Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia
Menée sur 223 patients adultes atteints d'une leucémie myéloïde aiguë (62 avec mutations IDH, 161 sans), cette étude évalue l'intérêt de la mesure de la concentration sérique d'un oncométabolite, 2HG, pour identifier les patients susceptibles de répondre à une thérapie ciblée sur IDH
Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements is not established. We studied whether 2HG measurements in AML patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Serum from 223 adults with de novo AML (62 IDH-mutated, 161 wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry (LC-MS). Pretreatment 2HG levels ranged from 10 to 30,000ng/ml and were elevated in IDH-mutants (median 3004ng/ml), compared to the wild-type cohort (median 61ng/ml) (p<0.0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating curve (ROC) analysis, a discriminatory level of 700ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels >700ng/ml, IDH mutations were identified in nine samples. IDH-mutant patients with 2HG levels >200ng/ml at complete remission experienced shorter overall survival compared to those with 2HG<200ng/ml (HR 3.9, p=0.02). We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that serum measurement of an oncometabolite provides useful diagnostic and prognostic information, and can improve patient selection for IDH-targeted therapies.
Blood , résumé, 2013