Blood Journal
Leading the way in experimental and clinical research in hematology

NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study

  1. Vahid Asnafi1,2,*,
  2. Agnès Buzyn1,*,
  3. Sandrine Le Noir1,2,*,
  4. Frédéric Baleydier1,2,
  5. Arnauld Simon1,
  6. Kheira Beldjord1,2,
  7. Oumedaly Reman3,
  8. Francis Witz4,
  9. Thierry Fagot5,
  10. Emmanuelle Tavernier6,
  11. Pascal Turlure7,
  12. Thibaut Leguay8,
  13. Françoise Huguet9,
  14. Jean-Paul Vernant10,
  15. Francis Daniel9,
  16. Marie-Christine Béné4,
  17. Norbert Ifrah11,
  18. Xavier Thomas12,
  19. Hervé Dombret13, and
  20. Elizabeth Macintyre1,2
  1. 1Université Paris 5 Descartes and Assistance Publique Hôpitaux de Paris (AP-HP) and Hematology Department, Hôpital Necker-Enfants-Malades, Paris;
  2. 2Institut National de la Santé et de la Recherche Médicale (INSERM) EMI0210;
  3. 3Department of Hematology, Centre Hospitalier, Caen;
  4. 4Department of Hematology and laboratoire d'immunophénotypage, Hôpitaux de Brabois, Vandoeuvre les Nancy;
  5. 5Department of Hematology, Hôpital d'Instruction des Armées Percy, Clamart;
  6. 6Department of Hematology, Institut de Cancérologie de la Loire, St Priest en Jarez;
  7. 7Department of Hematology, Centre Hospitalier Dupuytren, Limoges;
  8. 8Department of Hematology, Centre Hospitalier du Haut Lévêque, Pessac;
  9. 9Department of Hematology, Hôpital Purpan, Toulouse;
  10. 10Department of Hematology, Hôpital Pitié Salpétrière, Paris;
  11. 11Department of Hematology, Centre Hospitalier, Angers;
  12. 12Department of Hematology Hôpital Edouard Herriot, Lyon; and
  13. 13Department of Hematology Hôpital St-Louis, Paris, France

Abstract

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.

  • Submitted October 17, 2008.
  • Accepted December 4, 2008.
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