Safety and efficacy of selinexor sequential azacytidine in newly diagnosed patients with myelodysplastic syndromes EB1 or EB2: A single-center, single-arm, phase ib/II trial Free

Background: Higher-risk MDS (HR-MDS), defined by the Revised International Prognostic Scoring System (IPSS-R) as intermediate, high, or very-high-risk disease, has a median overall survival of less than two years. HMAs yield low complete response (CR) rates and are associated with transient responses, often leading to disease progression or relapse. There is a critical unmet need for novel, well-tolerated, and more effective therapies for HR-MDS. Selinexor is an oral, first-in-class selective inhibitor of nuclear export compound that inhibits exportin 1 (XPO1). Our preclinical studies have shown that Azacytidine sequential Selinexor had strong synergetic effect in MDS both in vitro and in vivo.

Methods: We conducted a single-center, single-arm, phase Ib/II trial in newly diagnosed patients with MDS-EB1 or EB2. The primary endpoints of phase Ib trial were to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of Selinexor. The primary endpoint of phase II trial was to access the overall response rate (ORR) including complete remission (CR), partial remission (PR), marrow complete remission (mCR), and hematological improvement (HI) according to International Working Group criteria (IWG) 2006. Secondary key endpoints of phase II trial included the followings: (1) safety and tolerability of Azacytidine sequential Selinexor; (2) cytogenetic response and molecular response.

Results: Between Sept 6, 2022 and January 5, 2025, 12 patients were enrolled in phase Ib study and 27 patients were enrolled in phase II study. At Phase Ib, the following selinexor dosages were administered: 60mg biw (n=3), 60mg qw (n=3), 40mg biw (n=3) and 40mg qw (n=3). Two patients in the 60mg biw group discontinued treatment because of grade 3 nausea, vomiting and anorexia, which reached the MTD. One patient in the 60mg qw group discontinued treatment because of nausea, vomiting, fatigue and Herpes simplex virus infection. The most common grade 3 or 4 adverse events (AEs) of phase Ib study were hematologic toxicities: neutropenia (100%), thrombocytopenia (66.7%) and anemia (25.0%). The most common non-hematologic AEs were: fatigue (58.3%), anorexia (50.0%), nausea (41.6%), vomiting (41.6%), hypocalcemia (41.6%), dizziness (33.3%), hyponatremia (25.0%). Totally, 36 patients included in the phase Ib/II trial were evaluable for efficacy assessment. According to the IWG 2006 response criteria, ORR was 94.4%, including 14 CR (38.9%), 7 mCR+HI (19.4%) and 13 mCR (36.1%). For 17 patients with TP53 mutations, ORR was 100%, including 8 CR (47.1%), 4 mCR+HI (23.5%) and 5 mCR (29.4%). Patients with TP53 mutations achieved higher CR than patients with TP53 wildtype (47.1% vs. 31.6%), though is not significant (P=0.342). Interestingly, among 23 patients with abnormal karyotypes, eleven patients (47.8%) achieved complete cytogenetic response (cCyR) and six patient (26.1%) achieved partial cytogenetic response (pCyR). The overall cytogenetic response rate (CyR) was 73.9%. Among the 16 patients with complex karyotypes (14 concurrent with TP53 mutation), 7 patients (43.8%) achieved cCyR and 6 patients (37.5%) achieved pCyR. The overall cytogenetic response rate was 81.3%. Among the 15 patients achieved CR or mCR+HI and received more than two cycles of AS regimen, including 8 patients with TP53 mutations using a VAF cutoff of 5%, 7 (87.5%) patients achieved NGS negativity and 1 patient had an obvious VAF decrease. Additionally, the patients with U2AF1, NPM1, RUNX1, WT1, BCOR, CBL, SF3B1 and PTPN11 mutations also achieved NGS negativity. At a median follow-up time of 23.8 months, the median OS in all the patients was not reached and the median PFS was 24.2 months (11.0~NR). The 2-year OS and PFS for all 36 patients were 83.7% and 50.1%, respectively. The median OS between TP53 mutant and wild-typed patients was not significantly different (NR [95% CI, 10.8m to NR] vs. NR [95% CI, NR]; P=0.096). The median PFS between TP53 mutant and wild-typed patients was not significantly different, either (9.23 months [95% CI, 5.3m to NR] vs. 24.43 months [95% CI, 18.1m to NR]; P=0.074).

Conclusion: Azacitidine sequential Selinexor regimen demonstrated a high response rate and was tolerable in newly diagnosed patients with MDS-EB1 or EB2. The patients with TP53 mutations had a higher CR rate and longer PFS and OS compared with literatures. The patients who achieved CR also obtained high cytogenetic and molecular biology response.