Ferritin change and predictors of anemia response in ruxolitinib-intolerant myelofibrosis patients treated with gecacitinib

Abstract

Abstract Introduction Gecacitinib (GCA), a JAK and ACVR1 dual inhibitor, demonstrated spleen, symptom, and anemia benefits in myelofibrosis (MF) patients. To investigate ferritin dynamics and factors predicting anemia response in MF patients treated with gecacitinib, we conducted a post-hoc analysis with data from a phase 2 ZGJAK006 study. Methods This study enrolled ruxolitinib-intolerant patients with MF. The detailed study design has been published. This exploratory post-hoc analysis included patients with red blood cell (RBC) transfusions within 3 months before enrollment or baseline hemoglobin ≤100 g/L. Patients missing baseline ferritin data were excluded. Anemia response assessment was assessed using the following criteria: 1) Transfusion-dependent patients becoming transfusion-independent within the first 24 weeks ; 2) non-transfusion-dependent patients with baseline hemoglobin of ≤100 g/L demonstrating a hemoglobin increase of ≥20 g/L starting within the first 24 weeks and sustained for ≥12 weeks; and 3) a ≥50% reduction in RBC transfusion frequency or units within the first 24 weeks for patients who had received transfusions within 3 months before study entry. The primary endpoint was 24-week rate of a ≥35% reduction in spleen volume from baseline (SVR35). The key secondary endpoints included 24-week rate of total symptom score reduction by 50% or more (TSS50). To explore factors potentially influencing anemia response, the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used. Variables considered included age, sex, DIPSS assessment, MF subtype, JAK2 V617F mutation status, baseline TSS, transfusion status, spleen volume, hemoglobin levels, and ferritin levels, time from diagnosis to initiation of gecacitinib, and prior ruxolitinib exposure. Results A total of 40 patients were included. The median baseline ferritin level was 735.9 ng/mL (range 49.8 to 5669.3), with 28 patients (70.0%) exhibiting levels above normal and 14 (35.0%) exceeding 1000 ng/ml. Baseline ferritin was higher in the 19 patients who received RBC transfusion within 3 months prior to enrollment compared to those who did not (median 286.3 ng/ml [range 49.8 to 2765.4] vs 1534.9 ng/ml [range 180.9 to 5669.3]; P = 0.0001). Median baseline hemoglobin was 77.5 g/L (range 45.0 to 104.0). Most patients (39/40) initiated gecacitinib at 100 mg BID; one patient started at 150 mg QD and escalated to 100 mg BID on day 16. By week 24, 19 patients (47.5%) achieved an anemia response. Among 20 patients who were transfusion-free within 3 months pre-study, responders had numerically lower baseline ferritin versus non-responders (median 241.4 [range 49.8 to 1224.0] ng/mL vs 339.5 [range 130.1 to 2765.4] ng/mL). Conversely, in previously transfused patients, responders exhibited numerically higher baseline ferritin (median 1664.7 ng/mL [range 398.6 to 5669.3] vs 1331.3 ng/mL [range 180.9 to 5585.5]). LASSO regression analysis identified 5 baseline predictor variables, including MF subtype, transfusion status, HGB levels, JAK2 mutation status and spleen volume. Multivariate logistic regression confirmed an association between anemia response and the presence of JAK2 mutation only (P = 0.0208). Patients achieving anemia response showed decreasing median ferritin levels from week 6 through week 48, with a median change of -109.5 ng/ml (IQR -240.3 to 106.2) and -321.2 ng/ml (IQR -422.9 to 19.0) from baseline to weeks 24 and 48, respectively. Platelet counts demonstrated a modest increasing trend in anemia responders. The SVR35 rate at week 24 was 57.9% (11/19) in anemia responders versus 19.0% (4/21) in non-responders (P = 0.0211). The TSS50 rate at week 24 was 63.2% (12/19) in responders and 42.9% (9/21) in non-responders (P = 0.2248). As of June 25, 2025, 18 patients (12 responders and 6 non-responders) remained on gecacitinib. The median treatment duration was 3.8 years (range 0.3 to 5.0) for responders and 1.5 years (range 0.0 to 4.3) for non-responders (P = 0.0039). Conclusions In our study, JAK2 mutation was significantly associated with anemia response to gecacitinib in ruxolitinib-intolerant MF patients. Ferritin decreased rapidly in patients achieving anemia response. Anemia responders showed significantly higher spleen response and longer treatment duration, with numerically higher symptom response.