Efficacy and safety of gecacitinib in thrombocytopenic myelofibrosis patients

Abstract Introduction Despite recent advances in treating myelofibrosis (MF)-associated splenomegaly and symptoms, disease- and treatment-associated cytopenias remain challenging.Gecacitinib (GCA), a JAK and ACVR1 dual inhibitor, demonstrated spleen, symptom, and anemia benefits in intermediate- and high-risk MF. A matching-adjusted indirect comparison of GCA versus ruxolitinb (presented on 2025 EHA congress; PS1839) reported GCA offered a trend of higher splenic benefits and was associated with significantly less grade 3/4 anemia and neutropenia compared with ruxolitinib (RUX). To evaluate the efficacy and safety of GCA in patients with MF and thrombocytopenia (platelet counts <100 × 109/L), we conducted a post-hoc analyses with pooled data sets from 4 clinical studies: ZGJAK016 (phase 3; GCA versus hydroxyurea; JAK inhibitor naïve), ZGJAK002 (phase 2; GCA optimal dosing frequency exploration; JAK inhibitor naïve), ZGJAK006 (phase 2; GCA single arm; intolerant to RUX), and ZGJAK017 (phase 2; GCA single arm; refractory or relapsed to RUX). Methods Detailed study designs for these studies have been published. In the ZGJAK016 study, patients received randomized treatment for 24 weeks (main study period); thereafter, patients who didn't achieved a 35% reduction in spleen volume from baseline (SVR35) at week 24 could receive open-label GCA 100 mg BID for an extension period, whereas patients who achieved a SVR35 could continue receiving the initially assigned treatment. In the other 3 studies, patients received open-label GCA at different doses (100 mg BID, 150 mg QD and 100 mg QD) for 24 weeks (main study period) and then could continue in the extension period. The primary endpoint of these study was 24-week rate of SVR35. The key secondary endpoints included 24-week rate of total symptom score reduction by 50% or more (TSS50), improvement in anemia at week 24 (including the conversion rate of baseline transfusion-dependence to independence, proportion of non-transfusion-dependent patients with baseline hemoglobin ≤100 g/L achieving an increase of ≥20 g/L, and reduction in red blood cell transfusion frequency or unit by ≥50%). Data were pooled from patients with platelet counts <100 × 109/L at baseline who received at least one dose of GCA, with enrollment dates from 2019 to 2022. Only 1 patient in the hydroxyurea group from ZGJAK016 had platelet counts <100 × 109/L, thereby being excluded. These post hoc, exploratory, efficacy and safety analyses are descriptive. Results A total of 24 of 273 patients (9%) received GCA in ZGJAK016 (n=1), ZGJAK002 (n=3), ZGJAK006 (n=12) and ZGJAK017 (n=8) had baseline platelet counts <100 × 109/L (moderate thrombocytopenia) and only 1 patient (6%) had baseline platelet counts <50 × 109/L (severe thrombocytopenia). Of the 24 patients, 19 patients received 100 mg BID as initial dose (JAKi-naïve, n=4; RUX-intolerant, n=7; RUX-refractory/relapsed, n=8), 4 and 1 received 150 mg QD and 100 mg QD (all were RUX-intolerant). The SVR35 rate at week 24 were 75%, 42% and 25% in the JAKi-naïve, RUX-intolerant and RUX-refractory/relapsed patients. The TSS50 rate at week 24 were 50%, 33% and 50%, respectively. The proportion of non-transfusion-dependent patients with baseline hemoglobin ≤100 g/L achieving a ≥20 g/L increase in hemoglobin level by week 24 were numerically higher in the JAKi-naïve patients (67%, 50% and 50%). Mean platelet counts either increased or were maintained from baseline levels over the 24-week main period. Overall, 79% of 24 patients completed the main study period. Half of the patients had dose suspension or reduction due to adverse events and 3 patients with lower starting dose had a dose increase to 100 mg BID (2 in the main period and 1 in the extension period). After study termination, 8 patients continued to take GCA for compassionate use. As of the data cutoff (25 June 2025), 4 patients were receiving GCA, with all remaining on therapy for >4 years. A median duration of treatment was 17.4 months (range, 0.5-69.4 months). The most common (occurring in ≥10% of patients) treatment-emergent adverse events during the initial 24-week treatment were generally consistent with those reported in the overall population. One exception was a higher incidence of thrombocytopenia (Any grade: 67%; Grade ≥3: 46%), however most were manageable and only 2 led to discontinuation. Conclusions GCA represents a safe and effective treatment option for MF patients with moderate thrombocytopenia.