# Preliminary Safety and Efficacy of Navitoclax Plus Ruxolitinib in Janus Kinase Inhibitor‐Naïve Patients With Myelofibrosis From the Multicenter, Open‐Label, Phase 2 Study (REFINE)

## TL;DR

A clinical trial found that combining navitoclax and ruxolitinib is safe and effective for treating myelofibrosis patients who haven't used JAK inhibitors before.

## Contribution

The study presents new evidence on the safety and efficacy of combining navitoclax and ruxolitinib in JAKi-naïve myelofibrosis patients.

## Key findings

- 63% of patients achieved a 35% reduction in spleen volume within 24 weeks.
- 41% of patients achieved a 50% reduction in symptom scores within 24 weeks.
- BMF improved in 48% of patients and anemia response rates were high.

## Abstract

Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti‐apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B‐cell lymphoma (BCL)‐XL/BCL‐2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi‐naïve patients with myelofibrosis. JAKi‐naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate‐2 and high‐risk myelofibrosis, and ECOG 0–2) and platelet count > 100 × 109/L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 109/L or > 150 × 109/L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR35) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS50) at week 24, change in grade of BMF, anemia response, and safety. Thirty‐two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow‐up was 44 months (5–58). 63% (20/32) of patients achieved SVR35 at week 24; median (range) time to first SVR35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS50 at week 24; median (range) time to first TSS50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion‐independent and 100% (2/2) for transfusion‐dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi‐naïve patients with myelofibrosis.

NCT03222609.