P737: LENZILUMAB AND AZACITIDINE IMPROVE HEMATOLOGIC ALTERATIONS OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN THE PREACH-M TRIAL

Topic: 8. Chronic myeloid leukemia - Clinical Background: Chronic myelomonocytic leukemia (CMML) is a rare, aggressive cancer with limited targeted therapy and a propensity to develop into acute myeloid leukemia. Standard of care (SOC) includes azacitidine (AZA), with complete and partial response (CR and PR) rates ranging between 10-17%. The pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central role in leukemic monocyte proliferation. Lenzilumab (LENZ) is a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class specificity and affinity. In pre-clinical models, its use resulted in a reduction of colony numbers and viability of CMML cells. Aims: The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ (ACTRN12621000223831p) in addition to SOC in CMML subjects with specific molecular markers. Methods: PREACH-M is a Phase 2/3 non-randomized, open-label precision medicine trial in 72 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML; cytopenia (hemoglobin < 100 g/L, platelets < 100 x 109/L or absolute neutrophil count < 1.8 x 109/L); white blood cell count (WBC) ≥ 13 x109/L; as well as TET2 and/or RAS pathway mutations (NRAS, KRAS, CBL). Key exclusion criteria include prior treatment with investigational agents; uncontrolled medical conditions; treatment with G-CSF within seven days of screening; radiotherapy within 28 days before treatment; and GM-CSF within 28 days of screening. Subjects exhibiting RAS pathway mutations receive 24 cycles (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 TET2 mutations receive the same AZA regimen and sodium ascorbate (IV; 30g for 7 days [15g 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 six months for 24 months for survival, disease status, and CMML-related therapy. The primary endpoint is the frequency of CR or PR, according to Savona Criteria, at any time during the first 12 cycles. Safety was also evaluated. This report describes the preliminary hematologic changes in six evaluable subjects that received LENZ/SOC and had at least three months of follow-up as of December 31, 2022. Results: All six subjects had abnormal WBC count, monocyte count, and blast differential at baseline and RAS pathway somatic mutations (CBL, n=4; NRAS, n=1; KRAS, n=1 at high variant allele frequency). Monocyte count normalized in all six subjects following LENZ/SOC treatment, including two high risk patients according to CPSS-Mol molecular profiling, while WBC count and blast differential normalized in five subjects (Table 1).Four of five subjects with abnormal hemoglobin at baseline normalized after treatment. All four subjects with abnormal platelet counts at baseline normalized after treatment. Platelet count and hemoglobin remained normal following treatment in those subjects with normal values at baseline (platelets, n=2; hemoglobin, n=1). Ten grade 3/4 Serious Adverse Events were observed including cytopenia or febrile neutropenia that was assessed as probably or definitely related to AZA; two were assessed by the investigator as possibly related to LENZ. Summary/Conclusion: In the first six evaluable subjects with proliferative CMML and RAS-pathway mutations, GM-CSF neutralization with LENZ and AZA resulted in changes in hematological parameters that trended towards normal values. Keywords: CMML, GM-CSF, Ras