Adding navitoclax to ruxolitinib treatment in patients with persistent or progressive myelofibrosis (MF) led to durable spleen volume reduction and improved total symptom scores, according to the results of a phase II clinical trial.
The results of the open-label, multicenter trial, led by Claire Harrison, BMBCh, DM, FRCP, FRCPath, of Guy’s and St. Thomas’ National Health System Foundation Trust, were published in the Journal of Clinical Hematology.
The trial included 34 adults with intermediate to high-risk MF who had disease progression or suboptimal response while on a stable dose of ruxolitinib 10 mg or more twice daily. All patients additionally received navitoclax 50 mg once daily as a starting dose, escalating in weekly increments to a maximum dose of 300 mg once daily if platelets were ≥75 × 109/L.
The trial’s primary endpoint was spleen volume reduction ≥35% (SVR35) at week 24 compared to baseline. Secondary endpoints included a reduction in total symptom score of at least 50% (TSS50) at week 24 compared to baseline, as well as hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety.
SVR35 was reported in 26.5% of patients at week 24. A total of 41% patients reached SVR35 at any point during the study, with this response reported as late as week 72. The estimated median duration of SVR35 was 13.8 months (95% CI, 8.2 to not estimable).
TSS50 was reported in 30% of patients at week 24, while BMF improved by one to two grades in 33% of evaluable patients. Anemia response was reported in 64% of patients, including a patient who had baseline transfusion dependence.
The median overall survival (OS) was not reached after a median follow-up of 21.6 months, the authors reported. The estimated survival at 24 months was 84% (95% CI, 63.0-93.9).
“It is encouraging that, although this cohort comprises patients who had suboptimal response to ruxolitinib, median OS was [not reached] at a median follow-up of 21.6 months,” the authors wrote. “This suggests that the addition of navitoclax to ruxolitinib may result in increased OS compared with conventional (eg, danazol, hydroxyurea, etc.) or targeted (eg, investigational JAK2 or non-JAK2 inhibitors, etc.) therapies received after ruxolitinib discontinuation.”
High-molecular-risk mutations were identified in 58% of patients, and 52% harbored at least three mutations. There was no significant difference in OS between patients with high-molecular-risk mutations (n = 19; not reached; 95% CI, 19.6 to not estimable) and those without high-molecular-risk mutations (n = 14; not reached; 95% CI, 26.1 to not estimable).
“Combining navitoclax with ongoing ruxolitinib was manageable in this difficult-to-treat population, demonstrating encouraging and durable efficacy outcomes for this patient population who have limited treatment options,” the authors wrote.
These findings are “potentially significant” for this population of patients, but the trial’s open-label design, small sample size, and lack of comparison group limit its interpretation, according to the authors.