KEY TAKEAWAYS
- This phase 2 trial REFINE aimed to evaluate the efficacy and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary myelofibrosis.
- The trial’s primary objective is to achieve a 35% or more significant reduction in SVR35 from baseline by week 24.
- Patients who experienced disease progression or inadequate response while receiving stable ruxolitinib monotherapy were included in Cohort 1a of the study.
- The addition of navitoclax resulted in a 35% or more significant reduction in SVR35and reduced symptoms in myelofibrosis patients who were no longer responding to ruxolitinib.
- Biomarker analyses were performed on 33 patients, 19 of whom (58%) had mutations associated with high molecular risk.
- Navitoclax, combined with ruxolitinib, effectively reduces spleen volume and symptoms in myelofibrosis
patients who no longer respond to ruxolitinib.
In patients with myelofibrosis who were no longer responding to ruxolitinib, the addition of navitoclax resulted in a 35% or more significant reduction in spleen volume (SVR35) and reduced symptoms, according to primary analyses of the REFINE trial’s cohort 1a. The results of cohort 1a exploratory post hoc biomarker analysis are presented below. Patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis will participate in REFINE, a phase 2, multicenter, open-label trial to evaluate the efficacy and safety of navitoclax alone or in combination with ruxolitinib. Patients who experienced disease progression or inadequate response while receiving stable ruxolitinib monotherapy were included in Cohort 1a of the research. Cohort 1a patients who had been on ruxolitinib for 12 weeks or more kept taking their usual dose while navitoclax was started at 50 mg daily and increased by 50 mg per week up to a maximum of 300 mg per day, dependent on tolerability—the change in SVR35 from baseline by week 24. According to International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet criteria, and change in grade of bone marrow fibrosis according to European consensus grading were secondary endpoints; overall survival and survival and characterization were exploratory endpoints—the Myelofibrosis Symptom Assessment Form (version 4.0) measured symptoms. Potential predictive biomarkers of the effectiveness of navitoclax-based combination treatment in patients with a suboptimal response to ruxolitinib, such as bone marrow fibrosis and variant allele frequency, were studied in exploratory analyses. ClinicalTrials.gov currently lists this ongoing trial as NCT03222609.
At least one dosage of navitoclax + ruxolitinib was administered to 34 patients in cohort 1a between November 14, 2017, and April 10, 2019. Of the total number of patients, 23 (68% were male) and 32 (94% were White. The median follow-up time for survivors as of the data cutoff date (May 6, 2021) was 26.2 months (interquartile range [IQR] 21.9-32.3). Biomarker analyses were possible for 33 patients, 19 of whom (or 58%) had mutations associated with high molecular risk. At week 24, five out of sixteen patients (31%) in the high molecular risk group and four out of thirteen (31%) in the non-high molecular risk group achieved SVR35. Four out of eleven patients (36%), compared to two out of eight patients (25%), in the high molecular risk group had TSS50 at week 24; seven out of eighteen patients (39%), compared to five out of fourteen patients (36%), in the high molecular risk group had an improvement in fibrosis by at least one grade; and four out of fourteen patients (28%), compared to two out of twelve patients (17%), in the non-high molecular risk, the group had reductions in variant Overall survival was better for patients who achieved a grade 1 or greater improvement in fibrosis and a 20% or more significant decrease in variant allele frequency (median overall survival not reached; 95% CI 19 months to not estimable) than for patients who did not achieve either of these outcomes. Changes in spleen size were also positively related to shifts in the concentrations of vascular cell adhesion molecule-1 (r=0.58; r=0.50), TIMP metallopeptidase inhibitor 1 (r=0.47; r=0.54), tumor necrosis factor receptor type II (r=0.55; r=0.40), and -2-microglobulin (r=0.57; r=0.57).
Source:https://www.thelancet.com/action/showFullTableHTML?isHtml=true&tableId=tbl1&pii=S2352-3026%2822%2900116-8
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03222609
Naveen Pemmaraju, Jacqueline S Garcia, Jalaja Potluri, Jason G Harb, Yan Sun, Paul Jung
Qin Q Qin, Srinivas K Tantravahi, Prof Srdan Verstovsek, Prof Claire Harrison/Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study/https://doi.org/10.1016/S2352-3026(22)00116-8
