Prognostic Significance of NOTCH1 and FBXW7 Mutations in Childhood T-Cell Acute Lymphoblastic Leukemia (T-ALL): Results From the EORTC Children Leukemia Group.
Authors: Clappier Emmanuelle , Collette Sandra , Grardel Nathalie , Girard Sandrine , Suarez Lydia , Brunie Ghislaine , Kaltenbach Sophie , Yakouben Karima , Mazingue Françoise , Robert Alain , Boutard Patrick , Plantaz Dominique , Rohrlich Pierre-Simon , Preudhomme Claude , Speleman Frank , Otten Jacques , Dastugue Nicole , Suciu Stefan , Benoit Yves , Bertrand Yves , Cavé Hélène 
Published: October 2019

Abstract
Abstract 909
T-ALL accounts for approximately 15% of childhood ALL. Despite major improvement of treatments, relapses still occur with dramatic prognosis. Efforts made in the past decade to understand T-ALL oncogenesis led to the identification of a number of oncogenes deregulated by genomic abnormalities, including TAL1, HOX11/TLX1, HOX11L2/TLX3, CALM-AF10, NUP214-ABL1, and MYB, some of them determining subtypes with distinct biological profiles. However, in EORTC trials, using BFM-derived protocols, these various genetic lesions have no prognostic impact, with the exception of a trend toward a favourable outcome for SIL-TAL1 fusion or HOX11 over expression (Cavé et al. 2004). Thus, risk-stratification remained based on early response to chemotherapy, as assessed by poor response to the (corticosteroid) prephase (PPR) and, in addition (58951 trial), on a high level (>10-2) of minimal residual disease (MRD) at completion of induction therapy. Hyperactivation of the NOTCH pathway by mutations of NOTCH1 or FBXW7 has been recently demonstrated in T-ALL. We investigated whether NOTCH1 and/or FBXW7 status could help to improve risk-stratification in T-ALL. We screened NOTCH1 and FBXW7 mutations by direct sequencing in 133 children with T-ALL enrolled in EORTC-CLG trials 58881 and 58951. Activating NOTCH1 mutations were found in 75 (56%) patients. Inactivating FBXW7 mutations were found in 20 (14%) patients, mostly in association with NOTCH1 mutations. Overall, 78 (59%) patients were considered NOTCH+ (NOTCH1 and/or FBXW7 mutated) whereas 55 (41%) were NOTCH- (NOTCH1 and FBXW7 wild type). NOTCH+ patients were distributed through all genetic subgroups. No significant relationships between NOTCH status and sex, age, WBC count, CNS or mediastinal involvement were observed. However, NOTCH+ had more often a cortical immunophenotype (53% vs 28%; p=0.02). NOTCH+ patients had a better early response to chemotherapy vs NOTCH- patients: lower PPR rate (20% vs 42%; p=0.02), and a lower incidence of high MRD level (13% (6/45) versus 30% (9/30); p=0.14). This led to less frequent switch to a very high risk (VHR) protocol for NOTCH+ versus NOTCH- patients (29% vs 49%, p=0.05). After a median follow-up of 4.6 years, 3 patients did not reach CR, 25 relapsed, 1 died in CR and 84 remained alive in CR; a total of 18 patients died. The outcome of NOTCH+ patients was similar to that of NOTCH- patients. The 5-yr EFS were 74% and 69% (p=0.8), respectively, and the 5-yr overall survival were 82% and 80% (p=0.7), respectively. However, prognostic importance of NOTCH status differed according to early response to treatment. In patients with a PPR, the NOTCH+ patients had a worse outcome than NOTCH- patients (5-yr EFS was 44% vs 58%; HR=1.54, p=0.43), whereas in non-PPR subgroup a reverse trend was observed (5-yr EFS was 83% vs 76%; HR=0.94, p=0.91). Similarly, in patients with high MRD levels the outcome was worse in NOTCH+ vs NOTCH- patients (5-yr EFS was 0% vs 47%, HR=11.7, p=0.03) whereas in MRD- patients the trend was reversed (5-yr EFS was 79% vs 71%, HR=0.88, p=0.83). Thus, although NOTCH1+ patients responded earlier and better to chemotherapy as compared to NOTCH1- patients, they did not show, overall, a better EFS. This was due to the poor outcome of NOTCH+ patients who had VHR features. In the German BFM trials, NOTCH1 mutations were also associated with lower rate of “poor response” to chemotherapy but this translated into a favourable outcome (see the ASH 2009 abstract of Kox et al.) NOTCH1- patients had a similar outcome in EORTC and BFM studies (5-yr EFS: 69% vs 74%) whereas NOTCH1+ patients had a lower 5-yr EFS in EORTC than in BFM studies (74% vs 87%). Noteworthy, in the EORTC trials the rate of isolated CNS relapses was quite high in NOTCH1+ patients (7.8%=6/77) as compared to NOTCH- patients (1.9%=1/53). Recently it was shown that NOTCH1 positively controls the expression of the chemokine receptor CCR7, an adhesion signal required for targeting T-ALL cells into the CNS (Buonamici et al. 2009). This may explain the higher propensity of NOTCH+ ALL to relapse in CNS. Although this is not the only difference in treatment between EORTC and BFM, the use of high dose methotrexate and intrathecal chemotherapy only, with omission of cranial irradiation prophylaxis in EORTC protocols, might have led to a suboptimal prevention of CNS relapses in NOTCH+ T-ALL, resulting in a lower EFS in EORTC trials as compared with German BFM in this group of patients.

Disclosures:
No relevant conflicts of interest to declare.