The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial

Juan Jose Rodriguez-Sevilla, Vera Adema, Kelly S. Chien, Sanam Loghavi, Feiyang Ma, Hui Yang, Guillermo Montalban-Bravo, Xuelin Huang, Xavier Calvo, Joby Joseph, Kristy Bodden, Guillermo Garcia-Manero and Simona Colla ()
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Juan Jose Rodriguez-Sevilla: The University of Texas MD Anderson Cancer Center
Vera Adema: The University of Texas MD Anderson Cancer Center
Kelly S. Chien: The University of Texas MD Anderson Cancer Center
Sanam Loghavi: The University of Texas MD Anderson Cancer Center
Feiyang Ma: University of California Los Angeles
Hui Yang: The University of Texas MD Anderson Cancer Center
Guillermo Montalban-Bravo: The University of Texas MD Anderson Cancer Center
Xuelin Huang: The University of Texas MD Anderson Cancer Center
Xavier Calvo: Hospital del Mar Research Institute (IMIM)
Joby Joseph: The University of Texas MD Anderson Cancer Center
Kristy Bodden: The University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero: The University of Texas MD Anderson Cancer Center
Simona Colla: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells’ (HSPCs’) aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had lower-risk MDS, 84% had intermediate-1 risk MDS according to the International Prognostic Scoring System score, and 80% failed hypomethylating agent therapy. The study met the primary endpoint of defining the clinical activity of canakinumab, and the secondary objective of determining the safety profile, including the rate of transfusion independence, the duration of response, progression-free survival, leukemia-free survival, and overall survival. The overall response rate was 17.4%, with all responses including hematological improvement. Sequential post-hoc prospective single-cell RNA sequencing analyses of HSPCs and bone marrow mononuclear cells at different time points during therapy showed that canakinumab’s on-target effects in hematopoietic populations expressing the IL-1β receptor decreased the TNF-mediated inflammatory signaling pathway but rescued ineffective erythropoiesis only in the context of lower genetic complexity. This study demonstrates that better stratification strategies could target lower-risk MDS patients more effectively.

Date: 2024
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DOI: 10.1038/s41467-024-54290-2

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