Abstract
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.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
