P079 | PROLONGED XPO1 INHIBITION BY ELTANEXOR INDUCES DIFFERENTIATION IN PATIENTS WITH NPM1-MUTATED ACUTE MYELOID LEUKEMIA

Despite recent advances in treating NPM1-mutated acute myeloid leukemia (AML), approximately 50% of patients still die from disease progression, highlighting the urgent need for new therapeutic options. We previously demonstrated that the interaction between mutant NPM1 (NPM1c) and the nuclear exporter XPO1 is essential for maintaining the leukemic phenotype. Prolonged inhibition of XPO1 by the investigational, oral XPO1 inhibitor eltanexor (KPT-8602) leads to loss of HOX gene expression, followed by differentiation and growth arrest of NPM1-mutated AML cells, independent of co-occurring mutations (Brunetti et al. 2018; Pianigiani et al. 2022). Building on these findings, we initiated a pilot, investigator-sponsored, phase IIa clinical trial (Protocol: ELENA-01; EU CT number: 2024-514724-16-01) to assess the safety and preliminary efficacy of eltanexor in 10 patients aged ≥60 years with relapsed/refractory NPM1-mutated AML, for whom no reimbursed therapeutic options are available. Eltanexor is administered orally at 20 mg/day, 5 days/week, in 28-day cycles. Co-primary endpoints are: 1) the rate of prolonged grade 3 or any grade 4/5 non-hematologic toxicities, and 2) response rate at the end of cycle 2. Exploratory endpoints include transcriptomic changes in leukemic cells from enrolled patients. At the data cut-off, two patients had been enrolled. UPN01, a 72-year-old female, had NPM1-mutated AML with IDH2, FLT3 (N676L), and NRAS mutations, relapsing after intensive chemotherapy and venetoclax plus azacitidine. UPN02, a 77-year-old male, had NPM1-mutated AML with a FLT3-ITD (allelic ratio 1.2 at screening) and a WT1 truncating mutation, relapsing after azacitidine and gilteritinib. No objective responses were observed after two cycles. At C1D22, UPN02 developed grade 2 differentiation syndrome, marked by a sharp rise in blasts (0 to 2000/μL) and neutrophils (500 to 6000/μL), accompanied by fever and mild renal failure. Symptoms resolved with steroids without suspending eltanexor. No prolonged grade 3 or any grade 4/5 adverse events (AEs) were reported, irrespective of attribution. The only drug-related AE was transient grade 2 hyponatremia. Importantly, no gastrointestinal AEs occurred. Both patients interrupted eltanexor due to lack of response, not toxicity. No skipped or missed doses were recorded. Although no objective responses were observed, the occurrence of differentiation syndrome, similar to what has been seen with Menin inhibitors, provides proof-of-concept for the proposed mechanism of action. Importantly, no safety signals were identified in the first two patients enrolled in the study. Analysis of transcriptomic data is currently ongoing.