Combination treatment of an IDH1 inhibitor with chemotherapy in IDH1 mutant acute myeloid leukemia
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LETTER TO THE EDITOR
Combination treatment of an IDH1 inhibitor with chemotherapy in IDH1 mutant acute myeloid leukemia Charu Gupta 1 & Stefan Kaulfuss 2 & Kerstin Görlich 1 & Basem Othman 1 & Anuhar Chaturvedi 1 & Michael Heuser 1 Received: 10 March 2020 / Accepted: 12 March 2020 # The Author(s) 2020
Dear Editor, The first clinical IDH1 inhibitor ivosidenib as a single agent in IDH1-mutated relapsed or refractory acute myeloid leukemia (AML) showed an overall response rate of 41.6% and a complete remission rate of 21.6% with a median duration of response of 8.2 months [1]. While these results are promising in this difficult to treat patient setting, they also suggest that mIDH1 inhibitors should be combined with other agents to improve efficacy. IDH1 mutations do not show a clear prognostic effect in AML patients who are treated with standard induction and consolidation therapy [2–5]. It is unclear how an IDH1 inhibitor acts in combination with standard chemotherapy and how the treatment sequence may affect treatment efficacy. We evaluated the mIDH1 inhibitor BAY1436032 in sequential or simultaneous combination with cytarabine plus doxorubicin in a previously reported IDH1 mutant PDX mouse model [6] (Fig. 1a). All treatment groups that were treated with BAY1436032 received the drug for 87 days (Fig. 1a). While the engraftment of human leukemic cells increased in the vehicle-treated mice at week 8 and in chemotherapy-treated mice at week 12 after the start of treatment, the percentage of leukemic cells decreased in BAY1436032-treated mice as well as in the groups receiving
Anuhar Chaturvedi and Michael Heuser contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-020-04001-w) contains supplementary material, which is available to authorized users. * Anuhar Chaturvedi [email protected] * Michael Heuser [email protected] 1
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
2
Bayer AG, Berlin, Germany
the sequential and simultaneous combination treatments (Fig. 1b). However, after the stop of treatment at week 12, the percentage of leukemic cells increased after week 16 in the group receiving BAY1436032 and after week 24 in the group treated with a sequential combination of BAY1436032 and chemotherapy (Fig. 1b). Similar to the combination with azacitidine [7], the percentage of leukemic cells in mice treated with the simultaneous combination of BAY1436032 and chemotherapy showed a delayed increase of blasts and slower leukemia kinetics (Fig. 1b). Importantly, 4 of 8 mice from this cohort had less than 10% human leukemic cells in the peripheral blood at the end of the study at 48 weeks (Fig. 1c). WBC counts constantly increased and hemoglobin as well as platelet counts decreased in all treatment groups but stayed normal in the group of mice treated simultaneously with BAY1436032 and chemotherapy (Fig. 2a, b, and c). While chemotherapy-tre
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