Add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: a randomized phase 3 study.

BACKGROUND

Ruxolitinib (JAK1/JAK2 inhibitor) is indicated for adults with intermediate or high-risk myelofibrosis; however, a subset of patients may exhibit a suboptimal response due to persistent PI3K/AKT activation. The phase 3, randomized, double-blind, placebo-controlled LIMBER-304 study (NCT04551053) investigated the efficacy and safety of add-on parsaclisib (highly selective PI3Kδ inhibitor) in patients with myelofibrosis and suboptimal or declining response to stable ruxolitinib monotherapy.

PATIENTS AND

METHODS

Adults with primary or secondary myelofibrosis who received ruxolitinib with palpable spleen and Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score (TSS) ≥10 were eligible. Primary end point was proportion of patients achieving ≥25% spleen volume reduction (SVR; baseline to week 24); key secondary end point was proportion of patients with ≥50% MFSAF-TSS reduction (baseline to week 24).

RESULTS

In total, 90 patients received parsaclisib/ruxolitinib; 87 received placebo/ruxolitinib. At week 24, 16.7% of patients receiving parsaclisib/ruxolitinib achieved ≥25% SVR vs 9.7% for placebo/ruxolitinib; this difference was not statistically significant. By week 24, ≥50% reduction in MFSAF-TSS was observed in 17.1% of patients receiving parsaclisib/ruxolitinib vs 14.1% for placebo/ruxolitinib. Higher rates of infections (including cytomegalovirus) and gastrointestinal disorders were observed with parsaclisib/ruxolitinib. Grade ≥3 treatment-emergent adverse events occurred in 60.0% of patients receiving parsaclisib/ruxolitinib vs 42.5% with placebo/ruxolitinib. The study was terminated early based on efficacy findings.

CONCLUSIONS

Study results suggested adding parsaclisib to stable-dose ruxolitinib was unlikely to offer clinically meaningful benefits. Further research is needed on the potential of JAK and PI3K inhibitor-based combination therapy for patients with myelofibrosis.