Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

Abstract

High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100–300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.

Anakinra and dexamethasone treatment of idarubicin‐induced mucositis and diarrhoea in rats

“…In an in vivo rat study, Ozcicek et al showed that the treatment of anakinra (50–100 mg/kg) restored the levels of inflammatory markers (IL‐1β, IL‐6 and TNF‐α) and reduced the morphologic GI damage induced by methotrexate (5 mg/kg) 24 . In the clinical study performed by Wardill et al in 2022, 26 patients treated with 300 mg anakinra after high‐dose melphalan (200 mg/m 2 ) avoided severe fever. They also showed in rats that the use of anakinra at a higher dose (200 mg/day for 5 days) reduced body weight loss and restored appetite and plasma citrulline, a marker used for small intestinal toxicity 45 .…”

“…While our observations for anakinra agree with corresponding data in humans, the translational potential of data generated in this rat model must be further explored. 26 For instance, the time-dependent effects, as well as the optimal dose range, dose ratio and synergistic effects of the two drugs must be elucidated. Pathogenesis of CIM involves a range of complex molecular and cellular events, such as the mucosal release of IL-1, IL-6, IL-10 and TNF-α and other relevant cytokines, and this warrants further mechanistic studies in a complex in vivo model that best mimics the clinical situation.…”

“…villus atrophy and diarrhoea). However, our positive data and the beneficial effects in both murine and clinical studies 24–26 indicate that anakinra should be further investigated for treating CIM.…”

“…While our observations for anakinra agree with corresponding data in humans, the translational potential of data generated in this rat model must be further explored 26 . For instance, the time‐dependent effects, as well as the optimal dose range, dose ratio and synergistic effects of the two drugs must be elucidated.…”

“…Another anti‐inflammatory drug is the IL‐1 receptor antagonist anakinra. Anakinra has been used in several in vivo studies, and showed promising efficacy data in reducing CIM in rats and mice, 24,25 as well as in a recent small clinical trial where CIM was successfully treated by anakinra 26 . While these two drugs have been investigated separately, the combination has never been studied in an in vivo preclinical CIM model.…”