Navitoclax and Ruxolitinib Show Potential in Treating R/R Myelofibrosis

Navitoclax (AbbVie) in combination with ruxolitinib (Jakafi; Incyte Corp) demonstrated durable responses and evidence of potential disease modification in relapsed/refractory (R/R) myelofibrosis (MF), according to data from the phase 2 REFINE trial (NCT03222609).¹

Red blood cells | Image Credit: © Q STOCK - stock.adobe.com

MF is a fatal myeloproliferative neoplasm characterized by reduced red blood cell production that leads to fibrosis of the bone marrow. Ruxolitinib, a Janus tyrosine kinase inhibitor, is the standard of care first-line treatment for MF, and it is capable of managing symptoms, as well as reducing fibrosis. It was approved by the FDA in 2011 and is indicated for the treatment of patients with high-risk MF.^2,3

In the phase 2 open-label, multicenter REFINE trial, a combination therapy of navitoclax and ruxolitinib was associated with tolerable safety and favorable reductions in spleen volume and overall symptoms. Navitoclax is an oral BCL-XL/BCL-2 inhibitor that induces apoptosis of malignant cells in MF, which study results suggest have improved benefits when combined with ruxolitinib. The REFINE trial evaluated navitoclax as a monotherapy compared with navitoclax plus ruxolitinib in 125 patients with R/R MM, who were separated into 2 groups: cohort 1a and cohort 1b.⁴

Cohort 1a received ruxolitinib ≥10 mg twice daily for ≥12 weeks and navitoclax 50 mg per day, with escalation to ≤300 mg if platelet count was ≥75 x 109/L. In cohort 1b, the participants received navitoclax 100/200 mg per day if platelet count was ≤150 or >150 x 109/L. The primary end point was spleen volume reduction of 35% or more (SVR35) at Week (W) 24, with secondary end points including a reduction of 50% or more in total symptoms score (TSS50) at W24, changes in bone marrow fibrosis (BMF) grade, anemia response, and safety.⁴

At the 21-month follow-up, SVR35 rate was 23% at week 24 and 39% at any time on study (median duration of 11 months). There was a TSS50 rate of 24% at week 24 and 46% at any time on study. BMF improved by ≥1 grade in 39% of patients receiving the combination treatment, and 23% of patients achieved an anemia response. The median overall progression-free survival were 52.3 months for patients on the combination and 22.1 months for those on the monotherapy.⁴

The most common adverse event was thrombocytopenia at 86% without clinically significant bleeding. However, this was manageable and reversible with a dose adjustment.⁴

The findings from the trial highlight the potential benefit of combining navitoclax with ruxolitinib for patients with R/R MF, offering potential disease modification alongside symptom and spleen volume reduction. These results underline the importance of continued research to optimize treatment strategies for this challenging condition and provide hope for improved outcomes for patients with MF.

REFERENCES

1. A study evaluating tolerability and efficacy of navitoclax alone or in combination with ruxolitinib in participants with myelofibrosis (refine). ClinicalTrials.gov Identifier: NCT03222609. Updated June 27, 2024. Accessed November 22, 2024. https://clinicaltrials.gov/study/NCT03222609

2. Study finds ruxolitinib may slow fibrosis progression in myelofibrosis. Pharmacy Times. September 24, 2024. Accessed November 22, 2024. https://www.pharmacytimes.com/view/study-finds-ruxolitinib-may-slow-fibrosis-progression-in-myelofibrosis

3. Ruxolitinib plus pegylated interferon alfa-2a show promise in newly diagnosed polycythemia vera. Pharmacy Times. November 1, 2024. Accessed November 22, 2024. https://www.pharmacytimes.com/view/ruxolitinib-plus-pegylated-interferon-alfa-2a-show-promise-in-newly-diagnosed-polycythemia-vera

4. Pemmaraju N, Somervaille T, Palandri F, et al. Addition of navitoclax to ruxolitinib in patients with myelofibrosis with progression or suboptimal response. Blood Neoplasia. November 2, 2024. doi:10.1016/j.bneo.2024.100056