Haemophagocytic lymphohistiocytosis (HLH) in patients with large B-cell lymphoma treated with standard of care (SOC) axicabtagene ciloleucel (Axi-cel).

Abstract

8057 Background: HLH is a rare but serious complication of chimeric antigen receptor (CAR) T cell therapy, characterized by severe immune activation, and immune mediated multi-organ failure. Diagnosis is difficult in the context of cytokine release syndrome (CRS) and optimal treatment and outcomes are unclear. Methods: Retrospective, descriptive analysis of patients with relapsed/refractory LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 - 10/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) defined as time from axi-cel infusion to progression/death or last follow-up. Diagnosis of HLH per HLH-2004 and CART cell therapy toxicity guidelines (Neelapu, 2018) Results: One hundred and five patients with relapsed/refractory LBCL included, 6 diagnosed with HLH. No significant difference in baseline characteristics, disease stage, international prognostic index or inflammatory markers at baseline between groups, with exception of platelet count which was lower in HLH group 116 [37-129] versus 141 [9-391] (p = 0.07). Development of HLH was early after CART cell infusion at a median 11 days [7 – 78 days] with 3 patients having bone marrow hemophagocytosis; all 6 had abnormalities in liver function tests, fibrinogen, triglycerides, and at least 1 ferritin level > 10,000. CART toxicity in HLH cohort: 4 patients experienced grade 0-1 CRS, and 1 with grade 2 CRS while 3 HLH patients experienced grade 3-4 IEC-associated neurotoxicity syndrome ( ICANS), and 2 patients had grade 0-1 ICANS. Five HLH patients treated with high dose steroids, and tocilizumab; anakinra administered in 2 patients. Four of 6 patients had resolution of HLH with treatment and didn’t require escalation to HLH specific therapy however 1 patient was treated with steroids/etoposide. PFS and overall survival (OS) were significantly shorter in HLH group, PFS 1 months vs 8 months, respectively (p < 0.001) and median OS 2 months vs not reached, respectively (p = 0.001) follow up 10 months (95% CI 8-12 months). One patient died of acute respiratory failure, 2 patients died of HLH and multi-organ failure without progressive disease (PD). Of 3 remaining patients, all had radiographic PD at day 30, 2 of whom died of PD. Conclusions: HLH is likely an underreported complication of CART cell therapy, and patients with HLH have significantly worse outcomes. In this series the majority of patients died of PD, not the syndrome itself. More information is necessary to design treatment strategies that won’t compromise CART outcomes.

Hemophagocytic lymphohistiocytosis‐like toxicity (carHLH) after CD19‐specific CAR T‐cell therapy

“… 13 In contrast to primary HLH patients with a predominate adaptive immune response and cytokine profile, cytokine profiles of carHLH patients, including our cohort, show evidence of both innate and adaptive type responses, including elevation of IL‐1beta (Fig 1E). 12,14 These findings support the use of steroids and cytokine‐directed therapies, such as anakinra and/or specific JAK inhibitors, with guarded consideration of emapalumab due to loss of anti‐leukaemic CAR activity in a preclinical model 2,4,6,7,15,16 . Further studies are needed to determine the efficacy and optimal dosing and timing of these agents, as well as any effects on CAR T‐cell expansion, persistence and anti‐leukaemic activity.…”

Immune cartography of macrophage activation syndrome in the COVID-19 era

“…With CAR T cell therapy, in which T cells are engineered against specific tumour antigens, the ensuing development of cytokine storm with MAS is both proportionate to the tumour volume and related T cell expansion, powerfully attesting to the theory that gain of function in adaptive immunity, and nothing else, is sufficient and adequate to precipitate a cytokine storm or MAS phenotype 72 , 73 . This observation lends further credibility to the theory that an immune hypersensitivity reaction originating in an antigen-driven adaptive CD4 + T cell response could also drive MAS (Fig.…”

Management of haemostatic complications of chimaeric antigen receptor T‐cell therapy

“…CAR‐T patients may also develop toxicities resembling HLH, sometimes referred to as carHLH in the literature. Such cases have been seen in patients with B‐ALL and DLBCL, with increased associated mortality observed 7,72,73 . Shah et al .…”

“…Such cases have been seen in patients with B-ALL and DLBCL, with increased associated mortality observed. 7,72,73 B-ALL patients receiving anti-CD19 CAR-T cells, namely a peak ferritin >100 000 μg/L with at least two other features present (deranged liver function, elevated creatinine, pulmonary oedema or evidence of HLH on bone-marrow examination). 7,74 HLH-like manifestations were seen in 33% of patients and only occurred in those with CRS.…”