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Gecacitinib Elicits Hematologic Responses, Spleen and Symptom Reduction Across Anemic Subgroups in Myelofibrosis

Gecacitinib, a dual JAK/ACVR1 inhibitor, showed spleen volume, symptom and anemia improvements in patients with myelofibrosis.

Myelofibrosis | Image credit: © Om.Nom.Nom - stock.adobe.com

Myelofibrosis | Image credit:

© Om.Nom.Nom - stock.adobe.com

The dual JAK/ACVR1 inhibitor gecacitinib demonstrated a dual-directional regulation of hemoglobin in patients with myelofibrosis with varying baseline hemoglobin levels, alongside clinical benefits such as spleen volume reduction, symptom alleviation, and anemia improvement, according to data from a post hoc exploratory analysis of the phase 3 ZGJAK016 trial (NCT04617028).1

Findings presented at the 2025 ASCO Annual Meeting showed that, across subgroups, the spleen volume reduction of at least 35% (SVR35) rates and the Total Symptom Score (TSS50) at week 24 were comparable and consistent with that observed in the intention-to-treat (ITT) population (n = 71). In the ITT population, the SVR35 rate at week 24 was 64.8%, and the TSS50 rate at week 24 was 62.0%.

“[Patients with] myelofibrosis post–polycythemia vera [PV] with elevated baseline hemoglobin exhibited the greatest hemoglobin decrease,” lead study author Yi Zhang, PhD, and colleagues wrote in a poster presentation. “Gecacitinib demonstrated 3 key benefits…for JAK inhibitor-naive myelofibrosis patients across all baseline anemia severities (mild, moderate, or severe), with an acceptable and manageable safety profile.”

Zhang is a professor in the Department of Hematology at The First Affiliated Hospital at Zhejiang University School of Medicine in Hangzhou, China.

Background and ZGJAK016 Trial Design

The double-blind, randomized phase 3 study evaluated the efficacy and safety of gecacitinib for the treatment of patients 18 to 75 years of age with primary myelofibrosis according to World Health Organization 2016 criteria, post-PV myelofibrosis according to International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment criteria, and high risk or intermediate-2 risk as defined by the Dynamic International Prognostic Scoring System (DIPSS) for Primary Myelofibrosis.2 Patients on the study were also required to have no plan to receive stem cell transplantation in the near future, a life expectancy of at least 24 weeks, palpable splenomegaly at least 5 cm below the left costal margin, peripheral blood blast count of 10% or less, and an ECOG performance status of 0 or 1.

Patients were randomly assigned to receive either oral gecacitinib twice daily or oral hydroxycarbamide twice daily. Of note, patients who were randomly assigned to the gecacitinib arm were categorized post hoc into subgroups according to whether their baseline hemoglobin levels were less than 100 g/L (moderate to severe anemia; n = 47), 100 g/L to the lower limit of the normal (LLN; mild anemia; n = 11), LLN to the upper limit of the normal (ULN; normal hemoglobin levels; n = 10), or more than ULN (elevated hemoglobin; n = 3).1

The primary end point was the proportion of patients with a SVR35 at week 24. Secondary end points included the proportion of patients with a TSS50, and a transfusion independence (TI) rate at week 24, which was defined as no red blood cell transfusions and no hemoglobin levels of lower than 80 g/L in the last 12 weeks before week 24.

Baseline Patient Characteristics

Among patients in the ITT population, approximately half had hemoglobin levels of less than 100 g/L (n = 47). In this subgroup, the median age was 63.2 years (SD, 8.7), in which 48.9% of patients were older than 65 years of age, and 51.1% were 65 years of age or older. Regarding DIPSS, 83.0% had intermediate-2–risk disease and 17.0% had high-risk disease. Notably, the mean MPN Symptoms Assessment Form TSS was 19.6 (SD, 13.8). The Independent Review Committee spleen volume was 1436.6 cm3, and the mean investigator-assessed spleen volume was 1710.9 cm3. Additionally, 87.2% of patients did not have transfusion dependence. Furthermore, 48.9%, 46.8%, and 4.3% of patients had present JAK2 V617F mutations, an absence of the mutation, or other, respectively. The majority of patients did not display CALR mutations (72.3%) or MPL W515L/K mutations (91.5%). Of note, the majority of patients had previously received 1 or more lines of therapy for myelofibrosis (70.2%). The mean time from myelofibrosis diagnosis was 1.4 years (SD, 2.6). The most common myelofibrosis subtype was primary myelofibrosis (80.9%), and the most common staging was myelofibrosis-3 (61.7%).

Additional Efficacy and Safety Data

In the ITT population, TI at baseline was observed in 69.0% of patients, and in 73.5% at week 24; non-TI at baseline was observed in 31.0% of patients, with 36.4% achieving TI at week 24. In patients with moderate to severe anemia, TI was observed in 55.3%, with 57.7% at week 24; non-TI at baseline was observed in 44.7% of patients, with 38.1% achieving TI at week 24. In those with mild anemia, TI at baseline was observed in 90.9%, of which 90.0% had TI at week 24; non-TI was observed in 9.2% of patients at baseline, none of whom achieved TI at week 24. Among patients with normal hemoglobin and elevated hemoglobin levels, TI at baseline was 100% in both groups, with 90.0% and 66.7% at week 24, respectively. No non-TI observations at baseline or TI at week 24 were reported in these 2 subgroups.

“Mean hemoglobin levels increased by week 2 across all gecacitinib subgroups. In the anemia subgroups, levels remained stable thereafter,” the study authors wrote. “In the normal subgroup, levels slightly decreased but remained above 110 g/L. In the elevated hemoglobin subgroup, levels showed a marked decrease. [Overall,] mean platelet counts decreased by week 2, except in the elevated hemoglobin subgroup, and then remained stable.”

Regarding safety, the incidence of grade 3 or greater treatment-emergent adverse effects (TEAEs) was similar among patients with anemia and the ITT population. However, grade 3 anemia was slightly higher in the group of patients with anemia compared with the ITT population (36.2% vs 26.8%). Furthermore, incidences of TEAEs leading to treatment discontinuation were comparable in the anemia vs ITT population (6.4% vs 7.0%).

In the ITT population, the most common TEAEs occurring in at least 20% of patients included thrombocytopenia (any grade, 38%; grade 3 or higher, 15.5%), anemia (36.6%; 26.8%), upper respiratory tract infection (15.5%; 0%), and leukopenia (14.1%; 2.8%). The most common TEAEs among patients with mild anemia were also thrombocytopenia (43.1%; 15.5%), anemia (32.8%; 31%), upper respiratory tract infection (17.2%; 0%), and leukopenia (17.2%; 3.4%). Moreover, patients with moderate to severe anemia experienced thrombocytopenia (46.8%; 17.0%), anemia (36.2%; 36.2%), upper respiratory tract infection (21.3%; 0%), and leukopenia (21.3%; 4.3%).

References

  1. Zhang Y, Zhou H, Zhuang J, et al. An exploratory analysis of myelofibrosis (MF) patient subgroups by baseline hemoglobin levels in the gecacitinib phase 3 trial. J Clin Oncol. 2025;43(suppl 16):6571. doi: 10.1200/JCO.2025.43.16_suppl.657
  2. Jaktinib versus hydroxycarbamide in subjects with intermediate-2 or high-risk myelofibrosis. ClinicalTrials.gov. Updated November 13, 2023. Accessed June 18, 2025. https://clinicaltrials.gov/study/NCT04617028

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