Patients with clonal cytopenias of undetermined significance (CCUS) or lower-risk myelodysplastic syndromes (MDS) may benefit from treatment with the IL-1β inhibitor canakinumab, according to the results of a small study published recently in Nature Communications. The study showed that targeting the IL-1β pathway may help to improve hematologic parameters and reduce inflammatory cytokine levels in certain patients with these conditions.
“Canakinumab is an inhibitor of the IL-1β pathway, and IL-1β is a cytokine that is released by specific cells in the blood — like macrophages — and induces proinflammatory signaling,” said Simona Colla, PhD, of the University of Texas MD Anderson Cancer Center. “In MDS, the hematopoietic stem cell that gives rise to cells in the blood express high levels of IL-1β.”
In this clinical trial, led by Guillermo Garcia-Manero, MD, also of the University of Texas MD Anderson Cancer Center, researchers explored whether targeting the IL-1β pathway with canakinumab can overcome aberrant myeloid differentiation and clonal expansion in lower-risk MDS.
The nonrandomized, phase II study included 25 patients with previously treated disease. Initially, the study used a dose-finding run-in 3+3 phase, assigning patients to subcutaneous canakinumab at 150 mg and then 300 mg. After this, all patients received 300 mg of canakinumab. The median age of patients was 74 years, 60% were male, and 80% had failed hypomethylating agent (HMA) therapy.
The overall response rate was 17.4%; four of 23 evaluable patients responded with all responses including hematologic improvement. Of the four responders, three had failed prior HMA therapy. Transfusion independence was achieved in three patients, with a median duration of response of 8.53 months. Thirteen patients had stable disease.
With a median follow-up of 24.9 months, the median overall survival (OS) was 17.3 months. Among patients with prior HMA therapy, the median OS was 29.4 months in the HMA-naïve cohort and 17.3 months in the HMA-failure cohort.
“We saw that in patients who responded, canakinumab was able to rescue the aberrant production of red cells at the hematopoietic stem cell level,” Dr. Colla said. “We could see downregulation of the pathway, suggesting that it could target, in a specific way, IL-1β.”
The researchers also discovered that only two patients with erythroid hematologic improvement over 12 months and red blood cell transfusion independence had specific genetic mutations.
“What we discovered was that these two patients who responded had particular alterations, one in TET2 and one in DNMT3A; they had low genomic complexity and not many mutations or genetic alterations,” Dr. Colla said. “For this reason, we concluded that patients with low genetic alterations can benefit from canakinumab.”
In contrast, resistance to canakinumab was linked with higher genetic complexity, suggesting that “other intrinsic factors and extrinsic factors contribute to patients’ cytopenias and mutant cells’ clonal expansion.”
Overall, canakinumab had an acceptable side effect profile; no patients discontinued therapy. The most common treatment-emergent adverse event was neutropenia; the median duration of grade 3 or higher neutropenia was 14 days (range = 5-36), and the median absolute neutrophil count nadir was 0.540 (range = 0.150-0.990). There were no dose-limiting toxicities.
Dr. Colla acknowledged several limitations to the study, including its small size and the lack of a control group. In addition, the researchers noted that canakinumab may not be effective in patients with MDS and greater genetic complexity.
Additional studies of canakinumab are planned in patients with CCUS or untreated lower-risk MDS; these will clarify “whether the modulation of IL-1β-induced inflammation can improve these patients’ peripheral blood cytopenias and reduce their risk of developing cardiovascular disorders, thus modifying the course of the disease.”
Any conflicts of interest declared by the authors can be found in the original article.
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.
Perspectives
Immune dysregulation and aberrant inflammatory signaling play critical roles in the pathophysiology of MDS, with an expanding body of evidence unravelling these complex pathways.1 Consequently, modulation of immune signaling represents a promising therapeutic strategy.
This study investigated canakinumab, a monoclonal antibody targeting IL-1β, in patients with previously treated, lower-risk MDS. Canakinumab demonstrated a favorable safety profile, with cytopenias representing the most common adverse events including the majority of grade 3 and 4 events, not unexpected in the MDS population. Efficacy was limited, with four out of 25 patients demonstrating hematologic improvement (three erythroid and one platelet), with two patients demonstrating durable transfusion independence of more than 12 months.
The enrolled patient population is a key consideration and limitation in this study, which likely affected clinical efficacy. The study targeted a population of patients with “lower-risk” MDS; yet, the majority of patients had higher-risk disease by IPSS-M criteria (not yet developed at time of protocol development), and 80% had failed to respond to HMA therapy, thereby representing a population with advanced disease. Indeed, innate immune activation, including activation of the NLRP3 inflammasome, has been shown to preferentially play a vital role in the pathogenesis of low-risk MDS in comparison with higher-risk disease states.2,3
This represents a key consideration in MDS trials moving forward, because MDS represents a heterogenous group of entities in which therapies may have preferential activity in specific disease subyptes. Highlighting this important point, the authors performed elegant correlative studies including single-cell RNA sequencing and cytokine profiling, demonstrating effective on-target activity of canakinumab that only resulted in restoration of hematopoiesis and clinical response in a subgroup of patients. These data highlight the importance of performing robust correlative studies in future MDS trials.
Although efficacy was limited, this study does demonstrate the potential of this emerging therapeutic strategy in MDS, which may hold further promise in “precursor” states such as clonal hematopoiesis of indeterminate potential and CCUS. Immune signaling is inherently complex, and the optimal therapeutic targets will need further delineation. Importantly, additional immune modulating therapies are now in clinical development, such as NLRP3 and IRAK inhibitors, with early data presented at recent scientific conferences.
Anthony Hunter, MD
Assistant Professor
Department of Hematology and Medical Oncology
Winship Cancer Institute of Emory University
COI disclosure: Dr. Hunter was a consultant for GSK, Cogent Biosciences, PharmaEssentia, Blueprint Medicines, Sobi (CTI BioPharma), and Incyte. He received research support from Incyte, Cogent Biosciences, Ascentage Pharma, Blueprint Medicines, Syntrix Biosystems, Novartis, and PharmaEssentia.
References
- Vegivinti CTR, Keesari PR, Veeraballi S, et al. Role of innate immunological/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review. Exp Hematol Oncol.2023;12(1):60.
- Basiorka AA, McGraw KL, Eksioglu EA, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;128(25):2960-2975.
- Peng X, Zhu X, Di T, et al. The yin-yang of immunity: immune dysregulation in myelodysplastic syndrome with different risk stratification. Front Immunol. 2022;13:994053.