Prospective Analysis of TEL and MLL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study.
Authors: Rubnitz Jeffrey , Wichlan David , Devidas Meenakshi , Shuster Jonathan , Kurtzberg Joanne , Bell Beverly , Hunger Stephen , Chauvenet Allen , Pui Ching-Hon , Camitta Bruce , Pullen Jeanette 
Published: October 2019

In a retrospective study, we previously demonstrated that TEL gene rearrangements, representing the TEL-AML1 fusion created by the t(12;21), conferred a favorable prognosis among children with newly diagnosed acute lymphoblastic leukemia (ALL). In 1996, we undertook a prospective study of patients greater than one year of age with B-precursor ALL consecutively enrolled on the ALinC16 study to confirm this result in an independent cohort of patients with extended follow up, to determine the incidence of TEL and MLL gene rearrangements, and to determine if TEL gene status should be used for risk classification. Among 928 cases studied, TEL gene rearrangements were detected in 244 (26%), including 29% of standard-risk and 21% of high-risk cases by the National Cancer Institute/Rome criteria. TEL-rearranged cases had a median age of 4.4 years (91% < 10 years) and a median presenting leukocyte count of 12 × 109/L (81% < 50 × 109/L). Cases with germline TEL had similar features, with a median age of 5.0 years and a median presenting leukocyte count of 12 × 109/L. At a median follow-up of 7.8 years, the 5-year event-free survival (EFS) ± SE for patients with TEL rearrangements was 86% ± 2%, compared to 72% ± 2% for those with germline TEL (p<0.0001). TEL rearrangements were associated with a favorable outcome among standard risk patients (5-yr EFS 88% ± 3% vs. 78% ± 2%, p=0.001) as well as high risk patients (5-yr EFS 81% ± 5% vs. 62% ± 3%, p=0.003). TEL rearrangements were associated with a favorable outcome among patients with rapid early responses to therapy (5-yr EFS 87% ± 2% vs. 75% ± 2%, p=0.0002), but the association did not attain statistical significance among those with slow early responses (5-yr EFS 71% ± 12% vs. 56% ± 6%, p=0.16). Overall, patients with TEL rearrangements had an outcome similar to that of patients with trisomies 4 and 10 (5-yr EFS 86% ± 2% vs. 82% ± 3%, p=0.18). By contrast, MLL rearrangements were detected in only 19 cases (2%) and the 5-yr EFS for patients with this genetic abnormality was 58% ± 11%, compared to 76% ± 1% for those with germline MLL (p=0.02). MLL rearrangements were associated with a significantly worse outcome among standard-risk patients (5-yr EFS 55% ± 2% vs. 82% ± 2%, p=0.01), but not among high-risk patients (5-yr EFS 63% ± 2% vs. 66% ± 3%, p=0.57). However, these findings should be interpreted with caution because of the small number of patients with MLL rearrangements in each risk group. The finding of TEL rearrangements in association with a favorable prognosis among both standard-risk and high-risk patients indicates that TEL gene status should be incorporated into current risk classification schemes for childhood ALL. We suggest that patients with TEL rearrangements and good early responses to therapy should be assigned to lower-risk treatment protocols.