IDH1 and IDH2 Inhibitors

There are many different mutations and factors that cause Acute Myeloid Leukemia (AML). The most common mutation is found in the gene coding for the FLT3 proteins, which is found in about 30% of all AML patients. One of the second most common mutations is found in the IDH1 and IDH2 genes. Combined, these mutations are responsible for about half of all AML cases. Finding treatments that can target these mutations is crucial to finding a cure. There are 2 target treatments currently available for relapsed and refractory patients and older patients or patients that cannot tolerate intensive chemo.

IDH1 Inhibitors

Ivosidenib (Tibsovo): Newly Diagnosed and Relapsed/Refractory IDH1 Mutated AML 

Ivosidenib is an orally administered anticancer drug designed for patients with IDH1 mutated AML.  The first clinical trials for ivosidenib were specifically for relapsed/refractory (R/R) patients with the IDH1 mutation. The study results show that 1/3 of the patients entered complete remission (CR) including CRh which is CR with partial recovery of peripheral blood counts. These results prove ivosidenib to be an effective therapy, but it is still unclear if it is compared to other therapies for R/R AML for patients with the IDH1 mutation. 

Until recently, Ivosidenib was only available for R/R AML patients but recent trials have led to FDA approval for patients 75 and older. They were able to test ivosidenib on older patients (75+) and on patients that cannot tolerate intensive chemo. The results were promising, with CR and CRh seen in 45% of the patients. 

Ivosidenib is now available for both newly diagnosed and R/R AML patients. One advantage to using ivosidenib over other treatments is that it can be administered orally. It should be noted though, that 25% of the newly diagnosed patients and 15% of the R/R patients showed an adverse effect called Differentiation syndrome (DS) which, if not treated early, can be potentially fatal. 

IDH2 Inhibitors

Enasidenib (Idhifa): Relapse/Refractory IDH2 Mutated AML

Enasidenib (Idhifa) is an IDH2 inhibitor that is administered orally. Clinical trials show a 20% complete remission (CR) and another 20% partial remission out of the 214 patients treated in an early phase clinical trial. Early phase clinical trials show enasidenib to be relatively tolerable making it a viable treatment option for patients with relapsed/refractory (R/R) IDH2 mutated AML. It appears to be a useful alternative for older patients who are unable to be treated with the standard intensive chemotherapies but further research needs to be done. 

The early phases of the clinical trial tested the drug on younger patients but a phase 3 trial is currently underway. Its purpose is to investigate enasidenib safety and efficiency in older patients (60+). There are currently 319 patients enrolled and it is scheduled to be completed in December 2022. 

Combination Treatments 

Both of these treatments, Ivosidenib and Enasidenib, have relatively effective outcomes but combination treatments could make them both more effective.

A phase I trial for ivosidenib in combination with another anti-cancer drug shows 60% complete remission (CR) in patients and 70% CR + CRh. The trial is currently recruiting and now onto phase 3 to determine the benefits of this approach. 

A Phase I trial of enasidenib treatment in combination with induction and consolidation therapy in patients with newly diagnosed IDH-mutated AML is also underway. They are currently recruiting in their phase 3 trial and expect competition by 2024.