Isocitrate dehydrogenase inhibitors (Daiichi Sankyo)

The development of oral therapies impacts the management of acute myeloid leukemia and myelodysplastic syndromes, especially for targetable mutations including IDH1/2.

We discuss IDH1/2 activity and inhibitor therapy in various settings, including monotherapy, combination therapy with hypomethylating agents, and other approaches.

Olutasidenib, enasidenib, and ivosidenib are approved for relapsed AML. Ivosidenib is approved for relapsed MDS and alone or with azacitidine in newly diagnosed AML. However, unanswered questions exist. In newly diagnosed AML, ivosidenib + azacitidine shows a survival benefit compared to azacitidine, but it is unknown whether ivosidenib + azacitidine demonstrates improved survival compared to ivosidenib. Ivosidenib + azacitidine demonstrated a survival benefit not seen with enasidenib + azacitidine. It is unclear whether newly diagnosed AML should be treated with azacitidine + ivosidenib or azacitidine + venetoclax. Azacitidine + venetoclax shows excellent response rates in IDH mutated disease. Retrospective data show low response rates of IDH inhibitor therapy post-venetoclax whereas HMA + venetoclax retains activity post IDH inhibition. The role of IDH inhibition post-transplant is unclear. Single-arm studies show post-transplant maintenance is safe; however, randomized trials are needed. Similarly, IDH inhibitors can be combined with chemotherapy however randomized studies are needed.

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide andMycobacterium tuberculosisinduce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.