Lenzilumab Demonstrates Clinical Benefit in Patients With Chronic Myelomonocytic Leukemia

A phase I study found that lenzilumab, an engineered human IgG1K monoclonal antibody that neutralizes granulocyte-macrophage colony-stimulating factor (GM-CSF), was associated with a clinical benefit in approximately one-third of patients with chronic myelomonocytic leukemia (CMML). The study results, published in Blood, suggested this novel antibody has some activity in what is an aggressive hematologic neoplasm with limited therapeutic options and where cellular GM-CSF hypersensitivity is common.

This phase I clinical trial enrolled 15 patients who were refractory to, intolerant of, or ineligible for hypomethylating agents (HMAs) or hydroxyurea therapy. The purpose of the study, as for most phase I trials, was to evaluate safety and identify the recommended phase II dose of lenzilumab in this patient population.

The investigators studied 3 dose levels: 200 mg, 400 mg, and 600 mg. Each treatment dose was intravenously administered on days 1 and 15 of cycle 1, then on day 1 of subsequent 28-day cycles. Three patients were assigned to the 200- and 400-mg dose levels, and 9 patients were enrolled in the 600-mg dose group.

Responses to therapy were assessed with the Myelodysplastic Syndromes/Myeloproliferative Neoplasm International Working Group (IWG-MDS/MPN) response criteria, which were published in Blood in 2015.

Approximately 20% of patients enrolled in the trial were treatment-naïve, whereas 60% (n=9) had previously received an HMA and/or experimental therapies, and 20% (n=3) were previously treated with hydroxyurea. The median age at baseline was 74 years (range = 52-85), and the majority of patients (80%) were men. Patients were classified based on their CMML subtype:

  • CMML-0 (n=9): the presence of <2% blasts in blood and <5% blasts in bone marrow
  • CMML-1 (n=3): the presence of 2-4% blasts in blood and/or 5-9% blasts in bone marrow
  • CMML-2 (n=3): the presence of 5-19% blasts in blood and/or 10-19% blasts in bone marrow

Most (11/15, 73%) enrolled patients had normal cytogenetics. At screening, the most frequently observed mutated genes were TET2 (60%), ASXL1 (53%), SRSF2 (47%), and RAS pathway (NRAS or CBL) mutations (40%). At enrollment, the median hemoglobin level was 9.7 g/dL (range = 7.6-14 g/dL), and the median white blood cell count was 10×109/L (range = 5.3-59.8 ×109/L). The median absolute monocyte count was 4.5×109/L (range = 1.3-10×109/L), the median platelet count was 147×109/L (range = 16-942×109/L), and approximately 66% of patients had MPN-type CMML (WBC >13×109/L) at screening.

There were no dose-limiting toxicities or treatment-emergent toxicities associated with any of the treatment doses, and the investigators observed no study drug−related or grade 3 or 4 toxicities in any group. A total of 2 patients in each group had grade 3 neutropenia, whereas 1 patient in each group had grade 4 neutropenia; these were not deemed to be related to the study drug. Grade 2 anemia and neutropenia were reported in 1 patient in each group.

 “Given the lack of toxicity and modest efficacy, future research will focus on identifying combination therapies that include lenzilumab or other GM-CSF inhibitors.”

—Eric Padron, MD

The median duration of therapy was 110 days (range = 14-798). A total of 4 patients (27%) achieved a clinical benefit based on IWG-MDS/MPN criteria, including 3 platelet responses and 1 neutrophil response. The median duration of best response was 5.5 months (range = 1-14). In addition, 1 patient who experienced a reduction in bone marrow myeloblasts from 6% to 1% underwent an allogeneic hematopoietic cell transplantation.

Three of the 5 responding patients and 1 of the nonresponding patients had NRAS mutations. According to the authors, this finding may be “consistent with prior reports suggesting that GM-CSF hypersensitivity in CMML is more prominent in patients with RAS pathway mutations.”

The researchers also performed progenitor colony forming assays in 3 patients, including 1 responder who had an NRAS mutation and 2 nonresponders with NRAS wild type. In this subset of patients, the researchers observed a noticeable GM-CSF hypersensitivity in the responding patient compared with the nonresponders.

According to corresponding study author Eric Padron, MD, of the Moffitt Cancer Center in Tampa, Florida, this is the first study that evaluated neutralization of GM-CSF as a therapeutic strategy in CMML. “Given the lack of toxicity and modest efficacy,” he said, “future research will focus on identifying combination therapies that include lenzilumab or other GM-CSF inhibitors.” Dr. Padron added that further studies are needed to investigate the efficacy and safety of lenzilumab in pediatric patients with juvenile myelomonocytic leukemia, who also have GM-CSF hypersensitivity.

Limitations of this trial include its small sample size and lack of a control group.

The authors report no relevant conflicts of interest.


Patnaik MM, Sallman DA, Mangaonkar A, et al. Phase 1 study of lenzilumab, a recombinant anti-human GM-CSF antibody, for chronic myelomonocytic leukemia (CMML). Blood. 2020 Apr 15. [Epub ahead of print]