A Multicenter, Prospective, Observational Study of Jaktinib in Newly Diagnosed Myelofibrosis

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 myelofibrosis (PMF) is 67%, significantly higher than that observed in Western counterparts (35%), underscoring a critical unmet need for therapies that address both splenomegaly and 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. Advances in understanding this pathway have led to the development of JAK inhibitors, with ruxolitinib (2011), fedratinib (2019), pacritinib (2022), and momelotinib (2023) approved by the U.S. Food and Drug Administration (FDA) for the treatment of MF symptoms and splenomegaly. In China, ruxolitinib is the first JAK inhibitor approved for the treatment of MF. However, its efficacy in the Chinese population is modest, with a ≥35% spleen volume reduction (SVR35) rate of only 27% at week 24 (A2202 study), compared to 31.7% in Asian patients and 41.9% in Western patients (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. Hydroxyurea (HU) is commonly used as cytoreductive therapy in China, but its efficacy in treating MF-associated splenomegaly is variable and typically limited to approximately one year; nearly 50% of patients experience worsening anemia or cytopenia with HU therapy.

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 present with or are at risk of developing anemia. 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 III study ZGJAK016 (NCT04617028) compared jaktinib with HU in JAK inhibitor-naïve intermediate- to high-risk MF patients. The results demonstrated that jaktinib is superior to HU in reducing spleen size, with favorable safety and tolerability, and may offer potential improvements in patients' quality of life. Furthermore, 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, further validating its role in first-line management.

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 newly diagnosed MF treated 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 (e.g., 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 newly diagnosed MF, providing clinicians with data to optimize first-line treatment strategies and improve long-term outcomes in this patient population.