Interleukin-1 (IL-1) and the inflammasome in cancer.

Canakinumab, a monoclonal antibody targeting pro-inflammatory cytokine interleukin (IL)-1β, improved hemoglobin levels while preventing recurrent cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This cardiovascular (CV) preventive effect was greater in patients with TET2 mutations associated with clonal hematopoiesis (CH). The current proteogenomic analysis aimed to understand the clinical response to canakinumab and underlying proteomic profiles in the context of CH and anemia. The analysis included 4595 patients from the CANTOS study who received either canakinumab or placebo and evaluated multiplexed proteomics (4785 proteins) using Somascan@ and targeted deep sequencing for CH mutations. Incident anemia was more common in the presence of CH mutations but reduced by canakinumab treatment. Canakinumab treatment was significantly associated with higher hemoglobin increment in patients with concurrent CH mutations and anemia compared to patients with CH mutations without anemia or without CH mutations. Compared to those without CH mutations, the presence of CH mutations was associated with proteomic signatures of inflammation and defense response to infection, as well as markers of high-risk CV disease which was further enhanced by the presence of anemia. Canakinumab suppressed hepcidin, pro-inflammatory cytokines, myeloid activation, and complement pathways, and reversed pathologically deregulated pathways to a greater extent in patients with CH mutations and anemia. These molecular findings provide evidence of the clinical utility of IL-1β blockade and support further study of canakinumab in patients with concurrent anemia and CH mutations. The study was funded by Novartis Corporation, US and registered at clinicaltrials.gov (NCT01327846).

Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.

Activation of Distinct Inflammatory Pathways in LR-MDS Is Determined By Genetics

Topic: 23. Hematopoiesis, stem cells and microenvironment Background: Canakinumab is a fully human monoclonal antibody that neutralizes interleukin (IL)-1β. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) – a randomized, double-blind, placebo-controlled trial that enrolled 10,061 patients with previous myocardial infarction– canakinumab prevented recurrent cardiovascular (CV) events and fewer patients in the canakinumab group developed lung cancer. A CANTOS exploratory genomic substudy revealed that canakinumab treatment reduced more major adverse CV events in patients with TET2 variants than those without clonal hematopoiesis (CH) mutations. CH is associated with an increased risk of lung cancer and other tumors. CH mutations are associated with higher levels of circulating inflammatory cytokines, which led to the hypothesis that inhibition of IL-1β may provide preferential benefits to patients with CH mutations for the development of non-hematological malignancies. Aims: To explore the associations between 1) CH mutations and development of non-hematological malignancies and 2) canakinumab treatment and the development of non-hematological malignancies in patients with or without CH mutations, utilizing the large prospective CANTOS trial Methods: To determine the association of IL-1β inhibition and risk of solid tumor for patients with different types of CH mutation, time-to-event analysis and cross-sectional Fisher exact test were performed in a subset (n=3,923) of CANTOS participants with targeted deep sequencing of CH mutations at baseline. Results: The baseline characteristics were balanced between treatment groups among patients with the same group of individual CH mutations. Patients with TET2 mutations in the placebo arm had more frequent non-hematological malignancies (16.1%, 5/31 patients), while patients carrying TET2 mutations in the canakinumab arm had significantly reduced incidence of non-hematological malignancies (4.2%, 3/71 patients, P=0.05, Figure A). Patients with DNMT3A mutations had more frequent lung cancer incidence than other groups in the placebo arm (7.4%, 3.2%, 2.0%, and 2.3% in patients with DNMT3A, TET2, other CH mutations, and no CH mutations, respectively). However, with canakinumab treatment, a lower lung cancer incidence was observed in patients with DNMT3A (0/56 patients) or TET2 mutations (0/71 patients), while other groups treated with canakinumab had higher lung cancer incidence (2.9%, 1.5% in other CH mutations and no CH mutations, respectively, Figure B). While skin cancers other than melanoma were most frequently diagnosed in patients with TET2 mutations (9.7%, 3/31 patients, P=0.01) in the placebo arm, a significantly reduced skin cancer incidence was observed in patients with TET2 mutations treated with canakinumab (0/71 patients, P=0.03, Figure C). The time-to-event analysis of the cumulative incidence of cancers revealed that canakinumab treatment is significantly associated with reduced risk of any non-hematological malignancies (Figure D) and skin cancers other than melanoma in patients with TET2 mutations, but not in other groups, compared to the placebo (P=0.019 and 0.01, respectively), as well as lung cancers in patients with TET2 or DNMT3A mutations, compared to the placebo (P=0.01). Summary/Conclusion: This evaluation of CH mutation and the development of non-hematological malignancies revealed different rates of cancer incidence in different CH subtypes with and without canakinumab treatment. These data may support the role of IL-1 β inhibition for cancer prevention in patients with specific CH mutation. Keywords: Inflammation, Clinical outcome, Clonal hematopoiesis of indeterminate potential, Solid tumor 

P1339: impact of clonal hematopoiesis and canakinumab on non-hematological malignancy: analysis of the cantos randomized clinical trial

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Activation of Distinct Inflammatory Pathways in LR-MDS Is Determined By Genetics

P1339: impact of clonal hematopoiesis and canakinumab on non-hematological malignancy: analysis of the cantos randomized clinical trial