Blood cancer cells under the microscope: © stock_acc – stock.adobe.com
IO-202 demonstrated a complete response (CR) of 27.8% and an overall response rate (ORR) of 66.7% when coupled with azacitidine in patients with chronic myelomonocytic leukemia (CMML) who were naïve to standard-of-care hypomethylating agents (HMAs) in a phase 1 dose escalation-expansion trial (NCT04372433).1
Overall, both the monotherapy and combination therapy showed encouraging findings and suggest that targeting the leukocyte immunoglobulin-like receptor B4 (LILRB4), which is highly expressed in neoplastic monocytic cells, may provide a needed specific therapeutic avenue for this aggressive disease.
CMML is a rare and aggressive hematologic malignancy that has been associated with myelodysplastic syndrome (MDS).2 CMML was classified as a subtype of myelodysplastic syndrome (MDS) in 1982.2 However, its unique characteristics, including increased circulating monocytes and a distinct molecular profile, have led to its reclassification as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap condition.3
This overlap presents a therapeutic challenge, as current HMA therapies for CMML often result in poor outcomes, with response rates of less than 50%. The need for targeted therapies has been underscored by the limited efficacy of other agents, such as the BCL-2 inhibitor venetoclax (Venclexta), which has shown poor results in acute myeloid leukemia (AML) with monocytic features and may not improve overall survival in CMML.
Study Design
This was a multicenter, nonrandomized, first-in-human phase 1 study with both a dose-escalation and a dose-expansion component. The study’s primary objectives were to assess the safety and efficacy of IO-202 as a monotherapy and in combination with azacitidine. The part 1 dose-escalation portion enrolled 46 patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R CMML. This included a monotherapy cohort and a combination therapy cohort with azacitidine.
Part 2 was a dose-expansion portion that included a specific cohort (Part 2B) dedicated to patients with CMML who were HMA-naïve, and who were prioritized for enrollment due to promising early activity. Patients were required to be at least 18 years old with a confirmed diagnosis of myelomonocytic or monocytic/monoblastic AML or CMML.
Using a standard 3+3 design for dose escalation, IO-202 was administered via intravenous infusion on a 28-day cycle, with azacitidine given at its approved dose. Patients were premedicated before IO-202 administration. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For efficacy, responses in CMML were evaluated based on the 2015 International Working Group MDS/MPN response criteria, which defines objective responses as complete response (CR), marrow response (MR), partial remission (PR), and clinical benefit (CB)
Leukocyte immunoglobulin-like receptor B4 (LILRB4) expression, the target of IO-202, was analyzed in a central laboratory using flow cytometry on bone marrow and peripheral blood samples. The drug’s pharmacokinetics and immunogenicity were also analyzed to assess how azacitidine affects IO-202 and to detect any anti-drug antibodies, according to lead author Ahmed Aribi and colleagues.1
Outcomes in HMA-Naive CMML
The study’s most significant findings emerged from the cohort of 21 patients with HMA-naïve CMML. The median age of these patients was 71 years (range 54-82), with 66.7% being male. Many patients had high-risk disease features, including high-risk CPSS-Mol scores and unfavorable ASXL1 genetic mutations.
The combination regimen led to a CR rate of 27.8% (5/18) and an ORR of 66.7% (12/18) among efficacy-evaluable patients. These responses were not only rapid, with a median time to first response of 1 cycle, but also durable.
Notably, 7 patients (38.9%) were able to proceed to allogeneic hematopoietic cell transplantation (allo-HCT) after receiving the therapy, with 6 of them achieving a response beforehand. In the subset of patients with the highest LILRB4 expression, the ORR was 100% and the CR rate was 33.3%, which supports the drug’s mechanism of action, Aribi A et al wrote.1
Safety
Safety data showed that the combination was well-tolerated, with all grade 3 or above treatment-related adverse events in the combination cohorts attributed to azacitidine alone or a combination of azacitidine and IO-202. There were only 3 grade 3 treatment-related adverse events attributed to IO-202 itself, diarrhea, somnolence, and infusion-related reactions, all of which were resolved with supportive care.
Limitations and Future Directions
As a phase 1 study, the trial’s primary focus was safety and dose determination, which inherently limits the generalizability of its efficacy findings. The sample sizes for each cohort were small, particularly for the R/R CMML group, with only 5 patients receiving the combination therapy in the dose-escalation phase.
Further, the study was nonrandomized and did not include a control arm. Additionally, the impact of anti-drug antibodies on the drug’s pharmacokinetics was not conclusive due to high variations in drug exposure at low dose levels.
Despite these limitations, the study’s results are highly encouraging for a disease with a poor prognosis. The robust clinical activity observed in patients who are HMA-naïve CMML, particularly the high response and CR rates, warrants further investigation.
The study’s authors conclude that the data support the initiation of a future pivotal study of IO-202 in combination with azacitidine for patients with HMA-naïve CMML. This next step is crucial to confirm the efficacy and safety of this new therapeutic strategy and to solidify its potential as a much-needed treatment for this patient population.