The primary endpoint of 35% or greater reduction in spleen volume was met with manageable safety.

  • Major Finding: The primary endpoint of 35% or greater reduction in spleen volume was met with manageable safety.

  • Concept: Thrombocytopenia without clinically significant bleeding was the most common adverse event and was reversible.

  • Impact: This combination demonstrated safety and durable efficacy in this difficult-to-treat population.

The JAK/STAT signaling pathway is constitutively activated in myelofibrosis and drives disease progression as well as overexpression of antiapoptotic B-cell lymphoma proteins, such as BCL-Xl and BCL-2. As preclinical models have shown that resistance to JAK inhibitors can be overcome by also targeting BCL-XL, Harrison and colleagues conducted a phase II clinical trial to evaluate the combination of navitoclax, a BCL-XL/BCL-2 inhibitor, with the JAK/STAT inhibitor ruxolitinib in 34 patients with myelofibrosis who progressed or suboptimally responded to ruxolitinib monotherapy. The primary endpoint was a 35% spleen volume reduction (SVR35) at 24 weeks, and the secondary endpoints were a greater than 50% reduction in total symptom score after 24 weeks and a change in grade of bone marrow fibrosis (BMF). The primary endpoint of the study was met, with nine (26.5%) patients achieving SVR35 at 24 weeks and 14 (41%) patients achieving SVR35 at any point in the study. A 50% reduction of spleen length was observed in 17 (50%) patients at the 24-week time point in addition to a 50% reduction in symptoms seen in six (30%) patients at week 24, with an improvement in BMF also being detected in 11 (33%) patients over the course of the study. The median overall survival was not reached. A majority (76%) of patients required navitoclax dose reduction due to adverse events (AE), most commonly thrombocytopenia—a known side effect of inhibition of BCL-XL, which is required for platelet survival. Ruxolitinib dose was also reduced in 68% of patients due to AEs. All 34 patients experienced at least one AE, with 88% having ≥ grade 3 AEs. The most common AEs of any grade included thrombocytopenia, diarrhea, fatigue, and nausea. No treatment-related deaths were observed. Thus, this study demonstrates that this treatment combination was safe and had encouraging and durable efficacy in this difficult-to-treat population, suggesting the need for its further evaluation in phase III studies, which are currently underway.

Harrison CN, Garcia JS, Somervaille TCP, Foran JM, Verstovsek S, Jamieson C, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. J Clin Oncol 2022 Feb 18 [Epub ahead of print].

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