Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

Mathieu Simonin (1, 2, 3) , Aline Schmidt (4) , Christophe Bontoux (1, 3) , Marie-Émilie Dourthe (1, 3, 5) , Etienne Lengliné (6) , Guillaume P Andrieu (3, 1) , Ludovic Lhermitte (1, 3) , Carlos Graux (7) , Nathalie Grardel (8) , Jean-Michel Cayuela (6) , Françoise Huguet (9) , Isabelle Arnoux (10) , Stéphane Ducassou (11) , Elizabeth Macintyre (1, 3) , Virginie Gandemer (12) , Hervé Dombret (6) , Arnaud Petit (2) , Norbert Ifrah (4) , André Baruchel (5, 6) , Nicolas Boissel (6) , Vahid Asnafi (1, 3)

1 Hôpital Necker - Enfants Malades [AP-HP]
2 CHU Trousseau [APHP]
3 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
4 CHU Angers - Centre Hospitalier Universitaire d'Angers
5 Hôpital Robert Debré
6 AP-HP - Hopital Saint-Louis [AP-HP]
7 CHU UCL Namur
8 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
9 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
10 TIMONE - Hôpital de la Timone [CHU - APHM]
11 CHU Bordeaux
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]

IDH1 and IDH2 mutations (IDH1/2 Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2 Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with TALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2 Mut. Mutational patterns of IDH1/2 Mut in TALL present some specific features compared to AML. Whereas IDH2 R140Q mutation was frequent in TALL (25 of 51 mutations), the IDH2 R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2 Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated TALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

Mots clés: IDH1; IDH2; T-ALL

Domaines: Médecine humaine et pathologie

Mathieu Simonin, Aline Schmidt, Christophe Bontoux, Marie-Émilie Dourthe, Etienne Lengliné, et al.. Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL. Journal of Hematology and Oncology, 2021, 14 (1), ⟨10.1186/s13045-021-01068-4⟩. ⟨hal-03218266⟩