The Il-1β Inhibitor Canakinumab in Previously Treated Lower-Risk Myelodysplastic Syndromes: A Phase 2 Clinical Trial

Authors

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
Simona Colla

Publication Date

11-13-2024

Journal

Nature Communications

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.

Keywords

Humans, Myelodysplastic Syndromes, Male, Interleukin-1beta, Female, Antibodies, Monoclonal, Humanized, Aged, Middle Aged, Aged, 80 and over, Erythropoiesis, Treatment Outcome

DOI

10.1038/s41467-024-54290-2

PMID

39537648

PMCID

PMC11561093

PubMedCentral® Posted Date

11-13-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes