Expert Highlights Tolerability and Safety of Ziftomenib in Phase 1 Trial

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.

Transcript:

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.

Reference

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