated cases (48% vs. 29%, p=0.006).

The CR/CRi rate for the full cohort was 65% (N=181/279). Patients with CD7+ or CD56+ were less likely to attain CR/CRi (59% vs. 72%, p=0.023). After a median follow up of 28.3 months, median OS was 11.4 months (95% CI: 9-14 months). Patients who were CD7+ vs. CD7- (median 6.8 vs. 15.4 months, p: <0.0001) or CD56+ vs. CD56- (median: 6.5 vs. 14.2 months, p= 0.0003) had significantly shorter OS. No significant difference in OS was observed between CD7+/CD56+ vs. CD7+ or CD56+ cases (p= 0.084).

MVA was performed adjusting for HCT and prognostic molecular markers (IDH1, IDH2, NPM1, N/KRAS, FLT3-ITD, PTPN11, and TP53) and complex karyotype. In MVA, CD7+ (HR: 1.71, 95% CI: 1.21-2.42, p=0.003) and CD56+ (HR: 1.50, 95% CI: 1.05-2.14, p=0.025) remained independent predictors of OS. Surface CD7+ or CD56+ stratified patients within the higher (median OS: 8.4 vs. 35 months, p=0.002) and intermediate (median OS: 6.1 vs. 19.1 months, p=0.007) benefit mPRS groups. Compared to MVA models inclusive of mPRS and additional mutations, the addition of surface CD7 and CD56 status improved model performance (c-index without vs. with: 0.69 vs. 0.71).

Conclusions

The immunophenotypic markers CD7 and CD56 identify patients with adverse outcomes following HMA+VEN therapy independent of mPRS risk group, additional genetic mutations, and underlying cytogenetics. Combining CD7 and CD56 with the mPRS criteria improves OS discrimination and incorporation of these markers should be considered to improve risk stratification and prognostication following HMA+VEN treatment in AML.