Journal
BLOOD
Volume 113, Issue 17, Pages 3918-3924Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-10-184069
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Funding
- Association Cent Pour Sang La Vie
- Association Laurette Fugain [RAF ALF Ndegrees06-03]
- PHRC [94-95-97.02]
- Soutien des therapeutiques innovatrices couteuses Reseau de Biologie Innovatrice en Ouco-hematologie (RuBIH) [LALA-94]
- Promoteur Hospices Civils de Lyon [GRAALL-2003]
- Le Programme Hospitalier de Recherche Clinique [P0200701, P030425/AOM03081]
- Ministere de l'Emploi et de la Solidarite (Paris, France)
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Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD + proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL. (Blood. 2009;113:3918-3924)
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