IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen
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 kar...
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Nature Portfolio
2021
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oai:doaj.org-article:4d3149eacd9c4e0bbd45e7fcb3834c442021-12-02T17:01:49ZIDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen10.1038/s41598-021-88120-y2045-2322https://doaj.org/article/4d3149eacd9c4e0bbd45e7fcb3834c442021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88120-yhttps://doaj.org/toc/2045-2322Abstract 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.Marta LiburaEmilia BialopiotrowiczSebastian GiebelAgnieszka WierzbowskaGail J. RobozBeata Piatkowska-JakubasMarta PawelczykPatryk GorniakKatarzyna BorgMagdalena WojtasIzabella FlorekKarolina MatiakowskaBozena JazwiecIwona SolarskaMonika Noyszewska-KaniaKarolina PiechnaMagdalena ZawadaSylwia CzekalskaZoriana SalamanczukKarolina KarabinKatarzyna WasilewskaMonika PaluszewskaElzbieta UrbanowskaJustyna Gajkowska-KulikGrazyna SemenczukJustyna RybkaTomasz WrobelAnna EjdukDariusz KataSebastian GrosickiTadeusz RobakAgnieszka PlutaAgata KominekKatarzyna PiwockaKarolina PyziakAgnieszka Sroka-PoradaAnna WrobelAgnieszka PrzybylowiczMarzena WojtaszewskaKrzysztof LewandowskiLidia GilAgnieszka PiekarskaWanda KnopinskaLukasz BolkunKrzysztof WarzochaKazimierz KuliczkowskiTomasz SachaGrzegorz BasakWieslaw Wiktor JedrzejczakJerzy HolowieckiPrzemysław JuszczynskiOlga HausNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
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Medicine R Science Q 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 IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Marta Libura |
| title |
IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| title_short |
IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| title_full |
IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| title_fullStr |
IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| title_full_unstemmed |
IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| title_sort |
idh2 mutations in patients with normal karyotype aml predict favorable responses to daunorubicin, cytarabine and cladribine regimen |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/4d3149eacd9c4e0bbd45e7fcb3834c44 |
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