FRANKFURT, Germany — A novel agent has shown promise in the treatment of chronic myelomonocytic leukemia (CMML), a rare, aggressive malignancy of myeloid cells with an inherent risk of transforming into acute myeloid leukemia in about 15% to 20% of patients.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%–50%, and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, Australia, in an interview with Medscape Medical News.
Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the 2023 European Hematology Association (EHA) Congress here, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%–60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm — so, patients that have KRAS, NRAS, or CBL mutations — are just responding beautifully to [lenzilumab], and that really has taken me by surprise,” Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, told Medscape that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Durrant said, preclinical research from investigators at the Moffitt Cancer Center in Tampa, Florida, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M Details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate (ASC) 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Thomas said.
Here at EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Thomas told Medscape that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Thomas reported no relevant financial relationships. Durrant is an employee and director of Humanigen.
European Hematology Association Congress 2023: Abstract P737. Presented June 8-11, 2023.
Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.
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