Single agent selinexor is active in patients with myelofibrosis refractory or intolerant to JAK inhibitors

Myelofibrosis (MF) is caused by expansion of mutated hematopoietic stem and progenitor cells that results in bone marrow (BM) fibrosis, ineffective erythropoiesis, elevated inflammatory cytokines, and extramedullary hematopoiesis. Most MF patients experience constitutional symptoms that impair quality of life. Cytopenias, thromboembolism, and leukemic transformation cause morbidity and mortality [ 1 ]. Aberrant JAK/STAT pathway activation by mutations in JAK2 , CALR , or MPL is central to MF pathogenesis, and JAK inhibitors (JAKis) are the standard of care. Ruxolitinib, the first JAKi approved for MF, effectively reduces spleen volume and symptoms in ~40% of patients, but many responses are only transient [ 2 ]. Myelosuppression frequently necessitates dose reduction, compromising symptom control. While JAK2 V617F variant allele frequency (VAF) and fibrosis are reduced in some patients, JAKis do not eliminate the malignant clone, leaving patients at risk of progression. The limited efficacy of JAKis has stimulated research into targeting other pathways involved in MF pathogenesis [ 3 ]. Although activity was observed for several agents, to-date, JAKis have remained the only FDA-approved MF drugs. Allogeneic stem cell transplant (SCT), while potentially curative, is associated with high morbidity and mortality, and many patients are ineligible [ 4 ].