P081 | EVALUATION OF PTPN11 MUTATION SUBTYPES AND THEIR POTENTIAL IMPACT ON CLINICAL OUTCOMES: A SINGLE-CENTER EXPERIENCE.

Background: PTPN11mutations can be found in 1.5%–12% of AML cases. They have been reported to cluster mainly in the N-terminal Src homology region 2 (N-SH2) and phosphatase (PTP) domains. Mutations in both domains remove the autoinhibition of the protein, leading to alterations in the RAS/MAPK pathway and ultimately to leukemogenesis. The prognostic role of PTPN11 is still controversial: although several studies showed an association with poor prognosis in intensively treated patients, PTPN11 mutations were not included in the ELN 2022 risk stratification. Conversely, the recently refined ELN 2024 guidelines have classified PTPN11-mutated patients as having a poor expected benefit from treatment with hypomethylating agents (HMA) plus venetoclax. Aim: To investigate interactions between mutations in different domains of PTPN11 gene with baseline characteristics and outcomes. Results: From 2011 to 2025, 31 PTPN11mut AML patients were observed in our Centre, of whom 22 (71%) with PTPN11-N-SH2 domain and 9 (29%) with PTP domain mutations. Characteristics of patients are detailed in Table 1. There weren’t significant differences at baseline (age, WBC, platelets, LDH, ELN 2022 risk stratification) between the two groups. Of note, pts with PTP-domain mutations had a significant lower VAF (median 5%) compared to N-SH2 domain (23%, P=0.030), that suggests a different dynamic in leukemogenic process. The number of co-mutations did not differ between the two domains (median 3 vs 3, P = 0.814). As regards treatment, 21 pts (72.4%) were treated with intensive chemotherapy and 8 (27.6%) received HMA plus venetoclax. We observed a trend toward a higher probability of complete remission after first line therapy (either intensive or less intensive), in patients with PTP domain (66.7%) compared to those with N-SH2 domain mutations (31.8%, P=0.114). Coherently, pts harbouring PTP-domain mutations showed a trend toward lower EFS (26.8 months) as compared to those with N-SH2-domain mutations (NR, P=0.350), although not reaching statistically significance. No difference in OS were highlighted. Conclusions: Although limited by the number of cases, our results suggest that the involved domain might influence the actual role of PTPN11 mutations on leukemogenesis and prognosis. Studies on larger cohorts are warranted to elucidate a differential effect on response to therapeutic options and outcome that could support an adapted indication to treatment modalities and HSCT in these patients.