15 Jun PREACH-M Trial: Humanigen Study Evaluates Lenzilumab and Azacitidine for CMML
Medical Research Interview:
Dr. Daniel Thomas MD PhD FRACP FRCPA
Program Leader, Blood Cancer
Precision Medicine Theme at the South Australia Health Medical Research Institute
Clinical Hematologist, Royal Adelaide Hospital
Associate Professor, Adelaide Medical School, The University of Adelaide
MedicalResearch.com: What is the background for this study? Would you briefly describe the condition of CMML?
Response: Chronic myelomonocytic leukemia (CMML) is a rare, but increasingly frequent, clonal stem cell disorder that results in hyperproliferation of inflammatory monocytes, a form of white blood cells. It features both myelodysplasia and myeloproliferation. CMML is most often found in older adults and leads to anemia, decreased quality of life, and an increased risk of acute myeloid leukemia (AML).
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that stimulates production, growth, differentiation, activation, and function of myeloid cells (monocytes, neutrophils, and eosinophils). In the presence of RAS-pathway mutations, a greater sensitivity to GM-CSF contributes to the hyperproliferation of myelocytes in myelodysplastic leukemias such as CMML, juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML). In CMML, greater sensitivity to GM-CSF stimulates excessive monocytic precursor proliferation.
The PREACH-M Trial, which stands for PREcision Approach to CHronic Myelomonocytic Leukemia, assesses the efficacy of lenzilumab in addition to azacitidine in treatment-naïve CMML participants with RAS-pathway mutations (KRAS, NRAS, CBL) and separately high dose ascorbate in participants with TET2 mutations who do not have RAS-pathway mutations. The study is currently underway and actively enrolling. It is being conducted and funded by the South Australian Health and Medical Research Institute (SAHMRI).
MedicalResearch.com: How does this treatment combination differ from other therapeutic modalities for CMML?
Response: The only approved treatment for CMML is hypomethylating agents such azacitidine, decitabine, and more recently the oral combination of decitabine and cedazuridine but it is not clear that these therapies, as single agents, are effective in prolonging survival in the higher risk proliferative forms of the disease. No treatments with novel mechanisms of action have been approved for the treatment of CMML in 30 years.
Presently, CMML can only be cured through stem cell transplantation from a matched donor.
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 preliminary results from the PREACH-M trial indicate that lenzilumab may interrupt monocytic hyperproliferation and disease progression that results from the GM-CSF hypersensitivity in leukemic cells with RAS-pathway mutations.
MedicalResearch.com: What are the main findings?
Response: The study currently has 17 active participants, ten of which were evaluable on June 9, 2023 when the EHA poster was presented, which means they have received at least 3 months of therapy and their hematologic disease parameters have been assessed. All evaluable patients have shown meaningful hematologic improvements and clinical benefit from lenzilumab treatment in addition to azacytidine.
Each parameter (blood monocytes, bone marrow blast percentage, platelet count, blood hemoglobin concentration, and spleen size) has exhibited a durable return to normal or near normal values, with statistical significance. Two of the ten participants have been in the trial for 18 months, the longest of any participants, and exhibit lasting improvement. No participants have relapsed. One participant is now a candidate for stem cell transplantation, which may lead to a potential cure in that patient.
The pro-inflammatory marker of disease, C-reactive protein, which was elevated at baseline in most patients, also normalized with a trend towards statistical significance..
Lenzilumab is providing clinical benefit, improving clinical parameters, quality of life and systemic inflammation in the participants studied so far; all of which occur early in treatment and appear durable.
MedicalResearch.com: What are the next steps in this study?
Response: The PREACH-M trial is a phase 2/3 trial. We plan to unveil new data showing comprehensive clinical responses according to established criteria, somatic mutation frequencies and bone marrow plasma inflammatory cytokine levels at international meetings later this year.
Humanigen and SAHMRI are assessing regulatory pathways that may enable early results to support a regulatory submission and potential provisional registration or approval by the Therapeutic Goods Administration in Australia. We are also considering opening up PREACH-M, or a similar study in other countries such as the UK and the US, subject to resourcing and Humanigen’s corporate strategy.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: Dr. Thomas has no disclosures.
Dr. Durrant is a paid employee and director of Humanigen and receives compensation in this role.
The presentation, entitled “Lenzilumab and Azacitidine Improve Hematologic Alterations of Chronic Myelomonocytic Leukemia in the PREACH-M Trial,” highlighted new data in poster format (P737) at 6:00 pm CEST on June 9, 2023, during the 2023 European Hematology Association congress.
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Last Updated on June 15, 2023 by Marie Benz