Expert Highlights Tolerability and Safety of Ziftomenib in Phase 1 Trial

An expert from Duke Health says that patients with NPM1-mutatant relapsed/refractory acute myeloid leukemia did not experience any significant safety signals following treatment with ziftomenib.

During a conversation with CancerNetwork® regarding the phase 1/2 KOMET-001 trial (NCT04067336), Harry Erba, MD, indicated that 4 of 20 patients with NPM1-mutated relapsed/refractory acute myeloid leukemia developed differentiation syndrome following treatment with 600 mg of ziftomenib.

In the NPM1 group, all but 1 event was grade 1/2. Notably, hydroxyurea and dexamethasone were used to manage events of differentiation syndrome at a dose of 10 mg twice a day.

However, Erba, a hematologic oncologist at Duke Health, also indicated that patients with KMT2A-rearranged disease experienced an increase in differentiation syndrome. This was particularly noted in patients associated with low response to treatment, which could be due to treatment withdrawal.


At the 600 mg dose, in the NPM1-mutated patient population, we did not see any significant safety considerations. In fact, among patients with an NMP1 mutation treated with ziftomenib at 600 mg daily, we saw 4 patients with differentiation syndrome, all of [whom] were easily managed with appropriate dosing of hydroxyurea and dexamethasone when necessary at 10 mg twice daily.

We did not see any significant GI [gastrointestinal] toxicity, [nor] did we see Qt prolongation. There was no obvious signal for an interaction with SYP-3a/4 inhibitors.

On the other hand, in patients with the KMT2A-rearranged disease, we did see a significant safety concern for differentiation syndrome in those patients associated with a low response, likely due to early withdrawal of the drug because of the concern of a rapid proliferation of the blasts and these extramedullary sites of disease.


Erba HP, Fathi AT, Issa GC, et al. Update on a phase 1/2 first-in-human study of the menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022; 140(suppl 1):153-156. doi:10.1182/blood-2022-167412

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