A recent phase 2 clinical trial has explored the efficacy of canakinumab, an IL-1β inhibitor, in patients with relapsed or refractory lower-risk myelodysplastic syndromes (MDS). The open-label, single-arm study, the results of which were published in Nature Communications, offers a potential therapeutic option for patients who have failed previous treatments. Conducted at the University of Texas MD Anderson Cancer Center, the trial (NCT04239157) enrolled patients between August 2020 and June 2023.
Study Design and Patient Population
The study included patients with lower-risk MDS, defined by an International Prognostic Scoring System (IPSS) score of low or intermediate-1 risk, or a Revised IPSS (IPSS-R) score ≤3.5. All patients had a hemoglobin level <10 g/dL and symptomatic anemia or transfusion dependency. Participants were required to have completed previous antineoplastic treatments at least two weeks before enrollment and had an ECOG performance status score ≤2. Key exclusion criteria included previously untreated MDS, uncontrolled infection, and pregnancy or lactation.
The trial began with a dose-finding run-in phase, starting with subcutaneous canakinumab at 150 mg and escalating to 300 mg. Subsequently, all newly recruited patients received 300 mg of canakinumab subcutaneously on day 1 of each 4-week cycle. The primary endpoint was the rate of hematologic improvement (HI), while secondary objectives included transfusion independence (TI), duration of response (DoR), progression-free survival (PFS), leukemia-free survival (LFS), overall survival (OS), and safety profile.
Efficacy and Safety Results
Responses were assessed using the modified International Working Group 2006 criteria for MDS. The study reported the HI rate for canakinumab along with 95% confidence intervals (CIs) using the normal approximation method. Transfusion independence (TI) was defined as no transfusion requirements during an 8-week period or longer. Time-to-event endpoints (OS, PFS, LFS, and DoR) were estimated using the Kaplan–Meier method and compared using the log-rank test, with further analysis using the Cox proportional hazards model.
Safety was evaluated in all patients who received at least one dose of canakinumab through adverse event (AE) assessment, clinical laboratory test results, physical examinations, and vital signs. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
Exploratory Analyses
In addition to clinical endpoints, the study incorporated exploratory analyses, including single-cell RNA sequencing (scRNA-seq) and cytokine quantification in bone marrow plasma. These analyses aimed to provide insights into the mechanisms of action of canakinumab and its impact on the bone marrow microenvironment. Bone marrow aspirations and biopsies were performed before therapy, at cycle 2 day 28 (±3 days), and every three cycles thereafter to assess treatment response and disease progression.
Cytokine Analysis
Multiple cytokines, chemokines, and growth factors were quantified from bone marrow plasma using the MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel A. This comprehensive analysis aimed to identify potential biomarkers associated with response to canakinumab and to elucidate the drug's immunomodulatory effects within the bone marrow milieu.
Implications for MDS Treatment
The results of this phase 2 trial suggest that canakinumab may offer a potential treatment option for patients with relapsed or refractory lower-risk MDS. Further research is needed to confirm these findings in larger, randomized controlled trials and to better understand the mechanisms underlying the drug's activity in this patient population.
