NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951

Abstract

Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH þ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH þ patients showed a better early response to chemotherapy as compared with NOTCHÀ patients, according to the rate of poor pre-phase 'responders' (25% versus 44%; P ¼ 0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P ¼ 0.01) at completion of induction. However, the outcome of NOTCH þ patients was similar to that of NOTCHÀ patients, with a 5-year event-free survival (EFS) of 73% and 70% (P ¼ 0.82), and 5-year overall survival of 82% and 79% (P ¼ 0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH þ ) versus 42% (NOTCHÀ), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH þ ) versus 78% (NOTCHÀ). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1 þ patients (8.3%), which could be related to a higher propensity of NOTCH þ leukemic blasts to target the CNS.

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

“…Despite major improvements in our understanding of the molecular genetics of T-ALL, [36][37][38][39] the mechanisms that lead to the abnormal proliferation and survival of T-lymphoblasts remain largely unknown. Therefore, treatment of this neoplasm remains a challenge for clinicians.…”

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Development and progression of T-ALL have been linked to mis-regulation of Notch signaling (Aifantis et al, 2008;Clappier et al, 2010). In particular, we previously showed that Notch3 intracellular domain (N3 IC ) transgenic (tg) mice develop a very aggressive T-ALL with high penetrance, representing a suitable model of the human disease (Bellavia et al, 2000).…”

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

“…35 advances in the molecular typing of leukemia, many new genetic alterations, including mutations and deletions, have been identified. However, their prognostic values have not been widely verified and the results may be controversial [24][25][26][27][28][29][30][31][32][33][34].…”