Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells

Abstract

CAR T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T-cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Amongst 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase and occasionally hemophagocytosis. Development of carHLH was associated with pre-infusion NK-cell lymphopenia and higher bone marrow T/NK-cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK-cell lymphopenia amplified pre-infusion differences in those with carHLH without evidence for defects in NK-cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.

Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy

“…Importantly, patients with carHLH did have a higher number of infections in the late post CAR T cell therapy period. This is likely since carHLH often occurs later than CRS and may require treatment with immunosuppressive agents such as anakinra and steroids (18,29), as we saw in our patient population. The use of immunomodulatory agents to treat CAR-mediated side effects, the inflammatory response with elevated cytokines and/or the intensive supportive management in the ICU may all contribute to risk of infections in these patients (30)(31)(32).…”

Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy

“…In its severe form, CRS symptomatology shares features of hemophagocytic lymphohistiocytosis (HLH), which appears to be on the spectrum of CRS. Indeed, in pediatric patients with ALL treated with tisagenlecleucel (formerly known as CTL019), we found that all patients with severe CRS met HLH-2004 criteria for HLH 5 , and the association of CRS with HLH manifestations was recently reported with a CD22-directed CAR T-cell product 8 . Common laboratory abnormalities in severe CRS include hyperferritinemia, elevated c-reactive protein (CRP), transaminitis, and coagulopathy marked by hypofibrinogenemia.…”

“…Abnormal cytokine levels are seen, including elevations in interleukin-1 (IL-1), IL-6, IL-8, IL-10, interferon-gamma (IFN-ɣ), tumor necrosis factor-alpha (TNF-α), granulocyte macrophage-colony stimulating factor (GM-CSF), IP10 (CXCL10), MCP1, MIG (CXCL9), and MIP1β, a pattern shared with HLH [5][6][7] . It is notable that both high-grade CRS and HLH manifest substantial elevations in interferon-ɣ (IFN-ɣ) 5,8 . In HLH, IFN-ɣ is considered a key driver of inflammation, and interestingly, elevated IFN-ɣ following CAR T-cell infusion and prior to the onset of CRS has been shown to predict grade 4 or 5 CRS 5,8,9 .…”

“…It is notable that both high-grade CRS and HLH manifest substantial elevations in interferon-ɣ (IFN-ɣ) 5,8 . In HLH, IFN-ɣ is considered a key driver of inflammation, and interestingly, elevated IFN-ɣ following CAR T-cell infusion and prior to the onset of CRS has been shown to predict grade 4 or 5 CRS 5,8,9 . Additionally, IFN-ɣ is one of the several serum cytokines that are differentially elevated in patients with neurologic toxicity post CAR T-cell therapy 10 .…”

Siglecs as Therapeutic Targets in Cancer

“…However, even CD22 expression can be low or even null in several human lung cancer cells, including pancreatic, prostate, breast, and liver cancers to be considered targetable (https://www.proteinatlas.org/ENSG000000121 24-CD22/pathology, accessed on 3 November 2021) [46]. More importantly, CD19/CD22 CAR-T cell therapy can lead to hemophagocytic lymphohistiocytosis-like toxicities due to persistent elevation of inflammatory cytokines in concert with pronounced NK-cell lymphopenia [47,48]. Activating and inhibitory pathways in Siglec-2 (CD22) as targets in cancer.…”