ASH 2023: Navitoclax And Ruxolitinib Trials to Treat Myelofibrosis

Janus kinase (JAK) inhibitors are used to stop signaling pathways and growth factors in myelofibrosis. They also provide symptom improvement and spleen volume reduction in patients with myelofibrosis. At the 65th Annual American Society of Hematology (ASH) conference in 2023, Dr. Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston, discussed an abstract that utilized a JAK inhibitor combined with navitoclax, a BCL-2 inhibitor that showed successful results. 

Phase III TRANSFORM-1 Trial

TRANSFORM-1 is an ongoing, phase 3 study designed to see if a combination of navitoclax and ruxolitinib was more effective and safe in the assessment of change in spleen volume when compared to ruxolitinib alone in participants with myelofibrosis.

Results showed:

• Spleen volume reduction of 63.2% in the navitoclax/ruxolitinib group vs. 31.5% in the placebo group. This was the first randomized trial in JAK inhibitor naive patients with navitoclax + ruxolitinib that led to a spleen reduction rate that as twice as high as those patients receiving ruxolitinib alone
• Most patients were male, with a median age of 69
• Adverse side effects were experienced by 85% of the navitoclax/ruxolitinib group vs 70% of the placebo group
• Adverse side effects included: low platelet count, anemia, diarrhea, pneumonia, low neutrophil levels
• Side effects were determined to be manageable with medication dose changes

Earlier Results from the Phase 2 REFINE Trial

Results published from this trial in 2022 showed that the addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib.

Patients who were in the group receiving navitoclax + ruxolitinib: 

• Received ruxolitinib for 12 weeks or more with disease progression
• Navitoclax (50mg-300mg) was added to the treatment regimen
• Myelofibrosis status improved with this drug combination
• Patients showed pronounced antitumor activity

Conclusion

“There remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival.” These two trials offer effective and important data for the ongoing treatment of myelofibrosis. Additional evaluation fo the phase 3 TRANSFORM trial is ongoig.