Watch our interview with Jacqueline Garcia, MD.
More than one-third of patients with myelofibrosis (MF) who had not responded adequately to monotherapy with the FDA-approved JAK inhibitor ruxolitinib and were then treated with a combination of navitoclax and ruxolitinib experienced a clinically meaningful spleen response and a reduction in total symptom score (TSS), according to results from a phase II study. The drug combination also resulted in reduced fibrosis in some patients, noted study co-author Jacqueline Garcia, MD, from Dana-Farber Cancer Institute in Boston, who presented these findings at the 2019 ASH Annual Meeting.
“At this time, there are no approved therapies for when patients have disease progression on ruxolitinib or when there’s evidence or concern for resistance in patients on long-standing ruxolitinib, so we rely heavily on investigational therapies,” Dr. Garcia told ASH Clinical News. “The combination of navitoclax and ruxolitinib looks to be promising.”
Navitoclax is a small molecule that binds with high affinity to BCL-XL, BCL2, and BCL-W, causing cell death by apoptosis, the authors explained. BCL-XL inhibition has been shown to overcome resistance to JAK inhibition, even in the JAK2-mutated setting, leading researchers to hypothesize that combining navitoclax with ruxolitinib could overcome JAK inhibitor resistance in this single-arm, open-label study.
A total of 34 patients were enrolled in the trial (median age = 68 years; range = 42-86). Sixteen patients had primary MF (47%), and 17 patients had high-risk mutations (52%; high-risk mutations were defined as ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1). All participants had received at least 12 weeks of continuous ruxolitinib therapy prior to initiation of study treatment and the median time on ruxolitinib prior to study entry was 21 months (range = 4-71).
Per study protocol, there was no washout period for ruxolitinib. Participants remained on their steady dose of ruxolitinib (at least 10 mg twice daily), then navitoclax was added on starting at a dose of 50 mg/day and increasing if tolerated to a maximum dose of 300 mg/day.
With no FDA-approved therapies for patients whose myelofibrosis progresses while on ruxolitinib, clinicians rely heavily on investigational therapies.
Patients were on navitoclax add-on therapy for a median of 330 days, “highlighting how well tolerated therapy was,” Dr. Garcia said, adding that 68% of patients (n=23) were able to titrate up to the maximum navitoclax level.
At data cutoff (November 18, 2019), 9 patients had discontinued study treatment, 3 due to an adverse event (AE), 2 for disease progression, and 4 for other, unidentified reasons.
As the researchers hypothesized, adding navitoclax to ruxolitinib overcame JAK inhibitor resistance, resulting in splenomegaly improvement for most patients (n=16/30; 53%). Of 30 patients who were evaluable for efficacy, 9 (30%) reached the primary endpoint of ≥35% reduction in spleen volume (SVR35) from baseline by week 24.
However, “when we looked at best response on study, we were pleasantly surprised to see that 43% of patients achieved an SVR35, suggesting that additional benefits could be seen beyond the first 6 months [of navitoclax and ruxolitinib],” Dr. Garcia said. “Longer follow-up may be needed to fully appreciate the overall response.”
In addition, 25% of patients experienced at least a grade 1 reduction in bone marrow fibrosis, which may be consistent with disease modification.
The combination treatment also resulted in a reduction in symptom burden, measured by TSS. At baseline, median TSS was 12 (range = 0-30); at week 24, the score had dropped to 7 (range = 0-23). Of 17 patients who were evaluable for TSS, 11 (65%) experienced a reduction from baseline symptom level, including 6 (35%) with a ≥50% reduction.
In the safety analysis, which included all 34 enrolled patients, every participant experienced at least 1 any-grade AE, while 8 patients (24%) experienced a serious AE. The most commonly reported serious AEs included anemia, pancytopenia, splenic infarction, and upper abdominal pain. No serious single AE occurred in more than 1 patient, the authors noted, but 1 patient experienced a grade 5 AE (pneumonia) that was considered unrelated to navitoclax administration. Among the 15 patients (44%) who experienced grade ≥3 thrombocytopenia, events were manageable and reversible with temporary dose hold or modification, Dr. Garcia reported.
Although the results are promising, the study’s implications are limited by the small patient population and the lack of a comparator arm. Dr. Garcia noted that ongoing trials are continuing to evaluate the navitoclax and ruxolitinib combination, as well as navitoclax monotherapy, in patients with MF.
Study authors report relationships with AbbVie, which sponsored the trial.
Harrison CN, Garcia JS, Mesa RA, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Abstract #671. Presented at the 2019 ASH Annual Meeting, December 9, 2019; Orlando, FL.