ASH 2024 | The management of patients with R/R AML who develop resistance to IDH inhibitors

So, IDH-mutated AML is actually quite common. Around 30% of patients will have either IDH2 mutation, which is around 15 to 20% of all acute myeloid leukemia patients, and around 7 to 10% will have IDH1 mutation. We also know that targetable IDH1 and IDH2 targeted therapy drugs are now available. We have IDH1 inhibitors, which are ivosidenib and olutasidenib, and we have the IDH2 inhibitor, enasidenib. Those drugs were approved based on Phase II trials, and the ivosidenib was approved based on the Phase III randomized control trial data, the trial called Agile, which actually demonstrated that addition of ivosidenib as a single agent is cited in dramatically improved the response rates and the survival of those patients who have IDH1-mutated acute myeloid leukemia. 

Nevertheless, in the vast majority of patients, these therapies are not curative. Recent data actually suggests that the possibility to offer those patients who fail IDH inhibitors as their acute myeloid leukemia therapy that venetoclax plays an important role and that actually the response rates are actually quite high from 40 to 70% when you use venetoclax-based therapies, when patients do not respond or relapse after IDH1 or IDH2 inhibitors. Importantly, that the optimal backbone to venetoclax can also be considered if patients relapse after azacitidine-ivosidenib, perhaps venetoclax with low-dose chemotherapy backbone could be a potentially good salvage therapy for them. 

There’s also data suggesting that if you try to treat the patients in an alternative approach, is that you offer them venetoclax-based therapies as a first-line therapy, and then at relapse offer them IDH inhibitors, their relapse rates are absolutely poor, and almost none of those patients will respond unfortunately. So again, this is something concerning actually, that we have to actually understand how to sequence those drugs optimally, but now, based on the data we have, now it seems that venetoclax may be a better drug in the second line. Of course, it’s not approved for that, but still, data shows that. Secondly, if the patients were already exposed to venetoclax and IDH inhibitors, we also should look at the other targetable mutations, such as FLT3, because we have approved FLT3 inhibitors for relapsed/refractory settings, gilteritinib and quizartinib. And of course, the recent development of menin inhibitors, so especially for those patients who have NPM1 mutation or KMT2A gene rearrangement, because patients with IDH inhibitors quite commonly have a mutation of NPM1 as well. So menin inhibitors in those patients who had previously received IDH inhibitors and are now in the relapsed refractory situation, they could possibly be considered for menin inhibitor salvage therapy if they have an NPM1 mutation.

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