The Efficacy and Safety of Selinexor Plus Ruxolitinib Regimen in Ruxolitinib-Resistant Myelofibrosis: A Retrospective Study

Background Myelofibrosis (MF) includes two types: primary MF (PMF) and post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF, also known as secondary MF (SMF). Perturbation of the JAK/STAT signaling pathway is the hallmark of MF. Despite the meaningful improvements JAK inhibitors provide in managing splenomegaly and symptoms, they do not significantly impact disease progression. Consequently, issues such as treatment failure, poor efficacy, leukemia progression, and safety concerns persist in managing MF, particularly in patients who respond poorly or are intolerant to the JAK inhibitor ruxolitinib (RUX). In recent years,Combination therapy with different mechanisms has emerged as a new approach to improve prognosis post-ruxolitinib. Selinexor (SEL), an oral XPO1 inhibitor, may inhibit MF through various pathways. The 2024 CSCO Guidelines for hematological malignancies recommend SEL as first-line treatment for PMF. Cell experiments have confirmed that selinexor has the potential to overcome JAK resistance. A parallel cohort phase 2 study reported that 71.42% of RUX-intolerant/resistant MF patients receiving the SEL plus RUX regimen had reduced spleen volume, and 38.09% achieved spleen response. Here, we report on the efficacy and safety of SEL combined with RUX in RUX-resistant MF patients in a retrospective study.

Method This is a retrospective single-center study aimed at evaluating the efficacy and safety of SEL combined with RUX regimen in RUX-resistant MF patients. The study included 21 MF patients with a poor response to RUX: 12 with PMF, 4 with post-PV MF, and 5 with post-ET MF. Patients received SEL at 20 mg, 40 mg, or 60 mg QW plus RUX (dosage determined by the investigator).

Result The median age is 56 (range, 37-71) years and the median duration of previous RUX treatment is 11.3 (6-39) months. 47.6% of patients had peripheral blood blasts of 1-9%. 16 (76.2%) patients harbored JAK2 mutations, 2 (9.5%) patients CALR mutations and 1 (5%) patient MPL mutations. All patients had splenomegaly, and 8 (38.1%) were transfusion-dependent. According to the DIPSS risk score, 11 patients (52.4%) were classified as high-risk, 5 (23.8%) as intermediate-2 risk, and 5 (23.8%) as unknown risk. Spleen size reduced in 16 (76.2%) patients with a median response time of 2.3 (1-3) months. Three patients underwent bridging to transplantation and are currently surviving with good recovery. Peripheral blood blasts decreased in 10 (47.6%) patients after one month of treatment. The most common adverse events during treatment were gastrointestinal reactions and cytopenias.

Conclusion The combination of SEL and RUX showed promising efficacy and manageable safety profile in RUX-resistant patients with myelofibrosis.

Keyword Selinexor; ruxolitinib; ruxolitinib-resistant; myelofibrosis