e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

Anakinra is safe in HSCT recipients and reinforces the mucosal barrier to control acute complications of high-dose melphalan: results from the AFFECT-1 (Phase IIA) trial and preclinical efficacy study (#211)

Hannah R Wardill 1 , Charlotte ME De Mooij 2 , Walter JFM van der Velden 2 , Hermie JM Harmsen 3 , Wim JE Tissing 4 , Nicole MA Blijlevens 2
  1. School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
  2. Haematology, RaboudUMC, Nijmegen, The Netherlands
  3. Medical Microbiology, University Medical Centre Groningen, Groningen, The Netherlands
  4. Paediatric Oncology / Haematology, University Medical Centre Groningen, Groningen, The Netherlands

Aims

Conditioning regimens containing melphalan are associated with a high risk of mucosal barrier injury (MBI) and associated fever/infection in haematopoietic stem cell transplant (HSCT) recipients. While initiated by direct cytotoxic injury, the depth and duration of MBI is dictated by hyper-activation of the IL-1b/CXCL1/neutrophil axis. The current study therefore aimed to a) determine the efficacy of IL-1 receptor antagonist (anakinra) in a validated rodent model of melphalan-induced MBI and b) evaluate its safety in HSCT recipients.

Methods

Preclinical: Male Wistar rats (150-180g, N=64) were treated with melphalan on day 0 (5 mg/kg, intravenously) ± twice daily anakinra (100 mg/kg subcutaneously, 5 days). Primary endpoint was plasma citrulline; validated biomarker of MBI. Secondary endpoints were weight loss, anorexia, body temperature (assessed using subcutaneous transponders to detect fever) and gut microbiome composition (assessed by 16S). 

Phase IIA: Patients with multiple myeloma undergoing high-dose melphalan conditioning were recruited and treated with anakinra (100, 200, 300mg i.v.) once daily from day -2 to +12. Primary endpoint was safety determined by occurrence of adverse events (determined by NCI CTCAE) and dose-limiting toxicities. Secondary/exploratory endpoints included time to engraftment, CRP, body temperature and systemic cytokines. 

Results

Anakinra minimized the intensity and duration of MBI (P=0.02) and its clinical consequences including weight loss (P=0.003) and anorexia (P=0.0001). By controlling mucosal injury, the gut microbiome was stabilized with expansion of enteric pathogens (E.coli) and subsequent fever prevented (P=0.0002).  Anakinra did not cause any adverse events or dose limiting toxicities nor did it change time to neutrophil recovery in Phase IIA investigation.

Conclusions

Anakinra is safe in HSCT recipients and has the capacity to reinforce the mucosal barrier to control systemic complications of melphalan. We are now commencing a Phase IIB multicentre, placebo-controlled, double-blinded trial to assess its clinical efficacy (AFFECT-2 trial: NCT04099901).