Jaktinib in Ruxolitinib-Treatment Failure Myelofibrosis: A Multicenter, Prospective, Real-World Observational Study

Myelofibrosis (MF) is a BCR::ABL1-negative myeloproliferative neoplasm (MPN) characterized by progressive splenomegaly, debilitating systemic symptoms, abnormal blood cell counts, and a risk of leukemic transformation. Patients often suffer from progressive anemia, thrombocytopenia, and systemic symptoms including fatigue, dyspnea, night sweats, weight loss, fever, and bone pain. Notably, the incidence of anemia at diagnosis in Chinese patients with primary MF (PMF) is 67%, significantly higher than that observed in Western counterparts (35%), underscoring a critical unmet need for therapies that address anemia in this population.

Mutations in JAK2, CALR, or MPL genes, found in approximately 90% of patients, lead to hyperactivation of the JAK-STAT pathway, which is pivotal in the pathogenesis of MF. JAK inhibitors have become a cornerstone of MF treatment. Ruxolitinib, a selective JAK1/JAK2 inhibitor, was the first approved JAK inhibitor and has demonstrated efficacy in reducing spleen size and improving symptoms. However, its long-term use is limited by several factors. In the Chinese population, the SVR35 rate at week 24 is only 27% (A2202 study), which is lower than the rates reported in Asian (31.7%) and Western populations (41.9% in COMFORT-I). Furthermore, treatment-related anemia and thrombocytopenia frequently necessitate dose reductions or discontinuation, with over 60% of patients requiring dose modification due to adverse events. Ultimately, a substantial proportion of patients discontinue ruxolitinib because of loss of response, lack of efficacy, or intolerance. After ruxolitinib discontinuation, the median survival is only 13 months, with worse outcomes in patients who also have anemia and thrombocytopenia. In China, treatment options for patients with ruxolitinib failure remain limited. Therefore, there is an urgent unmet clinical need for effective and well-tolerated therapies for MF patients who have failed ruxolitinib.

Jaktinib (also known as gecacitinib) is a novel inhibitor targeting both JAK and ACVR1. By inhibiting JAK1, JAK2, JAK3, and TYK2, it blocks the JAK-STAT signaling pathway, thereby alleviating inflammation and splenomegaly. Through a mechanism shared with momelotinib, jaktinib inhibits ACVR1 activity, which downregulates hepcidin expression, improves iron metabolism imbalance, and increases hemoglobin levels, thereby reducing the occurrence of anemia and transfusion dependency in patients with MF. This dual mechanism makes jaktinib particularly well-suited for MF patients who have developed anemia during or after ruxolitinib therapy.

Multiple clinical trials of jaktinib in MF have been conducted in China. The phase II study ZGJAK002 (NCT03886415) enrolled 118 patients with intermediate- or high-risk MF and demonstrated a SVR35 rate of 44.5% at week 24 (54.8% in the 100 mg twice-daily group vs. 31.3% in the 200 mg once-daily group, p = 0.0199), with TSS50 response rates of 69.6% and 57.5%, respectively, and low incidences of grade ≥3 drug-related anemia (24.0%) and thrombocytopenia (12.5%). The phase II study ZGJAK006 (NCT04217993) specifically evaluated jaktinib in patients with MF who were intolerant to ruxolitinib, demonstrating a SVR35 rate of 43.2% (95% CI 29.7%-57.8%) at week 24 with tolerable hematological toxicity. The phase II study ZGJAK017 (NCT04851535) further evaluated jaktinib in patients with MF who were resistant to ruxolitinib, and the phase III study ZGJAK016 (NCT04617028) compared jaktinib with hydroxyurea in JAK inhibitor-naïve MF patients. The 2026 Guidelines of the Chinese Society of Clinical Oncology (CSCO) have recommended jaktinib as a Category I core agent for patients with intermediate- or high-risk MF, as well as low-risk MF with symptomatic disease.

Given this robust clinical evidence, the present multicenter, prospective, real-world observational study aims to evaluate the effectiveness and safety of jaktinib in patients with MF who have failed ruxolitinib treatment (including refractory, relapsed, or intolerant cases) under routine clinical practice. As a non-interventional study, it will not influence treatment decisions but will systematically capture longitudinal data to reflect actual clinical outcomes. The primary endpoint is the proportion of patients achieving anemia response at week 24, defined as an increase in hemoglobin level or a reduction in transfusion requirement according to predefined criteria (IWG-MRT criteria). Secondary endpoints include MF-related symptom response rate (≥50% reduction in MPN-SAF TSS, TSS50) at week 24, the proportion of patients achieving ≥35% spleen volume reduction (SVR35) at week 24, progression-free survival (PFS), leukemia-free survival (LFS), overall survival (OS), and safety/tolerability assessed by adverse events, serious adverse events, laboratory abnormalities, and treatment discontinuation rates.

This study will generate essential real-world evidence on jaktinib in MF patients with ruxolitinib failure, providing clinicians with data to optimize treatment strategies and improve outcomes in this challenging patient population.