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
Affiliations
- Marta Libura
- Medical University of Warsaw
- Emilia Bialopiotrowicz
- Institute of Hematology and Transfusion Medicine
- Sebastian Giebel
- Maria Sklodowska-Curie National Research Institute of Oncology
- Agnieszka Wierzbowska
- Medical University of Lodz
- Gail J. Roboz
- Weil Cornell Medical College
- Beata Piatkowska-Jakubas
- Faculty of Medicine, Jagiellonian University
- Marta Pawelczyk
- Medical University of Warsaw
- Patryk Gorniak
- Institute of Hematology and Transfusion Medicine
- Katarzyna Borg
- Institute of Hematology and Transfusion Medicine
- Magdalena Wojtas
- Institute of Hematology and Transfusion Medicine
- Izabella Florek
- Faculty of Medicine, Jagiellonian University
- Karolina Matiakowska
- Faculty of Medicine, Nicolaus Copernicus University in Torun
- Bozena Jazwiec
- Medical University of Wroclaw
- Iwona Solarska
- Institute of Hematology and Transfusion Medicine
- Monika Noyszewska-Kania
- Institute of Hematology and Transfusion Medicine
- Karolina Piechna
- Institute of Hematology and Transfusion Medicine
- Magdalena Zawada
- Faculty of Medicine, Jagiellonian University
- Sylwia Czekalska
- Faculty of Medicine, Jagiellonian University
- Zoriana Salamanczuk
- Hopitaux Universitaires de Geneve
- Karolina Karabin
- Medical University of Warsaw
- Katarzyna Wasilewska
- Medical University of Lodz
- Monika Paluszewska
- Medical University of Warsaw
- Elzbieta Urbanowska
- Medical University of Warsaw
- Justyna Gajkowska-Kulik
- Nicolaus Copernicus Municipal Specialist Hospital
- Grazyna Semenczuk
- Dr Biziel University Hospital
- Justyna Rybka
- Medical University of Wroclaw
- Tomasz Wrobel
- Medical University of Wroclaw
- Anna Ejduk
- Institute of Hematology and Transfusion Medicine
- Dariusz Kata
- Medical University of Silesia
- Sebastian Grosicki
- Department of Cancer Prevention, School of Public Health, Silesian Medical University
- Tadeusz Robak
- Medical University of Lodz
- Agnieszka Pluta
- Medical University of Lodz
- Agata Kominek
- Laboratory of Cytometry, Nencki Institute of Experimental Biology
- Katarzyna Piwocka
- Laboratory of Cytometry, Nencki Institute of Experimental Biology
- Karolina Pyziak
- Ryvu Therapeutics S.A.
- Agnieszka Sroka-Porada
- Ryvu Therapeutics S.A.
- Anna Wrobel
- Ryvu Therapeutics S.A.
- Agnieszka Przybylowicz
- Ryvu Therapeutics S.A.
- Marzena Wojtaszewska
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences
- Krzysztof Lewandowski
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences
- Lidia Gil
- Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences
- Agnieszka Piekarska
- Department of Hematology and Transplantology, Medical University of Gdansk
- Wanda Knopinska
- Department of Hematology, Hospital of the Ministry of Internal Affairs and Administration with Regional Oncology Center
- Lukasz Bolkun
- Department of Hematology, Medical University of Bialystok
- Krzysztof Warzocha
- Institute of Hematology and Transfusion Medicine
- Kazimierz Kuliczkowski
- Medical University of Wroclaw
- Tomasz Sacha
- Faculty of Medicine, Jagiellonian University
- Grzegorz Basak
- Medical University of Warsaw
- Wieslaw Wiktor Jedrzejczak
- Medical University of Warsaw
- Jerzy Holowiecki
- Maria Sklodowska-Curie National Research Institute of Oncology
- Przemysław Juszczynski
- Institute of Hematology and Transfusion Medicine
- Olga Haus
- Faculty of Medicine, Nicolaus Copernicus University in Torun
- DOI
- https://doi.org/10.1038/s41598-021-88120-y
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 13
Abstract
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.