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Tagraxofusp was well tolerated and yielded modest efficacy signals as monotherapy in myelofibrosis.
Treatment with tagraxofusp-erzs (Elzonris) monotherapy did not lead to any dose-limiting toxicities (DLTs) and produced modest symptom score improvements in patients with myelofibrosis who were treatment naive or resistant/refractory to a prior JAK inhibitor, supporting further investigation of the agent as part of combination therapies, according to data from a phase 1/2 trial (NCT02268253).1
Findings published in Blood Neoplasia demonstrated that treatment-emergent adverse effects (TEAEs) did not lead to any dose reductions in patients treated with the agent at 12 µg/kg per day (n = 16). TEAEs led to dose interruptions in 44% of patients, with the most common including chills (n = 5), pyrexia (n = 5), and increased weight (n = 3). TEAEs led to treatment discontinuation in 22% of patients, which included capillary leak syndrome (CLS; n = 2), pneumonia (n = 2), dyspnea, embolism, fatigue, hypoalbuminemia, Clostridium difficile infection, and pyrexia (n = 1 each). TEAEs led to death in 14% of patients; however, none of these deaths were deemed treatment related. TEAEs leading to death included gastric perforation, septic shock, Clostridium difficile infection, intracranial hemorrhage, and pneumonia, with onset ranging from 11 to 22 following the final dose of tagraxofusp.
Regarding efficacy, at a median follow-up of 44.7 months (range, 8.6-50.4), patients in the relapsed/refractory population (n = 25) experienced an overall response rate of 4%, with the lone responder achieving a partial response. Seventy-two percent of patients had stable disease, 16% had progressive disease, and 8% were not evaluable for response. In patients with baseline splenomegaly (n = 16), 38% experienced any spleen volume reduction (SVR), including 2 patients with an SVR of at least 35% (SVR35); no patients achieved SVR35 at weeks 12 or 24, and the median time to best SVR response was 85 days (range, 15-1028). In the relapsed/refractory population, 60% experienced total symptom score (TSS) improvements at any time, including at least a 50% reduction in TSS (TSS50) at week 12 in 24% of patients, TSS50 at week 24 (16%), and TSS50 at any time (40%). The median time to TSS50 was 55 days (range, 23-239), and the median duration of TSS50 was 46 days (range, 15-989). The median progression-free survival (PFS) and overall survival (OS) in this population were 15.1 months (range, 3.1-19.1) and 19.3 months (range, 12.0-51.1), respectively.
In the treatment-naive population (n = 5), all patients experienced stable disease. In the 2 patients with baseline splenomegaly, 1 achieved any SVR. TSS improvements at any time were reported in 80% of patients, including 40% who reached TSS50. The median time to TSS50 was 43 days (range, 22-64), and the median duration was 208 days (range, 99-317). The median PFS and OS were 9.8 months (range, 4.5-not evaluable [NE]) and 26.6 months (range, 4.5-NE).
“Results from this phase 1/2 trial suggest that tagraxofusp monotherapy has modest clinical activity in patients with myelofibrosis,” lead study author Abdulraheem Yacoub, MD, and colleagues wrote in the publication. “As monotherapy for myelofibrosis, tagraxofusp is well tolerated, with no new safety signals, and has a manageable and predictable safety profile, consistent with its mechanism of action. Combination strategies are being explored to better understand the potential of tagraxofusp in the treatment of myelofibrosis.”
Yacoub is a professor of hematologic malignancies and cellular therapeutics at the University of Kansas Medical Center in Kansas City.
In December 2018,
In patients with myelofibrosis, CD123 is expressed on malignant and bone marrow accessory cells, aiding the proliferation of neoplastic cells.1 Given this expression and the varying levels of CD123 on malignant vs healthy cells, investigators sought to evaluate tagraxofusp—a CD123-targeted therapy—in patients with myelofibrosis.
The nonrandomized, open-label, multicenter phase 1/2 trial enrolled patients with treatment-naive or relapsed/refractory myelofibrosis, chronic myelomonocytic leukemia, advanced symptomatic systemic mastocytosis, or advanced symptomatic primary eosinophilic disorder during the escalation phase in stage 1. In stage 2, patients needed to have myelofibrosis per 2016 World Health Organization criteria with International Prognostic Scoring System (IPSS), Dynamic IPSS (DIPSS), or DIPSS-plus intermediate-2– or high-risk disease. Patients could not be eligible for immediate allogeneic stem cell transplant (allo-SCT), and those who experienced disease relapse after prior allo-SCT were excluded. Notably, patients with IPSS, DIPSS, or DIPSS-plus low- or intermediate-1–risk disease were allowed to enroll if they had at least 1 of the following: myelofibrosis-related anemia with a hemoglobin level of less than 10 g/dL; splenomegaly with a palpable size of more than 10 cm; leukocytosis with a white blood cells count of more than 25 × 109/L; marked thrombocytosis with a platelet count of more than 1000 × 109/L; or constitutional symptoms, defined as weight loss of more than 10% during previous 10 months, a fever greater than 37.5°C, or drenching night sweats for more than 6 weeks.
In stage 1, patients received tagraxofusp at 7 µg/kg, 9 µg/kg, or 12 µg/kg on days 1 to 3 of the first 4 21-day cycles, then on the same days in 28-day cycles in cycles 5 to 7, followed by days 1 to 3 of each 42-day cycle in cycle 8 and beyond. In stage 2, patients received the agent at 12 µg/kg on days 1 to 3 of 21-day cycles in cycles 1 to 4, then on days 1 to 3 in 28-day cycles in cycle 5 and beyond.
The primary end points of stage 1 were to determine the maximum tolerate dose and note any DLTs. Safety and responses were primary end points in stage 2.
At baseline, patients in the relapsed/refractory myelofibrosis population (n = 25) had a median age of 70.0 years (range, 55-83), and those in the treatment-naive cohort (n = 5) had a median age of 74.0 years (range, 67-81). The rates of female patients were 40% and 60%, respectively. The respective median platelet counts were 75.0 x 109/L (range, 16-651) and 36.0 x 109/L (range, 16-330); 44% and 40% of patients, respectively, had a platelet count greater than 100 x 09/L.
Most patients in the relapsed/refractory cohort (64%) and the treatment-naive cohort (80%) had primary myelofibrosis. DIPSS-plus risk scores in the relapsed/refractory cohort were intermediate-1 (16%), intermediate-2 (52%), and high (32%). Risk scores in the treatment-naive group were intermediate-2 (80%) and high (20%). The rates of patients with splenomegaly at baseline were 64% and 40%, respectively.
Additional safety data showed that the most common nonhematologic TEAEs included hypoalbuminemia (grade 1/2, 44%; grade 3/4, 3%), nausea (42%; 0%), dyspnea (28%; 11%), decreased appetite (36%; 0%), and peripheral edema (33%; 3%). Selected hematologic TEAEs comprised thrombocytopenia (8%; 19%), anemia (0%; 22%), febrile neutropenia (3%; 3%), leukopenia (6%; 0%), and neutropenia (3%; 0%). Hematologic treatment-related AEs included thrombocytopenia (6%; 8%), anemia (0%; 6%), febrile neutropenia (0%; 3%), leukopenia (3%; 0%), and neutropenia (3%; 0%).
CLS related to tagraxofusp occurred in 11% of patients at grade 1/2 (6%), grade 3 (3%), and grade 4 (3%). All instances of CLS were reported in cycle 1 at a median onset of 4 days (range, 2-8). All instances of CLS resolved at a median time of 6 days (range, 4-12). CLS led to treatment discontinuation in 2 patients (1 at grade 1 and 1 at grade 4); 2 patients continued with the same dose of tagraxofusp after recovering from CLS.
