In a phase II trial reported in the Journal of Clinical Oncology, Harrison et al found that the BCL-XL/BCL-2 inhibitor navitoclax showed activity in patients with myelofibrosis with disease progression or suboptimal response during ongoing ruxolitinib treatment.
As stated by the investigators, “Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models.”
Study Details
The international multicenter trial included 34 adult patients with intermediate- or high-risk myelofibrosis with progression or suboptimal response on a stable ruxolitinib dose of ≥ 10 mg twice daily. Patients were enrolled between October 2017 and April 2019. Oral navitoclax was added at a starting dose of 50 mg once daily, with once-weekly increases to a maximum of 300 mg once daily if platelet counts were ≥ 75 × 109/L. The primary endpoint was ≥ 35% spleen volume reduction (SVR-35) from baseline at week 24.
Responses
A total of 24 patients (71%) reached the maximum navitoclax dose of 300 mg once daily. SVR-35 at week 24 was achieved in nine patients (26.5%). Overall, 14 patients (41.2%) achieved SVR-35 at any time on study. Among all patients achieving SVR-35, median duration of response was 13.8 months (95% confidence interval [CI] = 8.2 months–not estimable).
KEY POINTS
- A ≥ 35% reduction in spleen volume was achieved in 26.5% of patients by week 24 and in 41.2% of patients overall.
- Median duration of response was 13.8 months.
Among 20 evaluable patients, ≥ 50% reduction in total symptom score from baseline on the Myelofibrosis Symptom Assessment Form version 4.0 was achieved in 6 (30%) at week 24. Among 11 patients with hemoglobin < 10 g/dL at baseline, 7 (64%) had anemia response, including 1 with transfusion dependence at baseline. Bone marrow fibrosis improved by 1 to 2 grades in 11 (33%) of 33 evaluable patients. With a median follow-up of 21.6 months (range = 6.7–28.9 months), median overall survival was not reached (95% CI = 26.1 months–not estimable), with an estimated survival at 24 months of 84%.
Adverse Events
The most common adverse events of any grade were thrombocytopenia (88%), diarrhea (71%), fatigue (62%), and nausea (38%). Grade ≥ 3 adverse events occurred in 30 patients (88%), most commonly thrombocytopenia (without clinically significant bleeding; 56%), anemia (32%), and pneumonia (12%). Serious adverse events occurred in 44% of patients, most commonly pneumonia (12%) and splenic infarction (6%). Adverse events led to discontinuation of navitoclax in five patients (15%) and ruxolitinib in two (6%). No treatment-related deaths were reported.
The investigators concluded, “The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR-35, improved total symptom score, hemoglobin response, and bone marrow fibrosis. Further investigation is underway to qualify the potential for disease modification.”
Naveen Pemmaraju, MD, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was funded by AbbVie. For full disclosures of the study authors, visit ascopubs.org.
