LENZ (lenzilumab)

On the therapeutic front, drugs targeting cytokine pathways, such as ruxolitinib (a JAK inhibitor) and lenzilumab (an anti-GM-CSF antibody), have shown early promise in modifying disease activity and improving symptoms. Understanding and targeting these inflammatory circuits may not only help slow disease progression but also improve quality of life for patients. As our knowledge grows, incorporating inflammation into both our diagnostic frameworks and treatment approaches will likely become standard in the care of CMML.

These include lenzilumab (anti-GM-CSF) and IO-202 (anti-LILRB4), which have demonstrated promising early efficacy signals but require further study. Established treatments, which include hypomethylating agents and hydroxyurea as well as the JAK1/2 inhibitor ruxolitinib, provide limited survival benefits in CMML, underscoring the urgent need for novel therapeutic development. Coordinated dedicated research efforts have started to evaluate new agents in CMML. Along with further diagnostic and prognostic refinement, these advances are welcomed for this rare and heterogenous disease.

P1, N=6, Terminated, Kite, A Gilead Company | Phase classification: P1/2 --> P1

P3, N=72, Withdrawn, Peter MacCallum Cancer Centre | Not yet recruiting --> Withdrawn

Interim analysis of the PREACH-M trial demonstrated that GM-CSF neutralization with LENZ/AZA, for the treatment of CMML with RAS-pathway mutations resulted in 55% CR, achieved early in treatment, durability up to 18 months, thus far, and no unexpected serious adverse events. These data suggest CMML is driven by a non-redundant cytokine that responds to immunotherapy. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.

Introduction: Chronic myelomonocytic leukemia (CMML) is characterized by accumulation of classical CD14+CD16- inflammatory monocytes driven in part by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine. CMML is a disorder of profound innate immune activation, driven by GM-CSF and other pro-inflammatory cytokines. Early treatment with LENZ/AZA, a precision immunotherapeutic approach, leads to a) efficacy in INNATE-1 that exceeds historical CR rates for hypomethylating agents1,2; and b) evolving efficacy in INNATE-2, in which pro-inflammatory activity is more robust. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.

Siltuximab which binds to site I of IL-6 receptor and prevents IL-6 binding to it, is not FDA approved, however used in selective tocilizumab resistance cases or as an alternative therapy (Riegler et al., 2019). Anakinra is an IL-1 receptor antagonist, which was found to improve CRS in association with tocilizumab when compared to tocilizumab alone (Jatiani et al., 2020). Lenzilumab, is a monoclonal antibody that neutralizes granulocyte-monocyte colony stimulating factor (GM CSF), was also used in preclinical studies and found to be lessening the severity of CRS without dampening CAR-T cell function (Sterner et al., 2019).Infections: The factors which increase the risk of infection in MM patients post-BCMA therapy are >3 prior lines of therapy, B-cell aplasia, infections 30-days before CAR-T, and post CAR-T lymphopenia...In most cases cytopenia would improve over a period of 12-months.Conclusion : Given the recent use of BCMA therapy in RRMM, there is no standard guideline on how to manage the complications associated with it. Larger studies with longer follow up needs to be conducted, to address the safety of the therapy for better patient outcome

All pts underwent lymphodepletion with cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day before a single infusion of axi-cel at a target dose of 2 × 106 cells/kg. Conclusions No new safety signals or DLTs were observed in pts treated with axi-cel plus lenzilumab. Addition of lenzilumab to the axi-cel regimen appeared to dose-dependently suppress the GM-CSF axis and reduce markers of systemic inflammation.

Within the last year alone, the FDA approved brexu-cel for adults w/ R/R B-ALL and expanded indications for liso-cel and axi-cel to include DLBCL w/ primary refractory disease or early first relapse...Anti-cytokine therapies beyond tocilizumab (anti-IL-6R mAb) are being investigated for prevention of CRS/ICANS, including lenzilumab (anti-GM-CSF mAb) and anakinra (IL-1R antagonist)...Accordingly, we designed and initiated a pilot study of Iomab-B w/ adoptive cellular therapy (Iomab-ACT; Fig 1A).Study design and Iomab-ACT is a single-institution pilot study of Iomab-B (w/o chemotherapy) as conditioning prior to 19-28z CAR-T in adults w/ R/R B-ALL or DLBCL (NCT04512716)...Unexpected toxicity (given low dose of ARC) observed in 1 pt included severe trilineage cytopenias lasting >8 wks (requiring RBC/PLT transfusion support, G-CSF, romiplostim) w/o marrow hypoplasia and w/o other apparent neoplastic or drug-induced etiology; this met criteria for dose-limiting toxicity and we will monitor in the next 3 pts...Key exploratory objectives include describing changes in circulating immune cells following ARC and 19-28z CAR T-cells w/spectral cytometry using a custom antibody panel (Fig 1B) and cytokine levels in cerebrospinal fluid. We hope to generate preliminary data to guide further study of CD45-targeted ARCs prior to CAR-T and other forms of adoptive cellular therapy.

Having demonstrated that GM-CSFRα is significantly upregulated on stimulated CART19 cells, we aimed to determine the impact of GM-CSF neutralization (clinical-grade anti-GM-CSF antibody, lenzilumab, 10 µg/mL) versus GM-CSFRα blockade (research-grade antibody, 10 µg/mL) on CART19 cell function and CART cell-monocyte interactions...In summary, our findings indicate significant differences on CART cell functions and CART cell-monocyte interactions when a specific cytokine, GM-CSF, is neutralized compared to blocking its receptor. Further mechanistic studies are ongoing to assess the functions of GM-CSFRα k/o and GM-CSF k/o CART cells.