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

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 karyotyp...

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Published inScientific 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
LanguageEnglish
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)
Online AccessGet full text
ISSN2045-2322
2045-2322
DOI10.1038/s41598-021-88120-y

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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.
AbstractList 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.
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.
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.
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.
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.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.
ArticleNumber 10017
Author Pyziak, Karolina
Roboz, Gail J.
Juszczynski, Przemysław
Noyszewska-Kania, Monika
Sroka-Porada, Agnieszka
Piatkowska-Jakubas, Beata
Robak, Tadeusz
Wojtas, Magdalena
Semenczuk, Grazyna
Karabin, Karolina
Paluszewska, Monika
Kuliczkowski, Kazimierz
Solarska, Iwona
Rybka, Justyna
Wrobel, Anna
Knopinska, Wanda
Gil, Lidia
Kata, Dariusz
Wojtaszewska, Marzena
Florek, Izabella
Wasilewska, Katarzyna
Haus, Olga
Zawada, Magdalena
Warzocha, Krzysztof
Bialopiotrowicz, Emilia
Gajkowska-Kulik, Justyna
Libura, Marta
Pluta, Agnieszka
Piwocka, Katarzyna
Jedrzejczak, Wieslaw Wiktor
Holowiecki, Jerzy
Grosicki, Sebastian
Giebel, Sebastian
Borg, Katarzyna
Basak, Grzegorz
Bolkun, Lukasz
Czekalska, Sylwia
Urbanowska, Elzbieta
Sacha, Tomasz
Jazwiec, Bozena
Piekarska, Agnieszka
Gorniak, Patryk
Ejduk, Anna
Wierzbowska, Agnieszka
Matiakowska, Karolina
Przybylowicz, Agnieszka
Salamanczuk, Zoriana
Piechna, Karolina
Pawelczyk, Marta
Lewandowski, Krzysztof
Kominek, Agata
Wrobel, Tomasz
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SSID ssj0000529419
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Snippet Mutations in isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation...
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...
Abstract Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA...
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StartPage 10017
SubjectTerms 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)
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Title IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen
URI https://link.springer.com/article/10.1038/s41598-021-88120-y
https://www.ncbi.nlm.nih.gov/pubmed/33976256
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https://pubmed.ncbi.nlm.nih.gov/PMC8113255
https://doaj.org/article/4d3149eacd9c4e0bbd45e7fcb3834c44
Volume 11
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