TY - JOUR
T1 - IDH Inhibitors in AML—Promise and Pitfalls
AU - McMurry, Hannah
AU - Fletcher, Luke
AU - Traer, Elie
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/4
Y1 - 2021/4
N2 - Purpose of Review: Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. Recent Findings: IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. Summary: IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.
AB - Purpose of Review: Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. Recent Findings: IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. Summary: IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.
KW - Acute myeloid leukemia (AML)
KW - Enasidenib
KW - IDH inhibitors
KW - IDH1
KW - IDH2
KW - Isocitrate dehydrogenase (IDH)
KW - Ivosidenib
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U2 - 10.1007/s11899-021-00619-3
DO - 10.1007/s11899-021-00619-3
M3 - Review article
C2 - 33939107
AN - SCOPUS:85105398849
SN - 1558-8211
VL - 16
SP - 207
EP - 217
JO - Current Hematologic Malignancy Reports
JF - Current Hematologic Malignancy Reports
IS - 2
ER -