Anakinra to Mitigate Hemophagocytic Lymphohistiocytosis-Like Toxicity Following Chimeric Antigen Receptor T-cell Therapy in Pediatric B-cell ALL

Abstract

Hemophagocytic lymphohistiocytosis-like toxicity following chimeric antigen receptor (CAR)-T cell therapy (carHLH) is a rare and fulminant complication. Currently, there are neither well-established diagnostic criteria nor optimal treatment option for carHLH. Given the similarities of hyperinflammatory process and cytokine profiles between cytokine release syndrome (CRS) and carHLH, tocilizumab and corticosteroids are the suggested front-line treatment options for both conditions. However, when carHLH is refractory to front-line treatment, alternative or adjunctive agents should be introduced to ameliorate ongoing hyperinflammation. Anakinra, a recombinant interleukin (IL)-1 receptor antagonist, has shown promising results in the management of carHLH. Although prospective trials are limited, the use of anakinra for severe CRS and carHLH has been increasing. In this case report, we present two cases of carHLH to discuss its characteristic clinical features, diagnostic criteria, and treatment option. In addition, we also highlight the clinical efficacy of anakinra for managing carHLH which was refractory to tocilizumab and dexamethasone.

Management of adverse events in young adults and children with acute B-cell lymphoblastic leukemia receiving anti-CD19 chimeric antigen receptor (CAR) T-cell therapy

“…Secondary HLH can occur in patients with severe infection, malignancy, or autoimmune disease, and is rarely associated with allogeneic hematopoietic stem cell transplantation and CAR T-cell therapy. Reports on HLH-like toxicity following CAR T-cell therapy (carHLH) are increasing, with fever, organomegaly, jaundice, gastrointestinal problems, and pulmonary complications being the major clinical features [ 18 , 41 - 43 ]. Although the incidence of carHLH is relatively rare (3–4%) [ 44 ], it has a high mortality rate.…”

“…Data regarding the clinical use of anakinra in children with carHLH are limited, and treatment guidelines for it have not yet been established. Anakinra is typically added to advanced CRS as a second-line treatment, and studies have shown that it may be effective in controlling CAR T-cell therapy-associated toxicities by suppressing inflammatory pathways [ 17 , 41 , 43 , 46 ]. Although the optimal dose and treatment duration has not been determined, a starting dose of 2 mg/kg subcutaneously or intravenously every 6 h (8 mg/kg/day, maximum daily dose of 400 mg) is administered from days to weeks, based on protocols used in autoimmune or rheumatic diseases [ 47 , 48 ].…”

CAR-T Cell Therapy in the Treatment of Pediatric Non-Hodgkin Lymphoma

“…CRS tendency to progress into or overlap with HLH makes lymphohistiocytosis more challenging in its management. HLH manifests itself mainly with fever, jaundice, organomegaly, as well as gastrointestinal and pulmonary problems [140,141]. Although diagnostic criteria for carHLH were suggested, such as peak serum ferritin level and development of organ failure (hepatic, renal, pulmonary), the scale is for now recommended for adults only and needs adjustment for pediatric patients [142].…”