Show Notes
Topics Covered
1. KOMET-007 and SNDX-5613-0708: Menin Inhibitors with Intensive Chemotherapy KOMET-007: Phase 1a/b study adding ziftomenib 600 mg once daily, starting on day 8, to 7+3 induction and continuing it through consolidation, in 99 patients with newly diagnosed NPM1-mutated (n=49; median age 60) or KMT2A-rearranged (n=50; median age 43) AML. Presented by Amer Zeidan at EHA 2026 (Abstract S130; NCT05735184). SNDX-5613-0708: Phase 1 dose-escalation study adding revumenib to cytarabine plus daunorubicin or idarubicin for up to two induction cycles in induction-eligible adults aged 18–75 (ECOG 0–2) with newly diagnosed KMT2A-rearranged, NPM1-mutated, or NUP98-rearranged AML. Two dose levels were tested: DL1 (110/220 mg) and DL2 (160/270 mg, the approved monotherapy dose). 31 patients were treated (13 at DL1, 18 at DL2) as of October 2025. Presented by Ibrahim Aldoss at EHA 2026 (Abstract PF489; NCT06226571).
Key results (KOMET-007 median follow-up 17.6 months NPM1-m, 11.0 months KMT2A-r):
• KOMET-007 CRc 96% (47/49) in NPM1-m and 90% (45/50) in KMT2A-r, 93% (92/99) overall; MRD negativity among CRs ~85% • KOMET-007 12-month OS 94% (NPM1-m) vs. 71% (KMT2A-r); median OS not reached in either cohort; 60-day mortality 2% and 4% • KOMET-007 safety: grade 3 differentiation syndrome 4%, no grade 4; no ziftomenib-related QTc prolongation • Revumenib + intensive chemotherapy, response-evaluable patients: DL1 (n=12) ORR/CRc 100%, CR 92%; DL2 (n=14) ORR 93%, CRc 86%, CR 79%; MRD-negative CR 100% (DL1) and 70% (DL2); responses similar across dose levels • Revumenib safety: no differentiation syndrome; one grade 3 QTcF prolongation DLT; any-grade QTcF prolongation ~15% at DL1
Discussion points: Both studies start the menin inhibitor after the cytotoxic days of induction, when there is less leukemia left to differentiate. Dr. Zeidner credits that timing and the chemotherapy itself for differentiation syndrome rates of 3–4%, compared with roughly 15–30% for single-agent menin inhibitors in relapsed/refractory disease. He saw no new QTc signal and no clear delay in count recovery. He cautioned that single-arm data can only be judged against historical expectations, and that the low early mortality reflects selected patients at academic centers. Ashwin questioned how much a high CR rate adds in NPM1-mutated disease, where 7+3 already works well. Dr. Zeidner agreed the two genotypes need separate readouts. In NPM1-mutated, FLT3 wild-type disease the goal is cure with chemotherapy, so relapse and survival are the open questions, and the randomized phase 3 KOMET-017 (7+3 plus ziftomenib or placebo) will answer them. In KMT2A-rearranged disease remission is a bridge to transplant, so he asks whether azacitidine-venetoclax plus a menin inhibitor could replace intensive induction. He is leading a single-arm study of that approach (RAVEN) in younger fit KMT2A-rearranged patients. Choosing between the two drugs, he finds differentiation syndrome rates comparable in NPM1-mutated disease (about 20–25%) and more severe in KMT2A-rearranged disease. Both drugs prolong the QTc. Revumenib carries the boxed warning and somewhat more grade 3 events, and he checks ECGs weekly when starting either one.
2. HOVON156/AMLSG28-18/PASHA Phase 3, open-label trial randomizing 768 adults with newly diagnosed FLT3-mutated AML fit for intensive chemotherapy 1:1 to gilteritinib 120 mg daily or midostaurin 50 mg twice daily, each with 7+3 induction and consolidation and followed by FLT3 inhibitor maintenance. Median age 59; FLT3-ITD allelic ratio ≥0.5 in 48%, FLT3-TKD in 21%, NPM1 co-mutation in 58%. The primary endpoint was OS. Presented by Marc Raaijmakers at EHA 2026 (Abstract LB5005; NCT04027309).
Key results (43.2-month median follow-up):
• OS (primary endpoint): median not reached in either arm; HR 1.02 (95% CI 0.81–1.28; P=0.86) • Median EFS 51.1 vs. 19.9 months (HR 0.83; P=0.052) • Post-CR morphologic relapse 21% (gilteritinib) vs. 36% (midostaurin) (HR 0
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