Hematologic and Non-CRS Toxicities

Introduction

Chimeric antigen receptor (CAR)–modified T-cell immunotherapy is highly effective for patients with relapsed and/or refractory B-cell malignancies, but significant adverse effects remain a concern. Systemic cytokine release syndrome (CRS) can occur in association with the inflammatory cytokine surge during in vivo CAR T-cell proliferation, and neurologic adverse effects commonly occur in this context. Significant progress has been made in CRS management, leading to a reduction in its incidence and severity. But there are additional toxicities that require further research focus for management guidance.

Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are potentially life-threatening syndromes brought on by excessive and unreserved immune activation. Primary HLH is frequently observed in infants and toddlers due to underlying genetic mutations. These mutations result in a lack of downregulation following immune activation, leading to a dysfunctional hyperinflammatory state. This is felt to involve macrophages, natural killer (NK) cells and cytotoxic T-cells. Macrophage activation leads to cytokine production which ultimately causes end organ destruction and organ failure. In normal states, NK and T-cells function to eliminate macrophages that have been activated in a negative feedback loop. In the pathologic state, lack of negative feedback allows for continued activation and cytokine production from macrophages. While MAS is observed in patients with rheumatologic disorders such as systemic juvenile idiopathic arthritis, secondary HLH describes patients who develop HLH in response to an identified inciting trigger such as a neoplastic process or viral infection. Diagnostic criteria include identification of a known genetic mutation or five of the following: fever >38.5C, splenomegaly, cytopenias involving two lines (hemoglobin <9 g/dL, platelets <100,000/uL or absolute neutrophil count <1000/uL), hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 mg/dL), hemophagocytosis in bone marrow, spleen, lymph node or liver, low or absent NK cell function, elevated ferritin (>500 ng/mL) and elevated soluble CD25 or IL-2 receptor alpha.

There is significant overlap between HLH/MAS diagnostic criteria and the signs and symptoms of CRS that develop in response to CAR T-cell therapy. In many of the patients meeting criteria for grade 3 or greater CRS, they also meet criteria for HLH/MAS. CAR T-cell–related HLH/MAS is currently considered to be secondary HLH/MAS, as it is felt to be due to the hyperinflammatory state initiated by CAR T-cell activation. The incidence of CRS-associated HLH/MAS is difficult to define, and there is controversy regarding the prevalence of CRS-associated HLH/MAS. Mahadeo et al. suggested considering the diagnosis of HLH/MAS if a patient's serum ferritin is greater than 10,000 ng/mL with concurrent hepatic, renal, or pulmonary toxicity (CTCAE grade 3 or higher) or hemophagocytosis noted on pathology. Neelapu et al. suggest it is rare, approximately 1% of patients treated in their experience. However, Teachey et al. report a different experience noting the significant overlap in CRS and HLH/MAS in patients with grade 3 or high CRS, suggesting a higher observed incidence. Given that most patients receive lymphodepleting chemotherapy prior to the CAR T-cell infusion and are immunocompromised, they are also at risk for infections concurrently and other potential causes for secondary HLH/MAS must also be evaluated if patients do not improve following CRS-targeted therapy. Teachey et al. suggested elevated levels of IFN-γ (>75 pg/mL) and IL10 (>60 pg/mL) were more suggestive of potential CRS-associated HLH and less likely to be due to infection, though this has not been demonstrated in analysis of cytokines evaluated during periods of CRS and documented infection. In addition, if a patient has a history suggestive of a previous HLH/MAS event or hyperinflammation is not improved with CRS-targeted therapies, one should consider investigating for primary HLH genetic mutations.

In line with general principles of secondary HLH/MAS treatment, therapy should be focused on the underlying cause, which is the CRS and the CAR T-cell activation. Some have recommended IL-6-directed therapy, which is also used for CRS and if there is lack of clinical response in 48–72 hours to consider HLH management per HLH-2004. Additionally, some practitioners are trialing anakinra, an IL-1 blocking agent for severe HLH. However, one must balance the need for additional therapy and the potential for eliminating the CAR T-cells with further cytotoxic therapy. These above issues highlight the difficulty in distinguishing the two entities, and further research is needed to guide management to intervene early if a patient is more likely to develop HLH/MAS and is in need of therapeutic interventions beyond IL-6-directed therapy and corticosteroids.

Hematologic Complications