Paper Details

ABSTRACT

Background:

The standard of care (SoC) for the treatment of patients (pts) with relapsed/refractory acute myeloid leukemia with Fms-related tyrosine kinase 3 mutations (FLT3m R/R AML) is the FLT3 inhibitor (FLT3i) gilteritinib (Admiral trial: 34%, CR+CRh; mOS  9.3 mo). However, real-world cohorts enriched for contemporary first-line treatments (i.e., with high-dose chemotherapy or venetoclax/HMA induction +/- HSCT and FLT3i) reveal that responses to gilteritinib are substantially lower.  Composite remissions (CCR) rates hover around 25–48%, and mOS is 4.5–7 mo, depending on disease characteristics (Othman et al., Blood Adv. 2024), highlighting the urgent need for novel agents in these settings.

Iadademstat (iada) is a specific, potent, oral covalent inhibitor of the epigenetic enzyme lysine-specific demethylase 1 (LSD1/KDM1A) and is synergistic with gilteritinib in FLT3m AML cells, including models resistant to venetoclax, azacitidine, or other FLT3is. The FRIDA Phase 1b study (NCT05546580) was designed to evaluate the safety and tolerability of iada+gilteritinib and to establish the recommended Phase 2 dose (RP2D) in pts with FLT3m R/R AML.

Methods and Results:

43 adult pts with FLT3m were treated in 11 US centers between March 2023 and December 2025 after receiving ≤ 2 prior lines of therapy (including quizartinib or gilteritinib if not refractory). Escalation consisted of 4 iada dose level (DL) cohorts in a 5dON-2dOFF schedule (5+2)/week with SoC gilteritinib at 120 mg QD in 28d cycles: DL0=100 μg iada for 4 wks (n=6); DL-1=75 μg for 4 wks (n=7); DL-2=75 μg for 3 wks (n=8) and DL-3b=50 μg for 4 wks (n=6). No DLTs occurred in the DLT period, but 1 retrospective DLT (prolonged cytopenia) was reported in DL0. 23 pts (7 in escalation+16 in expansion) were treated at the pharmacologically active DL-1 dose. Primary endpoints are treatment-emergent adverse events (TEAEs) and RP2D determination. Secondary endpoints include responses (ELN2022), OS, DoR and transfusion rate. Exploratory endpoints include measurable residual disease (MRD) and correlates between subpopulations and efficacy.

The median age of the pts was 67 years (range 20-84), 28 (65.1%) were male, and 29 (67.4%) Caucasian. At baseline, 29 (67.4%) had adverse risk (ELN 2022), 28 (65.1%) had ECOG 1 or 2, and 30 (69.8%), 8 (18.6%), and 3 (7%) had FLT3 ITD, TKD D835, or both. 83.7% of pts presented with 1 or more  ≥G3 cytopenia/s, 62.8% had AML with myelodysplastic-related changes, 51.2% were refractory to prior therapy. Prior treatments included targeted therapies in 90.7% (including 27.9% FLT3is and 60.6% venetoclax), high dose chemotherapy (48.8%) and at least 25.6% had prior transplantation. SAEs considered at least possibly related to iada were reported in 10 pts: febrile neutropenia (5), platelet count decreased, anemia, pneumonia, cellulitis orbital, dyspnea, differentiation syndrome and myocarditis (1 pt each). Pneumonia was the only death on study reported as possibly related to treatment. 37 pts were response-evaluable, 19 pts (51.4%) achieved CCR (3CRs, 5CRh, 11CRi), and 4 (11%) achieved MLFS, all except 1 by the end of Cycle 2. 14 (37.9%) did not respond. In DL-1, 12 out of 18 evaluable pts (66.7%) achieved CCR (3CRs, 3CRh, 6CRi), 1 achieved MLFS (5.6%) and 5 (26.3%) did not respond. DoR for CCR was 5.1 mo (95% CI 1.3, NE) and 5.4 mo (95% CI 1.0, NE) in the DL-1. With a median follow-up (FU) of 16.2 mo, the mOS was 6.2 (95% CI 5.6, 7.5) and 7.1 mo (95% CI 5.3, 12.7) in the DL-1. Overall, 30- and 60-day mortality was 2.3% and 4.7% (0% in the DL-1 cohort). 8 out of 36 (22%) transfusion dependent pts became independent and 6 out of 7 (86%) of transfusion independent pts remained independent during at least part of the treatment period. At the time of this report, 6 pts had undergone HSCT, 8 pts (7 in DL-1 cohort) are alive and in FU, 29 are dead and 6 are unknown.  PK/PD, MRD analysis, drug exposure, and correlative analysis will be presented at the Congress.

Conclusion:

Iada+gilteritinib demonstrated a manageable safety profile in FLT3m AML, similar to SoC treatment. Based on the PK, target engagement, safety, tolerability, and efficacy observed in the FRIDA study, the DL-1 of iada at 75 ug (5+2) every week is the RP2D for the combination with gilteritinib. In a high-risk, heavily pre-treated and refractory FLT3m AML population, the high 67% CCR and 31% 12-mo rate survival achieved at the RP2D support the further clinical development of this combination.