Durable efficacy of lenzilumab plus azacitidine in newly diagnosed proliferative CMML patients: Interim analysis after four years of study commencement

Abstract Introduction: Proliferative chronic myelomonocytic leukemia (CMML) is an increasingly recognized blood cancer involving pro-inflammatory monocytes with no approved treatments in Australia or United Kingdom. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M; ACTRN12621000223831) trial investigates novel CMML therapies directed by molecular proling. Lenzilumab (LENZ; Taran Therapeutics, Short Hills, NJ) a first-in-class monoclonal antibody that neutralizes GM-CSF. PREACH-M interim results show that LENZ/AZA improves clinical parameters in patients with CMML, including those with RAS pathway mutations (NRAS, KRAS, CBL, PTPN11, NF1, BRAF). This report updates the objective clinical responses from an interim analysis updated May 30, 2025. Methods PREACH-M is a Phase 2/3 non-randomized, uncontrolled, open-label trial in 54 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML stratified according to mutation status. Subjects exhibiting RAS-pathway mutations (NRAS, KRAS, CBL, PTPN11, NF1, BRAF) receive 24 cycles (every 28 days) of AZA (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles); while those with only TET2 mutations receive the same AZA regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for an additional 24 months. The primary endpoint is the frequency of complete response (CR) or partial response (PR) at any point during the first 12 cycles according to Savona Criteria. Secondary endpoints include responses according to modified 2006 International Working Group criteria and symptom improvement. Interim analyses are planned when at least 33% (n=18) and 66% (n=36) patients have completed 12 months of treatment. Results As of May 30 2025, 40 subjects were enrolled overall (19 receiving >12 months of treatment) and 32 subjects were enrolled in the LENZ/AZA arm (11 females, 21 males with mean age 73; mean white cell count 20x109/L, mean Hb 108 g/L; mean platelet count, 74x109/L, mean blast count, 8%). Mutations included CBL (50% of subjects), NRAS (31%), KRAS (47%), PTPN11 (6%), BRAF (1%), ASXL1 (50%) and TET2 (72%). LENZ/AZA subjects exhibited CPSS-MOL scores of intermediate risk 1 (n=4), intermediate risk 2 (n=7) and high risk (n=21). Overall, subjects had completed a median number of 17 cycles of LENZ/AZA at the time of reporting. 26 (81%) of subjects had not progressed, 2 went to allogeneic transplant (of which 1 had progressive disease), 3 (9%) had progressive disease (of which 1 was transplanted), 1 discontinued and 1 deceased. 22 subjects had evaluable responses within the first 12 months. 86% of patients attained a complete remission (CR) or marrow complete remission (mCR) within the first 12 months on study, according to IWG 2006 criteria. According to Savona criteria, 86% of patients achieved a complete response or an optimal marrow response within the first 12 months on treatment. Bone marrow blast counts decreased from a mean of 8% at baseline to 3% at 3 months (P=0.0001), 3% at 6 months (P=0.0005) and 4% at 12 months (P=0.008). Hemoglobin improved from 111 g/L to 124 g/L at 12 months (P=0.03). Platelet count improved from 90 x109/L at baseline to 147 x109/L at 3 months (P=0.02). Safety and tolerability for LENZ was excellent with no patients experiencing infusion related reactions. Treatment emergent adverse events occured in 25% of patients with a total of 55 grade 3 or 4 serious adverse events were reported, including anemia, thrombocytopenia and febrile neutropenia, none of which were considered causally related to LENZ. Of 22 patients with serial NGS data, 17 (77%) exhibited significant and durable decreases in mutation sub-clones including RAS pathway clones. Conclusion Interim analysis of the PREACH-M trial shows promising results with LENZ/AZA resulting in durable complete responses beyond 12 months with 86% of subjects achieving a complete remission or marrow complete remission without significant LENZ related toxicity.