In patients with acute myeloid leukemia (AML), the presence of mutations of the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) gene was found to be a prognostic factor for poor survival, according to a new study. The study results were published in the journal Blood Advances.
The study authors explained in their report that the protein encoded by PTPN11 expression, SHP2, a cytoplasmic phosphatase, is a regulator of RAS signaling. In patients with AML, PTPN11 is frequently found to be mutated.
The study was a retrospective analysis that included data from 1529 patients with newly diagnosed AML. Patient samples from bone marrow aspirates or peripheral blood obtained at diagnosis were screened for PTPN11 mutations in genomic DNA. Mutational screening was performed through targeted resequencing and with a panel that assays 54 genes linked to myeloid neoplasms.
A total of 106 patients, or 6.9% of the overall population, had PTPN11 mutations. In 97 patients there was a single mutation in this gene, while 9 patients had 2 separate mutations. All mutations were missense single nucleotide variants, and 76% of mutations were found in portion of the gene coding for the conserved N-terminal domain of SHP2. The median variant allele frequency was 24% (range, 5-52), and mutations were mostly subclonal (64%).
Presence of PTPN11 mutations was associated with a significantly higher rate of mutations in NPM1 (63%), and a trend toward higher rates of mutations in the genes DNMT3A (37%) and NRAS (21%). Patients with PTPN11 mutations demonstrated a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8%) than patients with wild-type PTPN11 did (39.1%; P <.001), based on 2017 ELN criteria. Mutated PTPN11 was also associated with a higher white blood cell count, compared with wild-type PTPN11 (P =.007).
Multivariable analysis suggested mutated PTPN11 is an independent risk factor for poorer survival outcomes. The hazard ratio (HR) for overall survival with mutated PTPN11 was 1.75 (P <.001), the HR for relapse-free survival with mutated PTPN11 was 1.52 (P =.013), and the HR for event-free survival with mutated PTPN11 was 1.35 (P =.022). Complete remission also occurred at a lower rate with mutated PTPN11 (odds ratio, 0.46; P =.008).
Negative impacts associated with PTPN11 mutations were mostly in patients with ELN favorable risk and in those whose PTPN11 mutations were subclonal. Patients with dominant PTPN11 mutations did not experience negative effects from PTPN11 mutations.
“Taken together, our data suggest that PTPN11 mutations are recurrent alterations in patients with AML and are an independent prognostic factor for poor survival, with worse clinical outcome in patients within the ELN favorable risk group,” the study authors concluded in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Stasik S, Eckardt JN, Kramer M, et al; for the Study Alliance Leukemia (SAL). Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia. Blood Adv. 2021;5(17):3279-3289. doi:10.1182/bloodadvances.2021004631