Durable Responses Observed in Chronic Myelomonocytic Leukemia Treated with Lenzilumab and Azacitidine

Introduction: Chronic myelomonocytic leukemia (CMML) is a rare cancer orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine that drives leukemic monocyte proliferation. Standard of care (SOC) for CMML treatment includes azacitidine (AZA), with a complete response (CR) rate of 16-21%. The PREcision Approach to CHronicMyelomonocytic Leukemia (PREACH-M; ACTRN12621000223831) trial investigates novel CMML therapies directed by molecular profiling. Lenzilumab(LENZ; Taran Therapeutics, Short Hills, NJ) a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class off-rate and affinity that neutralizes GM-CSF. PREACH-M interim results show that LENZ/AZA improves hematologic parameters, decreases spleen size, and dampens pro-inflammatory responses in CMML with RAS-pathway mutations. This report details the objective clinical responses from an interim analysis of the first 20 subjects who completed at least three months LENZ/AZA treatment.

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) 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) during the first 12 cycles according to Savona Criteria. Secondary endpoints include responses according to modified 2006 International Working Group criteria, 2 year overall survival, 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 August 1st 2024, 27 subjects were enrolled overall (18 receiving > 12 months of treatment) and 20 subjects were enrolled in the LENZ/AZA arm (9 females, 11 males with mean age 69; mean white cell count 37.8x109/L, mean Hb 108 g/L; mean platelet count, 72x109/L, mean blast count, 9%). Mutations included CBL (65% of subjects), NRAS (20%), KRAS (50%), ASXL1 (55%) and TET2 (70%). Subjects exhibited CPSS-MOL scores, of intermediate risk 1 (n=2), intermediate risk 2-3 (n=12), and high risk 4-6 (n=6). Overall, subjects had completed a median number of 13.5 cycles of LENZ/AZA at the time of reporting. 14 (70%) of subjects had not progressed, 2 went to allogeneic transplant and 4 (20%) had progressive disease. 85% 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, 85% of patients achieved a complete response or an optimal marrow response within the first 12 months on treatment. Importantly, 64% of patient achieving CR or marrow CR had detectable CBL mutations at baseline. Of the 10 subjects with dominant CBL mutations (VAF>10%), 90% achieved a CR or mCR in first 12 months with durable suppression of CBL clones. Of the 11 subjects with major clone KRAS/NRAS mutations (VAF>10%), 81% achieved a CR or mCR. Significantly, of all subjects who achieve CR or mCR at 3 months, 83% were still on study without progression at 12 months. Safety and tolerability for LENZ was excellent with no patients experiencing infusion related reactions. A total of nineteen grade 3 or 4 serious adverse events were reported, including anemia and febrile neutropenia, none of which were considered causally related to LENZ and six possibly related to azacitidine.

Conclusion: Interim analysis of the PREACH-M trial shows promising results with LENZ/AZA resulting in durable complete responses beyond 12 months with 85% of subjects achieving a complete remission or marrow complete remission without significant LENZ related toxicity. Significantly, 90% of patients with major clone CBL mutations achieved complete remission or marrow complete remission.