Strong Safety, Nuanced Efficacy Results for Canakinumab in Previously-Treated MDS

A phase II non-randomized clinical trial was conducted to evaluate the interleukin (IL)-1β inhibitor canakinumab for previously-treated myelodysplastic syndromes (MDS). Its findings were published in Nature Communications.

The trial investigators concluded that this agent was safe overall for use in this setting and “pharmacologically targeting the IL-1β pathway represents a promising therapeutic strategy for improving hematologic parameters and reducing inflammatory cytokine levels in patients with early-stage disease.” However, patients with high genetic complexity were seen to have greater resistance to this agent.

The cohort in this open-label, single-arm trial included 25 patients, had a median age of 74 years, and was 60% male. The patients had a median of two prior lines of therapy and in 80% prior hypomethylating agents were unsuccessful. 80% of the cohort was transfusion-dependent and 40% had SF3B1 mutations.

The trial began with an exploratory dose-finding run-in phase after which enrolled patients received 300 mg of subcutaneous canakinumab on the first day of a four-week cycle. The trial cohort had a median follow-up of 24.9 months.

Safety results were evaluated in the entire cohort. No patients discontinued therapy, reduced dose, or were removed from the study due to effects from the agent. Neutropenia was the most common treatment-emergent adverse event (TEAE) and cytopenia was the most common TEAE of grade 3 or worse severity. There was one mortality in the cohort due to sepsis determined to be unrelated to treatment.

The median overall survival in the cohort was 17.3 months, progression-free survival was 17.3 months, and leukemia-free survival was 16.3 months. Response was evaluable in 23 patients and their overall response rate was 17.4%. Four patients responded to treatment, three of whom achieved erythroid hematological improvement and one platelet hematological improvement. There were three patients who achieved transfusion independence and they had a median duration of response of 8.53 months.

The investigators noted that the patients in the cohort with SF3B1 mutations did not respond to canakinumab. Moreover, “[a]ll patients whose disease responded to canakinumab belonged to the lower-risk group by [molecular International Prognostic Scoring System], whereas all patients whose disease progressed during treatment were in the higher-risk group.”

Reference

Rodriguez-Sevilla JJ, Adema V, Chien KS, et al. The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial. Nat Commun. 2024;15(1):9840. doi:10.1038/s41467-024-54290-2