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Background: Chronic myelomonocytic leukemia (CMML) is a rare, aggressive cancer for which no targeted therapy exists. Standard of care (SOC) includes azacitidine (A), 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 stimulating leukemic monocyte proliferation. Lenzilumab (LENZ) is a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class specificity and affinity that neutralizes GM-CSF to prevent signaling through its receptor. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ in CMML (ACTRN12621000223831p) to improve outcomes beyond those afforded by SOC. 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 × 109/L or absolute neutrophil count < 1.8 × 109/L): white blood cell count ≥ 13 × 109/L; as well as TET2 and/or RAS pathway mutations (NRAS, KRAS, CBL). Key exclusion criteria include prior treatment with investigational agents; radiotherapy within 28 days before treatment; treatment with G-CSF within 7 days of screening; GM-CSF within 28 days of screening; and uncontrolled medical conditions. Subjects exhibiting RAS pathway mutations, with or without TET2 mutations, receive 24 cycles (28 days) of A (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 non-RAS pathway mutations receive the same A regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30 g 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 24 months for survival, disease status, and CMML-related therapy. The primary endpoint is the frequency of CR or PR at any time during the first 12 cycles according to Savona Criteria. Secondary endpoints include overall survival and progression-free survival at 2 years; proportion of subjects with clinical benefit at any point during the 24 cycles; impact on physical and functional capacity; social well-being according to Multidimensional Geriatric Assessment and quality of life; as well as hematological and non-hematologic safety. Results: As of December 31, 2022, eight subjects were treated with A and LENZ (5 females, mean age of 67 years; 3 males, mean age of 69 years); among them 6 were evaluable based on at least 3 months of follow-up. CR or objective responses were observed in all evaluable patients including 2 with high risk based on molecular profiling. 10 grade 3/4 Serious Adverse Events were observed of which 2 were assessed by the investigator as possibly related to LENZ. Conclusion: The ongoing PREACH-M trial evaluates GM-CSF neutralization with LENZ in addition to SOC, in the treatment of CMML with RAS pathway mutations. Citation Format: Devendra Hiwase, David Ross, Steven Lane, Agnes Yong, Kirsty Sharplin, David Yeung, Lisa Butler, Dale Chappell, Cameron Durrant, Timothy Hughes, Daniel Thomas. A phase 2/3, multicenter trial of lenzilumab and azacitidine in chronic myelomonocytic leukemia: The PREACH-M trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT085.

The health benefits of quercetin are limited by its low bioaccessibility. This could be improved by developing plant-based protein delivery systems. Encapsulating quercetin using untreated and high-intensity ultrasound treated (20 kHz at 139 W for 10, 15 and 20 min) soy protein isolate (SPI) produced composite nanoparticles at around 127-136 nm. Ultrasound treatments on SPI caused structural changes of proteins (e.g. around 6-fold increase of surface hydrophobicity and protein solubility) favorable to encapsulation. The encapsulation efficiency for quercetin complexed with 15 min ultrasound treated SPI (76.5 %) was around 10-fold of that with the native SPI (7.2 %). Quercetin was significantly more in vitro bioaccessible when complexed with the treated SPI (61.1 %-64.5 %), as compared to the free quercetin (10.5 %-13.0 %). Ultrasound treated SPI seems to be a promising nanocarrier to encapsulate hydrophobic bioactive ingredients with higher solubility, stability, and bioaccessibility.

Abstract 192 The polycomb group (PcG) proteins BMI-1 and EZH2 are key regulators of self-renewal processes in normal and leukemic stem cells. Of these two PcG proteins, BMI-1 is more highly expressed in chronic myeloid leukemia (CML) than in normal stem cells, and is associated with a more rapid disease progression in patients who are treated with drug therapy alone, implying that an increased level of “stem-ness” conferred by BMI-1 contributes to leukemogenicity. Conversely, CML patients with high BMI-1 expression prior to allogeneic stem cell transplantation (SCT) have better overall survival post-transplant (Mohty, et al, Blood 2008). To investigate the potential of PcG proteins as leukemia-associated antigens, and targets for graft-versus-leukemia (GVL) effects, we studied a cohort of 86 CML patients (54 chronic phase, 32 advanced phase) who received T-cell depleted SCT with T-cell add-back on day 45-100 post-SCT from HLA-identical sibling donors. Using quantitative real-time PCR, we measured the expression of EZH2, BMI-1 and its target for repression, CDKN2A (encoding p16INK4A) in CD34+ progenitors and their CD34-negative counterparts. Using flowcytometric detection of intracellular cytokines IFN-γ or TNF-α, and degranulation marker CD107a, in CD8+ cytotoxic T lymphocytes (CTL), we assessed immune responses to BMI-1 (TLQDIVYKL and CLPSPSTPV) and EZH2 (YMCSFLFNL and SQADALKYV) peptides in 25 HLA-A*0201+ patient-donor pairs. Seven of 17 (41%) HLA-A*0201+ CML patients had native immune responses to BMI-1 peptide, which was associated with higher BMI-1 expression in CD34+ progenitors (p=0.04, Mann-Whitney U test). Five of 25 (20%) healthy HLA-A*0201+ sibling donors had detectable immune responses to BMI-1 peptide. EZH2 was less immunogenic compared to BMI-1 in both patients and donors. The majority of peptide-specific CTLs analyzed by peptide-specific dextramers had central memory phenotype. BMI-1- or EZH2-specific T cells were readily detected after 7-day cultures using an ELISPOT assay in 75% of donors or patients where peptide-specific CTLs were detected ex-vivo. A higher expression of BMI-1 in CML patients pre-SCT and correspondingly lower expression of its target for repression, CDKN2A, was associated with improved leukemia-free survival (p=0.01), and reduced disease-related death (p=0.0001). In four HLA-A*0201+ patients whose donors had immune responses to PcG peptides, BMI-1 or EZH2-specific T cell responses were detected in the first 120 days post-SCT. CML patients who had donors with immune responses to BMI-1 peptide had improved leukemia-free survival compared to patients whose donors were non-responders (80% vs. 60% respectively). Immune responses to PcG proteins, in particular to BMI-1, may be relevant for disease control by GVL effects. Unlike CTLs specific for primary granular proteins such as proteinase 3 and elastase, which are also highly expressed in CML cells, CTLs against BMI-1 and EZH2 may be less susceptible to selective deletion processes resulting in tolerance, as these proteins are less ubiquitously expressed by mature progenitors which are expanded in CML, and are therefore good GVL and immunotherapy target candidates in CML. Furthermore, these CTLs have the potential to target leukemia stem cells. Disclosures: No relevant conflicts of interest to declare.