Treatments and outcomes of adult patients with TP53-mutated acute myeloid leukemia (AML) in the real-life –Report of the prospective french observational ALFA-PPP study.

Abstract Introduction The prognosis of AML harboring TP53 mutations remains exceptionally poor. Clinical trials specifically designed for TP53-mutated AML are scarce and fail to represent real-world patient populations. Furthermore, most outcome data for TP53-mutated AML come from retrospective studies, where therapeutic decisions are frequently made without prior knowledge of molecular results. To address these gaps, we used data from the prospective ALFA-PPP registry (NCT04777916) to investigate the real-world management of patients with TP53-mutated AML. Methods We report the observations of the first 1,108 newly diagnosed adult AML patients (April 2022-August 2024) who had a centralized genomic profiling at diagnosis (50-gene NGS panel), focusing on the presence of TP53 mutation. Kaplan-Meier methodology was applied to estimate overall survival (OS). Multivariable analyses were performed using logistic regression or Cox regression, where appropriate. Results One hundred and sixty-five patients harbored at least one TP53 mutation at diagnosis. There were 89 males and 76 females (median age 72y [IQR, 64-77]; ECOG-PS 0-1/2/3-4, 98/42/21; median WBC 3.1 G/L [IQR, 1.7-7.3]; median marrow blast 31% [IQR, 22-54]). The numbers of patients with de novo, secondary and therapy-related AML (t-AML) were 90 (54%), 26 (16%) and 49 (30%), respectively. ELN-2022 cytogenetic risk was intermediate in 20 (12%), adverse in 137 (83%), and unclassifiable in 8 (5%). Median TP53 variant allele frequency was 44% (IQR 23-73), and 121 (74%) patients were classified as having bi-allelic TP53 mutations. In the full cohort, in multivariable analysis, older age (OR, 1.28 [95%CI, 1.09-1.52]; p=0.003), lower blast count (OR, 0.82 [95%CI, 0.75-0.90]; p<0.001), and adverse cytogenetic risk (OR, 30.98 [95%CI, 18.74-53.85]; p<0.001) were predictive of the presence of TP53 mutations. Secondary AML (OR, 0.88 [95%CI, 0.45-1.70]; p=0.714) or t-AML (OR, 1.39 [95%CI, 0.82-2.34]; p=0.217) were not significantly associated with TP53 mutation status. In the TP53-mutated cohort, treatment decision was intensive in 37 (22%) (median age, 63 years [56-66]; including 17 CPX-351), less intensive in 106 (64%) (median age, 75 years [68-79]; 78 AZA-VEN, 10 AZA, 18 unknown), and best supporting care in 16 (10%) patients, while the 5/6 remaining patients died before treatment decision. A total of 22/165 (13%) patients received an allogeneic stem cell transplant (HSCT) including 17 intensively and 5 less-intensively treated patients. With a median follow-up of 24 months (95% CI, 17-28), the median OS of intensively and less intensively treated patients was 11.7 (95% CI, 7.6-15.7) and 4.8 (95% CI, 3.6-6.2) months, respectively. The 12-month OS rates of intensively and less intensively treated patients were 48% (95%CI, 34-67%) and 19% (95% CI, 13-28%), respectively. The median OS of patients who underwent HSCT was 17.2 months (95% CI, 2.8-12.9). In these patients, multivariable Cox analysis evidenced older age (HR, 1.3 [95%CI 1.1-1.5]), higher ECOG (HR, 1.7 [95%CI, 1.2-2.5]; p=0.004), higher medullary blasts count (HR, 1.1 [95%CI, 1.01-1.2]; p= 0.03), t-AML (HR 1.7, [95%CI, 1.2-2.5]; p=0.006) and adverse ELN-2022 cytogenetic risk (HR, 2.5 [95%CI, 1.2-5.1]; p=0.02) as predictors of shorter OS. TP53 bi-allelic status had no impact on OS (HR 1.07, [95%CI, 0.66-1.7]; p=0.7). Finally, we assess the objective factors independently associated with the choice of a less intensive treatment option in the full cohort. Interestingly, the presence of TP53 mutations was strongly associated with a less intensive treatment option (OR, 6.5 [95%CI, 3.3-13.1]; p<0.001) while an adverse-risk cytogenetics was not (OR, 1.7 [95%CI, 0.98-2.8]; p=0.06), suggesting that the knowledge of the mutation may have influenced the treatment choice. The other factors associated with less intensive therapy were older age (OR, 8.2 [95%CI, 6.2-11.2]; p<0.001), higher ECOG (OR, 2.6 [95%CI 1.5-4.6]), AML type (OR, 2.5 [95%CI, 1-4-4.7]; p=0.003 for secondary AML, and OR, 2.6 [95%CI, 1.5-4.7]; p<0.001 for t-AML), and, unexpectedly, male sex (OR 1.8, [95%CI, 1.2-2.8]; p=0.004). Conclusion This prospective real-life AML patient cohort confirms that patients with TP53 mutations display distinct features and face a nearly incurable disease course, even when intensively treated. In absence of effective therapies, the knowledge of TP53 status at diagnosis appears to influence the decision to pursue less intensive treatment options.