Unlike Paediatric T-ALL, Notch-1 and FBXW7 Mutations Do Not Seem to Predict a Better Outcome in Adult Patients: Data from the UKALLXII/ECOG2993 Protocol

A risk-adapted approach to the treatment of patients with acute lymphoblastic leukemia (ALL) has the potential of improving survival in high-risk patients and reducing therapy-related long-term sequelae in those at low-risk. The use of molecular markers that can further define risk are needed in this disease. Activating mutations of Notch-1 have been reported in over 50% of patients with T-ALL. Mutations in the heterodimerization domain (HD) lead to ligand-independent cleavage, whilst truncating mutations of the C-terminal PEST domain disrupt binding to the negative regulator FBXW7, leading to prolonged half-life of intracellular Notch (ICN). More recently, Notch-activating mutations in FBXW7 that prevent ICN degradation have been reported in 20% of patients. In pediatric patients treated on the ALL-BFM 2000 protocol, patients with Notch-1 mutations (MUT) had an excellent outcome with an event free survival (EFS) of 90% compared to 71% in wild type (WT) patients. The impact of FBXW7 mutations was not evaluated. We sought to address whether adults with Notch-1 and/or FBXW7 mutations also faired sufficiently well that they might avoid treatment intensification/transplantation. Notch-1 HD-N, HD-C, TAD and PEST domains, and FBXW7 WD40 domain were screened by denaturing high performance liquid chromatography and/or bidirectional sequencing in a cohort of 88 adult T-ALL patients treated on the MRC UKALLXII/ECOG2993 trial (54 UKALLXII, 34 ECOG2993). Overall, 51 patients (58%) had at least one Notch-1 mutation; 37 in the HD only, 8 in the PEST domain only and 6 in both HD and PEST domains. Sixteen patients (18%) had an FBXW7 mutation (7 R465C, 3 R505C, 2 R479Q, 2 R479L, 1 R465H, and 1 G423V) and, of note, 15 of these mutations altered conserved arginine residues in the WD40 domain thought to be responsible for binding to the Notch-1 PEST domain. Five FBXW7 MUT patients were Notch-1 WT. There was a positive association between having an FBXW7 mutation and a Notch-1 mutation in the HD only (Fishers exact test 2P.02). Furthermore, no patient had both an FBXW7 and a PEST mutation. This is consistent with the hypothesis that Notch-1 HD and FBXW7 mutations act in concert similar to dual HD and PEST mutations. Complete remission was achieved in 96% of patients. Median follow-up was 3.5 years. The Notch-1 WT and MUT groups received similar treatment (8 Vs 15 sibling allograft; 3 Vs 7 autograft; 3 Vs 3 matched unrelated donor allograft; 19 Vs 24 chemotherapy with maintenance alone; P.84). There was no significant association with white cell count (WCC) or age according to either Notch-1 or FBXW7 mutational status (Mantel Haenszel test for trend P>0.1 for each case). Outcome is shown in table 1. In contrast to the data in pediatric T-ALL, in this adult cohort Notch-1 mutational status was not associated with improved EFS or overall survival (OS); nor was there an association according to the type of Notch-1 mutation. Similarly, FBXW7 mutational status alone was not predictive of outcome. There was a suggestion that patients with either a Notch and/or an FBXW7 mutation had better EFS, although this did not reach statistical significance. Adjusting for treatment received in first remission did not affect the results. In conclusion, the outcome of adult patients remains poor irrespective of their Notch-1 and/or FBXW7 mutation status, and there is no evidence that these markers should influence therapy in this age group.