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IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

2021; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41598-021-88120-y

2045-2322

Marta Libura, Emilia Białopiotrowicz, Sebastian Giebel, Agnieszka Wierzbowska, Gail J. Roboz, Beata Piątkowska‐Jakubas, Marta Pawełczyk, Patryk Górniak, Katarzyna Borg, Magdalena Wojtas, Izabella Florek, Karolina Matiakowska, Bożena Jaźwiec, Iwona Solarska, Monika Noyszewska‐Kania, Karolina Piechna, Magdalena Zawada, Sylwia Czekalska, Zoriana Salamańczuk, Karolina Karabin, Katarzyna Wasilewska, Monika Paluszewska, Elżbieta Urbanowska, Justyna Gajkowska-Kulik, Grażyna Semeńczuk, Justyna Rybka, Tomasz Wróbel, Anna Ejduk, Dariusz Kata, Sebastian Grosicki, Tadeusz Robak, Agnieszka Pluta, Agata Kominek, Katarzyna Piwocka, Karolina Pyziak, Agnieszka Sroka‐Porada, Anna Wróbel, Agnieszka Przybyłowicz, Marzena Wojtaszewska, Krzysztof Lewandowski, Lidia Gil, Agnieszka Piekarska, Wanda Knopińska, Łukasz Bołkuń, Krzysztof Warzocha, Kazimierz Kuliczkowski, Tomasz Sacha, Grzegorz Basak, W Wiktor-Jędrzejczak, Jerzy Hołowiecki, Przemysław Juszczyński, Olga Haus,

Multiple Myeloma Research and Treatments

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.