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

• Published in: Scientific reports Vol. 11; no. 1; pp. 10017 - 13
• Main Authors: Libura, Marta, Bialopiotrowicz, Emilia, Giebel, Sebastian, Wierzbowska, Agnieszka, Roboz, Gail J., Piatkowska-Jakubas, Beata, Pawelczyk, Marta, Gorniak, Patryk, Borg, Katarzyna, Wojtas, Magdalena, Florek, Izabella, Matiakowska, Karolina, Jazwiec, Bozena, Solarska, Iwona, Noyszewska-Kania, Monika, Piechna, Karolina, Zawada, Magdalena, Czekalska, Sylwia, Salamanczuk, Zoriana, Karabin, Karolina, Wasilewska, Katarzyna, Paluszewska, Monika, Urbanowska, Elzbieta, Gajkowska-Kulik, Justyna, Semenczuk, Grazyna, Rybka, Justyna, Wrobel, Tomasz, Ejduk, Anna, Kata, Dariusz, Grosicki, Sebastian, Robak, Tadeusz, Pluta, Agnieszka, Kominek, Agata, Piwocka, Katarzyna, Pyziak, Karolina, Sroka-Porada, Agnieszka, Wrobel, Anna, Przybylowicz, Agnieszka, Wojtaszewska, Marzena, Lewandowski, Krzysztof, Gil, Lidia, Piekarska, Agnieszka, Knopinska, Wanda, Bolkun, Lukasz, Warzocha, Krzysztof, Kuliczkowski, Kazimierz, Sacha, Tomasz, Basak, Grzegorz, Jedrzejczak, Wieslaw Wiktor, Holowiecki, Jerzy, Juszczynski, Przemysław, Haus, Olga
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1059/99; 631/67/1990/283/1897; 631/67/68/2486; Acute myeloid leukemia; Cladribine; Cytarabine; Daunorubicin; Deoxyribonucleic acid; Deregulation; DNA; Epigenetics; Fludarabine; Humanities and Social Sciences; Isocitrate dehydrogenase; Karyotypes; Leukemia; multidisciplinary; Multivariate analysis; Mutation; Myeloid leukemia; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-88120-y

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.