Immune Effector Cell-Associated HLH-Like Syndrome as a Post CAR T-Cell Therapy Complication of Lymphoid Malignancies

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment landscape of lymphoid malignancies. However, the remarkable efficacy of CAR-T therapy is hindered by its toxicities, including an emergent one known as immune effector cell (IEC)-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS), a severe and potentially life-threatening complication. This article reviews the clinical manifestations, pathophysiology, and management of IEC-HS following CAR-T therapy in B-cell malignancies.¹

Clinical Features

IEC-HS is a hyperinflammatory syndrome characterized by uncontrolled activation of the immune system – particularly T cells, natural killer (NK) cells, and macrophages – which leads to a cytokine storm resulting in hemophagocytosis and multi-organ dysfunction. Following CAR-T therapy, IEC-HS can manifest clinically as fever, cytopenias, abnormal liver function tests, hyperferritinemia, increased concentrations of pro-inflammatory cytokines (including soluble interleukin-2 receptor and C-X-C motif ligand 9), hepatosplenomegaly, coagulopathy, and neurologic symptoms. While the exact incidence of IEC-HS after CAR-T therapy remains uncertain, it is considered a rare but potentially fatal complication.

In a recently published consensus, the American Society for Transplantation and Cellular Therapy (ASTCT) defined IEC-HS as a syndrome characterized by three main features: 1) signs of macrophage activation or HLH; 2) direct relationship to IEC therapy; and 3) presence of new onset or worsening of cytopenias, elevated ferritin levels, coagulopathy with low fibrinogen, and/or liver enzyme elevation (Table 1). Importantly, although HLH-like symptoms can occur in patients experiencing cytokine release syndrome (CRS), IEC-HS typically appears later, often after CRS has begun to resolve. In fact, according to the ASTCT consensus, a key factor in diagnosing IEC-HS is its chronological independence from CRS.²

Table 1. ASTCT criteria for IEC-HS

Definition	The development of a pathological and biochemical hyperinflammatory syndrome independent from CRS and immune effector cell-associated neurotoxicity syndrome that 1) manifests with features of macrophage activation/HLH, 2) is attributable to IEC therapy, and 3) is associated with progression or new onset of cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia, and/or transaminitis
Criteria for identification	Clinical or laboratory manifestations
Most common manifestations	Elevated and/or rapidly rising ferritin (required)
	Onset with resolving/resolved CRS or worsening inflammatory response after initial improvement with CRS-directed therapy
	Hepatic transaminase elevation
	Hypofibrinogenemia
	Hemophagocytosis in bone marrow or other tissues
	Cytopenias
Other manifestations that may be present	Lactate dehydrogenase elevations
	Other coagulation abnormalities
	Direct hyperbilirubinemia
	New-onset splenomegaly
	Fever
	Neurotoxicity
	Pulmonary manifestations
	Renal insufficiency
	Hypertriglyceridemia

Pathophysiology

The pathogenesis of HLH post CAR-T therapy is multifactorial and may involve immune dysregulation, excessive cytokine release, and macrophage activation syndrome. CAR T cells, when activated by tumor antigens, can trigger a strong immune response, releasing cytokines like interleukin 6, tumor necrosis factor alpha, and interferon gamma. This intense cytokine surge hyperactivates T cells, macrophages, and NK cells, leading to dysregulated macrophage activation and hemophagocytosis, causing HLH.³

Management Strategies

Early recognition and prompt treatment are critical for managing IEC-HS. Although secondary HLH treatment varies due to its diverse causes, high-dose corticosteroids are often utilized. Targeted therapies like anakinra, ruxolitinib, and tocilizumab may also help control inflammation in IEC-HS. Recently, the FDA-approved emapalumab, effective in primary HLH, has gained off-label use in IEC-HS for its biologic impact and safety. Supportive care, such as fluids, antibiotics, transfusions, and organ-specific interventions, are essential.⁴

Clinical Considerations and Future Directions

Several clinical considerations merit attention in the management of IEC-HS. These include the implementation of ASTCT consensus guidelines for diagnosis and management, development of risk stratification algorithms to identify patients at high risk of IEC-HS, and novel therapeutic strategies targeting specific immune pathways implicated in IEC-HS pathogenesis. Furthermore, long-term monitoring and surveillance are crucial to detect late-onset complications and optimize patient outcomes.⁵

Conclusion

IEC-HS represents a rare but potentially life-threatening complication of post-CAR-T therapy in B-cell malignancies, necessitating vigilant monitoring and timely intervention. Early recognition and a multidisciplinary approach are key to improving outcomes.

1. Teachey DT, Bishop MR, Maloney DG, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat Rev Clin Oncol. 2018;15(4):218.
2. Hines MR, Knight TE, McNerney KO, et al. Immune effector cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Transplant Cell Ther. 2023;29(7):438.e1-438.e16.
3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.
4. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy – assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
5. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545-2554.

Drs. Ombada and Sandhu indicated no relevant conflicts of interest.

Acknowledgment: This article was edited by Drs. Natalia Tijaro Ovalle and Urshila Durani