Scientific Reports (May 2021)

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

  • Marta Libura,
  • Emilia Bialopiotrowicz,
  • Sebastian Giebel,
  • Agnieszka Wierzbowska,
  • Gail J. Roboz,
  • Beata Piatkowska-Jakubas,
  • Marta Pawelczyk,
  • Patryk Gorniak,
  • Katarzyna Borg,
  • Magdalena Wojtas,
  • Izabella Florek,
  • Karolina Matiakowska,
  • Bozena Jazwiec,
  • Iwona Solarska,
  • Monika Noyszewska-Kania,
  • Karolina Piechna,
  • Magdalena Zawada,
  • Sylwia Czekalska,
  • Zoriana Salamanczuk,
  • Karolina Karabin,
  • Katarzyna Wasilewska,
  • Monika Paluszewska,
  • Elzbieta Urbanowska,
  • Justyna Gajkowska-Kulik,
  • Grazyna Semenczuk,
  • Justyna Rybka,
  • Tomasz Wrobel,
  • Anna Ejduk,
  • Dariusz Kata,
  • Sebastian Grosicki,
  • Tadeusz Robak,
  • Agnieszka Pluta,
  • Agata Kominek,
  • Katarzyna Piwocka,
  • Karolina Pyziak,
  • Agnieszka Sroka-Porada,
  • Anna Wrobel,
  • Agnieszka Przybylowicz,
  • Marzena Wojtaszewska,
  • Krzysztof Lewandowski,
  • Lidia Gil,
  • Agnieszka Piekarska,
  • Wanda Knopinska,
  • Lukasz Bolkun,
  • Krzysztof Warzocha,
  • Kazimierz Kuliczkowski,
  • Tomasz Sacha,
  • Grzegorz Basak,
  • Wieslaw Wiktor Jedrzejczak,
  • Jerzy Holowiecki,
  • Przemysław Juszczynski,
  • Olga Haus

DOI
https://doi.org/10.1038/s41598-021-88120-y
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 13

Abstract

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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.