JAK inhibitors are approved first-line therapy for patients with myelofibrosis (MF) with proven ability to reduce symptoms and induce spleen responses but do not have a well-established effect on the underlying mechanisms of disease progression. Many patients with preexisting cytopenias are often ineligible for JAK inhibitors, and those who do receive JAK inhibitor therapies can relapse and/or become refractory, thus being forced to terminate this treatment. Such patients are generally faced with poor prognosis, indicating a therapeutic need. One potential candidate to fill this void in the MF treatment landscape is tagraxofusp (TAG, SL-401), which is currently approved by the US Food and Drug Administration and European Medicines Agency for blastic plasmacytoid dendritic cell neoplasms. TAG is targeted against CD123, a protein expressed on myeloid cells and progenitors associated with MF disease progression. The goal of the present study is to evaluate safety and efficacy of TAG in patients with relapsed/refractory (R/R) MF.
In this phase 1/2 study, 39 patients with a median age of 70 years (range, 54-87 years) diagnosed with R/R MF were treated with TAG monotherapy. Patients in the stage 1 dose-escalation group (n = 4) received 7, 9, or 12 mcg/kg/day TAG intravenously on days 1 to 3, every 21 days (cycles 1-4), every 28 days (cycles 5-7), and every 42 days (for cycles 8+). Enrollment in the stage 2 expansion group (n = 35) was restricted to patients who met the Dynamic International Prognostic Scoring System-Plus intermediate-2 or high-risk disease criteria, were R/R or intolerant to JAK inhibitor therapy, and were not eligible for immediate allogeneic stem-cell transplantation. Patients in the stage 2 cohort were treated with TAG at doses of 12 mcg/kg/day every 21 days (cycles 1-4) and every 28 days (cycles 5+). The most common adverse events (incidence ≥10%) among patients treated with TAG were hypoalbuminemia (39%), headache (28%), pyrexia (31%), thrombocytopenia (26%), and elevated alanine aminotransferase (18%). Three patients experienced capillary leak syndrome (grade 3 or 4, 1 patient each) but was not associated with death.
Molecular mutations were observed in JAK2 (62%), CALR (8%), MPL (5%), and ASXL1 (23%). Cytogenetic abnormalities were observed in 10 patients. At baseline, 64% of patients had thrombocytopenia (<100 × 109/L), 21% had monocytosis (≥1.0 × 109/L), and 74% had splenomegaly. Of 24 evaluable patients, 13 with baseline splenomegaly achieved a spleen response, 3 with concomitant monocytosis, and 10 with concomitant thrombocytopenia. Spleen responses were assessed by spleen volume reduction in 15 patients of whom 7 (47%) achieved >10% reduction in spleen size, 4 (27%) had associated monocytosis and 7 (47%) had associated thrombocytopenia. Total symptom score (TSS) was reduced in 22 of 39 patients (56%), with 10 of 39 (26%) experiencing reductions in both TSS and spleen size versus baseline. In 14 patients, improvement of >50% in TSS scores was observed. Stable disease was achieved in 21 patients (60%). Median overall survival was 26.6 months (95% confidence interval, 9.0-51.1; range, 0.66-53.72). At the time of data cutoff (September 2021), 49% of patients were still alive.
Collectively, the current evidence validates the safety and efficacy of TAG monotherapy in MF patients who are refractory to JAK inhibitors and those with associated cytopenias and high-risk molecular mutations.
Source: Yacoub A, Patnaik MM, Ali H, et al. A phase 1/2 study of single agent tagraxofusp, a first-in-class CD123-targeted therapy, in patients with myelofibrosis that is relapsed/refractory following JAK inhibitor therapy. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 140.