MPN-379: Interim Results from an Ongoing Phase 1/2 Clinical Trial of Tagraxofusp, a CD123-Targeted Therapy, in Patients with Chronic Myelomonocytic Leukemia (CMML)

Abstract

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms (MDS/MPN) with poor outcomes, particularly in the relapsed/ refractory (R/R) setting. Current FDA-approved therapies have limited clinical impact. Clinical outcomes appear particularly poor in patients with proliferative features (high WBC counts, splenomegaly, high symptom burden) and high-risk cytogenetic and/or genomic features. Tagraxofusp (TAG) targets CD123, a biomarker expressed on CMML blasts and clonal monocytes; additionally, there is evidence of microenvironmental clonal plasmacytoid dendritic cells. Collectively, these features provide a rationale to assess the role of TAG in CMML patients. Objectives: To assess safety and efficacy of TAG in patients with CMML refractory/resistant/intolerant to HMAs, hydroxyurea, or intensive chemotherapy. Methods: Multicenter Phase 1/2 trial with TAG being administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1–3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8+) in stage 1 and 12 mcg/kg in stage 2. Results: Twenty-nine patients, including CMML-1 [n=19] and CMML-2 [n=10]; the median age was 70 years (range 42–87). Thirteen patients (45%) had baseline splenomegaly (spleen palpable below the left costal margin [BCM]); nine of these patients had baseline splenomegaly ≥5 cm BCM. The most common treatment-related adverse events (TRAEs, incidence ≥25%) were hypoalbuminemia, thrombocytopenia, and anemia. The most common ≥ grade 3 TRAEs were thrombocytopenia (34%), anemia (17%), and nausea (3%). Capillary leak syndrome was reported in seven patients (4 with grade 1–2; 3 with grade 3). Three patients, all with splenomegaly at baseline, achieved complete bone marrow responses (BMCRs), including one patient who was allografted in CR. Of note, two of these three BMCRs had proliferative CMML with high-risk cytogenetic and genomic features. Analysis of clinical benefit demonstrated a clinical reduction in splenomegaly in all patients with baseline splenomegaly (14/14): 71% (10/14) had spleen size reduction of ≥50%, and 60% (6/10) with baseline spleen size ≥5 cm had spleen size reduction of ≥50%. Conclusions: The interim results represent the clinical efficacy and safety of TAG monotherapy in a cohort of CMML patients, including patients with splenomegaly, a recognized poor prognostic factor in CMML. ( NCT02268253 )