TET2 Mutations Are Associated with Poor Outcome in Pediatric AML: A Report From the Children's Oncology Group

Abstract 569^FN2

Mutations of the TET2 gene are implicated in abnormal epigenetic regulation in myeloid cancers. Recent studies of adults with AML have suggested that TET2 mutations (TET2/Mut) are associated with an inferior outcome. However, the prognostic role of TET2/Mut in pediatric AML has not been previously described. We sequenced the entire coding region of the TET2 gene in 403 pediatric patients with de novo AML treated on Children's Cancer Group study CCG-2961 (n=169) and Children's Oncology Group study AAML03P1 (n=234). Patients with synonymous mutations and previously reported polymorphisms were considered to be TET2 wild type (TET2/WT). TET2/Mut were identified in 5.2% of patients (25 mutations in 21 patients). Four patients had two distinct mutations: 2 patients had 2 missense mutations, 1 patient had 2 nonsense mutations, and 1 patient had 1 nonsense mutation and 1 splice site mutation. There were 14 different missense mutations, 4 of these each present in 2 patients. There were 5 different nonsense mutations, 1 insertion with frame shift, and 1 splice site mutation. These mutations were scattered throughout the gene from amino acids 171 to 1973.

Presence of TET2/Mut was correlated with patient demographics, laboratory characteristics, and clinical outcome. There was no significant difference in gender, median age, presenting WBC count, or FAB classification between patients with or without TET2/Mut. There was a higher percentage of black patients in the TET2/Mut than the TET2/WT group (31.6% vs. 12.6%, P=0.031); there was no significant difference in other racial or ethnic groups. TET2/Mut was not associated with known high risk cytogenetic or molecular markers. There was a higher association of TET2 mutations with favorable risk t(8;21) which was present in 30% of TET2/Mut patients versus 13% of TET2/WT patients (P=0.045). TET2 mutations were not associated with other cytogenetic abnormalities or molecular mutations (FLT3/ITD, CEBPA, NPM1, or WT1 mutations). TET2/Mut and TET2/WT patients had similar clinical remission (CR) rates at the end of induction course 1 (90.5% vs. 80%, P=0.39) and end of induction course 2 (81.0% vs. 79.7%, P=1.00). TET2/Mut patients had an event-free survival (EFS) at 5 years from diagnosis of 29%±20% vs. 45% ±5% for TET2/WT patients (P=0.087). In patients who achieved an initial CR, those with TET2/Mut had a disease-free survival (DFS) at 5 years from remission of 32% ±21% vs. 52% ±6% for TET2/WT patients (P=0.027). Corresponding relapse risk at 5 years from remission was 53% ±23% for TET2/Mut patients vs. 37% ±6% for TET2/WT patients (P=0.10).

Due to the association of TET2 mutations with t(8;21), we inquired whether TET2/Mut have prognostic significance within the favorable risk core binding factor (CBF) subgroup of leukemia. Of the 91 patients with CBF leukemia, 9 patients (9.9%) had TET2/Mut. CBF patients with TET2/Mut had lower 5-year EFS (44%±33%) than TET2/WT patients (59%±11%, P=0.084). As CBF patients are considered a low risk group, they do not receive stem cell transplant consolidation in more contemporary clinical protocols. Therefore, we performed clinical outcome evaluation after censoring CBF patients at the time of transplant and found that TET2/Mut patients had an EFS of 39%±35% vs. 57%±12% for TET2/WT patients (P=0.042).

In summary, TET2 mutations are present in 5.2% of pediatric patients with de novo AML. Although TET2/Mut are not associated with known high risk markers, patients with these mutations have poor 5-year DFS and show a strong trend toward worse 5-year EFS. TET2/Mut may also be predictive of poor outcome in patients with CBF leukemia. Further evaluation of this molecular abnormality in patients treated on current pediatric cooperative group studies is warranted.