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Exploring Use of Navitoclax in Conjunction With Ruxolitinib in Patients With MF Who are JAKi-Naïve
According to a presentation at the 64th ASH Annual Meeting and Exposition, researchers indicated that the combination of navitoclax for the treatment of primary or secondary myelofibrosis (MF) and ruxolitinib among patients who were classified as Janus kinase inhibitor (JAKi)-naïve provided promising and suggestive evidence of disease modification.
In the Cohort-3 of the Phase II multicenter study known as the REFINE study, researchers recruited and enrolled patients with either primary or secondary MF with splenomegaly who were also JAKi treatment-naïve.
In this study, Francesco Passamonti, MD, University Hospital Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi, University of Insubria, Varese, VA, Italy, sought to explore whether the type of MF and risks were linked with clinical outcomes and response indicative of variant allele frequency (VAF) decrease and improvement in bone marrow fibrosis (BMF) among JAKi treatment-naïve patients with MF who were treated with a combination of navitoclax and ruxolitinib.
The trial participants were initiated on navitoclax at 100 mg daily or 200 mg daily if baseline platelet count was measured at 150X109 or less, or greater than 150X109/L, respectively.
Moreover, ruxolitinib was administered in twice-a-day dosing and the initial dose was determined by the baseline platelet count per instructions.
Spleen volume reduction of 35% or higher from baseline to week 24 was noted as the primary outcome, and important secondary and exploratory endpoints assessed included a decrease in bone marrow fibrosis (BMF)and a decrease in variant allele frequency (VAF) for driver mutations ( JAK2v627, CALR or MPL) respectively.
The study involved a total of 32 patients who were treated with navitoclax and ruxolitinib, who were also assessed for biomarker analysis.
Results revealed that 81% of patients had BMF grade improvement, and of these patients, 35% had ≥ 1-grade improvement at some point during the treatment period and the average time to improvement was documented as 12.3 weeks.
Additionally, the researchers discovered that 22% of patients had a complete resolution of BMF.
From baseline at week 12 or week 24, a decrease in driver gene mutation variant allele frequency [VAF] over 20% was observed in 50% of patients, and 36% of patients have a greater than 50% VAF decrease from baseline.
The authors also indicated that there were no variations in VAF decreases higher than 20% from baseline to week 12 or week 24 when comparing patient with or without high molecular risk (HMR) mutations reporting 47% (accounting for 7 out of 15 patients) vs 54% (accounting for 7 out of 13 patients), respectively.
The presenters wrote, “Among JAKi treatment-naïve patients with MF, the combination of navitoclax and ruxolitinib reduced splenomegaly in several high-risk groups known to confer poor prognosis. Reductions in BMF and VAF were independent of HMR mutations,” adding, “The reduction in BMF and VAF for the driver mutation JAK2V617 is encouraging and suggestive of evidence of disease modification with the combination of navitoclax and ruxolitinib.”
Reference: Passamonti F, Foran J, et al. The Combination of Navitoclax and Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Mediates Responses Suggestive of Disease Modification. Presented at 64th ASH Annual Meeting and Exposition. December 10-13, 2022. New Orleans, Louisiana. Abstract: 237.
