The Efficacy and Safety of Selinexor in Combination with Ruxolitinib in Ruxolitinib-Treated Myelofibrosis Patients: The Interim Analysis of a Prospective, Open-Label, Multicenter, Parallel-Cohort, Phase 2 Study

Background: Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Although JAK inhibitors have improved patients' splenomegaly and symptom burden, the clinical management of MF is still challenging for its limited treatment options, especially when patients become less responsive or intolerable to Ruxolitinib (RUX) treatment. Selinexor (SEL) is a novel, first-in-class, oral selective inhibitor of nuclear export agent that binds the karyopherin protein exportin 1 (XPO1). Preclinical studies showed SEL decreased viable cells and colony formation both in newly diagnosed and RUX-exposed MF cells. ESSENTIAL trial showed SEL's sustained spleen responses as a single agent in JAKi refractory MF. Besides, a phase I study reported, with SEL plus RUX in treatment-Naïve MF, 92% patients(pts) achieved SVR35, 69% had symptom response and 65% had stable or improved Hgb levels. We have presented promising efficacy and safety data in real-world setting of SEL plus RUX regimen in MF patients in 2023 ASH. Here we are to report the efficacy and safety of the regimen in RUX-treated patients in a prospective clinical trial.

Methods: This is a prospective, open-label, multi-center, parallel-cohort phase 2 study, examining SEL plus RUX regimen in RUX-treated MF pts. The study includes MF pts with suboptimal RUX responses or intolerable to RUX treatment. Pts are given SEL 40mg or 60mg QW plus RUX (dosage per investigator judgement, RUX intolerable pts will receive reduced dose of RUX). A total of 40 pts will be included into the study. The primary endpoint is spleen response assessed by palpation or CT/MRI scan per IWG-MRT and ELN response criteria. Key secondary endpoints include anemia response, symptom response defined as symptom resolution or alleviation according to TSS or physician's judgement, and safety.

Results:

Characteristics

By July 2024, 38 pts had received at least one dose of SEL, including 20 suboptimal RUX responses pts and 16 RUX intolerable pts. The median age was 66 years old. Mean duration of prior RUX treatment was 20.5 months (range:3.6-138). 24 pts had primary MF, 6 had post-PV MF, and 5 had post-ET MF. Median time from MF diagnosis to study enrollment was 7 years (0-32). JAK2, CALR and MPL mutations were present in 26 (68.42%), 5 (13.16%) and 1 (2.63%) pts respectively. 31（81.58%）had splenomegaly, and 9(23.68%) had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was intermediate 21 (55.26%), high risk 10 (26.32%) and unknown 7(18.42%). Median treatment duration was 151 days (16-696). 6 pts discontinued SEL for disease progression, 4 pts participate in other clinical trial, 1 pts achieve transplantation, 5 pts for toxicity and 2 pts for inability to afford the cost of medication.

Efficacy Analysis

The analysis of spleen response included 25 pts with spleen length assessment data by either palpation or CT/MRI. Spleen response is defined as length reduction more than 50% per IWG-MRT and ELN response criteria. 21(84%) pts had a reduction in spleen volume and 10 (40%) achieved spleen response. For symptom response, 30 pts are with available data. 26 (86.67%) pts had symptom alleviation, 9 (40.91%) achieved _50% reduction in TSS or symptom response assessed by physician, of which 1 achieved symptom resolution.4/9 (55.55%) pts PRBC transfusion-dependent became transfusion independent after treatment with SEL and RUX.

Safety

The most common TEAEs were nausea 36.84%, vomiting 23.68%, decreased appetite 21.05%, and anemia 36.84%. The most frequent TEAEs Grade 3 were anemia 18.42% and thrombocytopenia 5.26%.

Conclusion

In this preliminary analysis, the combination of SEL and RUX showed encouraging efficacy and manageable safety in RUX-treated pts with myelofibrosis.

No relevant conflicts of interest to declare.

Selinexor (SEL) is a novel, 􀀀first-in-class, oral selective inhibitor of nuclear export agent that binds the karyopherin protein exportin 1 (XPO1). Preclinical studies showed SEL decreased viable cells and colony formation both in newly diagnosed and RUX-exposed MF cells. ESSENTIAL trial showed SEL’s sustained spleen responses as a single agent in JAKi refractory MF. Besides, a phase I study reported, with SEL plus RUX in treatment-Naïve MF, 92% patients(pts) achieved SVR35, 69% had symptom response and 65% had stable or improved Hgb levels. We have presented promising efficacy and safety data in real-world setting of SEL plus RUX regimen in MF patients in 2023 ASH. Here we are to report the efficacy and safety of the regimen in RUX-treated patients in a prospective clinical trial.