Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome

Abstract

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.

Keywords: Chimeric antigen receptor T cell; Hemophagocytic lymphohistiocytosis; Macrophage activation syndrome.

Figure 1.

Primary HLH and IEC-Associated HLH-like syndrome (IEC-HS) A. Top panel: In primary (genetic) HLH, cytotoxic T cells with insufficient cytotoxic function due to defects in cytotoxic granule release or perforin are activated, cannot terminate their immunologic synapse, and with insufficient downregulation promote macrophage activation and cytokine release, which further activates cytotoxic T cells. The resulting T cell and macrophage activation results in release of IFN-γ, sIL-2R, IL-6, IL-10, IL-12, IL-18, IL-1β, TNF-α, IL-33, and ferritin. B. Bottom panel: In IEC-HS, CAR T cells are activated by CAR T cell recognition of tumor antigen which leads to cytotoxic granule release and tumor lysis. Sustained activation via engineered CAR recognition of tumor antigen results in T cell activation, proliferation, and cytokine release and resultant macrophage activation and release of soluble factors as seen with primary HLH.

Figure 2.

Intersection of IEC related toxicities and Timing of CRS and IEC-HS A. Visual of how various IEC based therapies contribute to inducing a host of IEC-associated hyperinflammatory syndromes—highlighting both the inter-relatedness and yet unique presentations of the various toxicities. B. Suggested paradigms for severe CRS with HLH-like multiorgan dysfunction and how this chronologically differs from IEC-HS presentations.

Figure 3.

Stepwise approach to treatment of IEC-HS Treatment recommendations are derived from expert opinion and warrant prospective study. Nonetheless, therapy should generally be initiated prior to development of life-threatening complications and, if possible, a time interval (e.g., 48 hours) should be allowed to observe for efficacy before additional agents are added to avoid cumulative toxicity of multiple immunosuppressive agents. Patients should be closely monitored for response to interventions, with potential for escalation in care and evaluation of alternative etiologies if there is worsening. (See table 3 for specific dosing recommendations) First-line therapy: Can start with anakinra +/− corticosteroids. While a range of dosing is provided, use of one or both agents and/or low versus higher dose is dependent on the clinical presentation of the patient and how rapidly the inflammatory response is worsening. For patients with grade 2 IEC-HS, starting with the lower end of the range for dual therapy, or higher-dosing for single agent intervention could both be considered. Second-line therapy: For patients with clearly worsening inflammatory parameters who are developing more severe manifestations of IEC-HS, recommendations are for dual-agent therapy at the higher-end of the range—with consideration for adding additional agents if the patient is rapidly worsening. Third-line therapy: Typically, corticosteroids/anakinra would continue as additional therapies are added to achieve control of the inflammatory response. Choice of therapy beyond ruxolitinib can be informed by unique patient considerations (e.g., etoposide for CAR T-cell associated lymphocytosis or emapalumab for highly elevated IFN-γ). An ongoing assessment for alternative etiologies should continue throughout the IEC-HS manifestations and treatment course. Consultation with infectious disease specialists and rheumatology should be considered to optimize supportive care for patients with sub-optimal response to initial therapeutic approaches or those with worsening manifestations. As clinical and laboratory parameters stabilize, gradually tapering immunosuppression is encouraged while monitoring for recrudescence of symptoms