1. IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.
- Author
-
Libura M, Bialopiotrowicz E, Giebel S, Wierzbowska A, Roboz GJ, Piatkowska-Jakubas B, Pawelczyk M, Gorniak P, Borg K, Wojtas M, Florek I, Matiakowska K, Jazwiec B, Solarska I, Noyszewska-Kania M, Piechna K, Zawada M, Czekalska S, Salamanczuk Z, Karabin K, Wasilewska K, Paluszewska M, Urbanowska E, Gajkowska-Kulik J, Semenczuk G, Rybka J, Wrobel T, Ejduk A, Kata D, Grosicki S, Robak T, Pluta A, Kominek A, Piwocka K, Pyziak K, Sroka-Porada A, Wrobel A, Przybylowicz A, Wojtaszewska M, Lewandowski K, Gil L, Piekarska A, Knopinska W, Bolkun L, Warzocha K, Kuliczkowski K, Sacha T, Basak G, Jedrzejczak WW, Holowiecki J, Juszczynski P, and Haus O
- Subjects
- Adolescent, Adult, Aged, Cladribine therapeutic use, Cytarabine therapeutic use, Daunorubicin therapeutic use, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Middle Aged, Pharmacogenomic Variants, Poland epidemiology, Randomized Controlled Trials as Topic, Retrospective Studies, Young Adult, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics
- Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2
+ ) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.- Published
- 2021
- Full Text
- View/download PDF