SUMMARY: Myelofibrosis (MF) is a progressive MyeloProliferative Neoplasm (MPN) characterized by bone marrow fibrosis, anemia, splenomegaly, and systemic symptoms. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact quality of life of an individual. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET).
The disease is frequently driven by mutations in JAK2, CALR, or MPL, with aberrant JAK-STAT signaling contributing to excessive inflammatory cytokine production, clonal proliferation, and cytopenias. Notably, thrombocytopenia (platelet count ≤100 × 10⁹/L) is a marker of high-risk disease, associated with poor prognosis and limited treatment options due to the hematologic toxicity of existing JAK inhibitors like Ruxolitinib and Fedratinib.
JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.
Pacritinib (VONJO®) is a JAK2/IRAK1/ACVR1 inhibitor with minimal JAK1 activity, allowing it to be administered at full dose in patients regardless of baseline platelet count. It is FDA-approved for the treatment of intermediate- or high-risk MF with platelet counts <50 × 10⁹/L.
PERSIST-2 Trial Design
PERSIST-2 was a randomized, controlled Phase 3 study evaluating Pacritinib in MF patients with baseline thrombocytopenia (platelets ≤100 × 10⁹/L), regardless of prior JAK inhibitor exposure. This study evaluated Pacritinib in MF patients with thrombocytopenia, a population typically underrepresented in prior JAK inhibitor trials.
Study Arms:
- Pacritinib 200 mg twice daily (BID) – now FDA-approved dose
- Pacritinib 400 mg once daily – discontinued due to unfavorable tolerability
- Best Available Therapy (BAT) – including low-dose Ruxolitinib
Patient Population (N=311):
- Median platelet count: ~54 × 10⁹/L
- 46% had received prior Ruxolitinib
- 63% were transfusion-dependent at baseline
Primary and Secondary Endpoints
- Primary endpoint: Proportion of patients achieving ≥35% Spleen Volume Reduction (SVR35) at Week 24, measured by MRI or CT.
- Key secondary endpoint: ≥50% reduction in Total Symptom Score (TSS50) based on the Myelofibrosis Symptom Assessment Form (MFSAF v2.0).
Primary Results:
Among patients receiving Pacritinib 200 mg BID (N=74) vs BAT (N=72):
- SVR35 at Week 24: 22% vs 3% (P=0.001)
- TSS50 at Week 24: 25% vs 14% (not statistically significant)
- Red blood cell transfusion independence at Week 24: 37% vs 14% (P=0.04)
- SVR was consistent across platelet subgroups, including <50 × 10⁹/L
Landmark OS Analysis (2024): Early Spleen Response Predicts Survival
A retrospective landmark analysis was conducted using a Week 12 timepoint to evaluate the association between early Spleen Volume Reduction and Overall Survival (OS) in PERSIST-2. Patients alive and on study at the 12-week assessment were included (N=173; Pacritinib N=89, BAT N=84).
- SVR thresholds analyzed: ≥35%, ≥20%, ≥10% (SVR10), and >0% (SVR0).
- Most prognostic threshold: SVR10 at Week 12 showed the strongest association with improved OS for Pacritinib (HR: 0.00; 95% CI: 0.00–0.14; P<0.01). No deaths occurred among SVR10 responders.
- No OS benefit was observed with any SVR threshold in the BAT group, including among Ruxolitinib-treated patients.
These findings suggest that even modest Spleen Volume Reduction (≥10%) at Week 12 may serve as a prognostic marker for survival benefit in thrombocytopenic MF patients receiving Pacritinib, but not with BAT, including Ruxolitinib.
Clinical Implications and Conclusion:
This analysis is the first to demonstrate a survival advantage associated with spleen response in thrombocytopenic MF patients, a subgroup often ineligible for full-dose JAK2 inhibition. Given that SVR10 at Week 12 predicts better OS only in Pacritinib-treated patients, early spleen response may serve as a meaningful clinical benchmark for assessing benefit in this high-risk population. These findings reinforce the role of Pacritinib as a frontline option for Myelofibrosis patients with low platelet counts, and highlight the need for individualized treatment based on disease biology and cytopenia profile.
Pacritinib response is associated with overall survival in myelofibrosis: PERSIST-2 landmark analysis of survival. Ajufo H, Bewersdorf JP, Harrison C, et al. Eur J Haematol. 2025;114(2):238-247. doi:10.1111/ejh.14321
