Combining Ruxolitinib With Novel Agents Shows Promise as Treatment for Patients With Myelofibrosis
A combination of ruxolitinib with novel agents, the most effective of which was siremadlin, demonstrated feasibility and benefits among patients with myelofibrosis (MF) who experience suboptimal response to ruxolitinib monotherapy, according to results from the ADORE clinical trial (NCT04097821) published in Blood Advances.
Ruxolitinib remains the standard of care for symptomatic MF, but approximately 70% of patients discontinue treatment after five years, with a third citing inadequate splenic response. The ADORE trial employed an open platform design to evaluate multiple novel agents siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793 in combination with ruxolitinib.
Previous research has demonstrated efficacy for ruxolitinib-combination treatments for the treatment of MF. Researchers conducted a phase 1b/2 to evaluate the efficacy of ruxolitinib combined with siremadlin. The primary end point was incidence of dose-limiting toxicities (DLTs). Secondary end points were adverse event incidence and severity, change in spleen volume reduction (SVR), and change in total symptom score (TSS).
Overall, 44 patients with MF and suboptimal ruxolitinib response were enrolled to receive a ruxolitinib-based therapy regimen. More than half of patients (n= 23) received ruxolitinib plus siremadlin, of which 3 completed treatments. Treatment discontinuation occurred in 20 of these patients due to AEs (43.5%), decision from physician (30.4%), and progressed disease (8.7%).
Most patients had primary MF (65.2%), with the remaining having secondary MF post-polycythemia vera (30.4%) or essential thrombocythemia (4.3%).
The recommended phase 2 dose of siremadlin was determined to be 30 mg orally. Of patients who received this dose, 1 experienced grade 4 thrombocytopenia and grade 4 neutropenia. For all patients who received ruxolitinib plus siremadlin, the most common adverse events were grade 3 or higher anemia 60.9%), thrombocytopenia (47.8%), and neutropenia (47.8%).
At 24 weeks, 60% of patients who received ruxolitinib plus siremadlin achieved an SVR reduction of more than 35%. Additionally, 21.7% of patients achieved a 50% or more reduction in TSS from baseline by 48 weeks.
"ADORE represents an innovative approach in the development of combination treatments, and available data illustrate the potential benefits of combining agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone,” the researchers concluded.
They added, “among the combinations investigated, siremadlin 30 mg and ruxolitinib demonstrated the most promising safety and efficacy profile.”
Source:
Ross DM, Heidel FH, Perkins AC, et al. ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. Blood Advances. Published online May 7, 2025. doi:10.1182/bloodadvances.2025015860
