PURPOSE Targeting the BCL-X_L pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-X_L/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 10⁹/L). The primary end point was ≥ 35% spleen volume reduction (SVR₃₅) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS₅₀) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR₃₅ was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR₃₅ of 13.8 months. TSS₅₀ was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR₃₅, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.