Secondary haemophagocytic lymphohistiocytosis (sHLH) or macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, e.g., COVID-19 infection, malignancy or autoimmune diseases. It is also a rare complication of allogeneic haematopoietic cell transplantation (allo-HCT), independent of the underlying trigger mechanism or underlying disorders associated with high mortality. There have been increasing reports of sHLH/MAS occurrence following CAR-T cell therapy, but its differentiation from cytokine release syndrome (CRS) is often difficult (Sandler et al. 2020).

The diagnosis of sHLH/MAS post-HCT requires observation of the clinical signs and symptoms of hyperinflammation, which can overlap with the symptoms of cytokine release syndrome or infectious complications, requiring a differential diagnosis. Typically, these symptoms include fever, cytopenia of more than one lineage, and multiorgan failure. Persistent fever without an identified infective cause or worsening fever in patients who have been treated for infection should prompt screening for sHLH/MAS (Karakike and Giamarellos-Bourboulis 2019). Serum ferritin is a suitable and readily available biomarker of sHLH/MAS and can also be used to monitor response to treatment.

CAR-T cell therapy, while emerging as an effective treatment for both haematological and nonhaematological malignancies, is associated with cytokine release syndrome (CRS), an acute toxicity resulting in hyperinflammation. Patients can present with CRS across a spectrum of severities, from low-grade constitutional symptoms to higher-grade systemic illness with multiorgan dysfunction, and in its most severe form, CRS can progress to fulminant sHLH/MAS. Neelapu et al. proposed diagnostic criteria for sHLH/MAS in patients with CRS post-CAR-T cell therapy demonstrating a peak serum ferritin measurement of >10,000 μg/L and two of the following findings: a grade > 3 increase in serum transaminase or bilirubin; grade > 3 oliguria or increase in serum creatinine; grade > 3 pulmonary oedema or histological evidence of haemophagocytosis in the bone marrow or organs (Neelapu et al. 2018) (Tables 30.1 and 30.2).

Table 30.1 Use of published criteria to support the diagnosis of sHLH/MAS after CAR-T cell therapy (adapted from Sandler et al. 2020)
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Table 30.2 The Hscore adapted to CAR-T cell therapy
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Table 30.3 Use of published protocols in the management of sHLH/MAS post-HSCT or CAR-T cell therapy
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For effective treatment of sHLH/MAS, aggressive immunosuppression is required to control the hyperinflammatory state. Prompt recognition and treatment are important and reduce mortality. Corticosteroids remain the cornerstone of induction treatment, although over half of patients are steroid resistant (Fukaya et al. 2008) (Table 30.3).

Anakinra, an IL-1 antagonist, is effective in refractory sHLH/MAS and relatively safe in patients with sepsis (Shakoory et al. 2016) (Eloseily et al. 2019). Thus, anakinra has been used for refractory sHLH/MAS and was found to be effective in adult sHLH/MAS for patients with severe sHLH/MAS. Intravenous immunoglobulin (IVIG) infusions may also be effective in steroid-resistant and infection (EBV)-triggered sHLH/MAS (Chen et al. 1995).

A treatment protocol for sHLH/MAS accepting the heterogeneity of this syndrome has been recently published. The first-line treatment is intravenous methylprednisolone (IVMP) 1 g/day for 3–5 days plus IVIG 1 g/kg for 2 days, which can be repeated on day 14. If there is evidence of established sHLH/MAS or clinical deterioration, anakinra is added at 1–2 mg/kg daily, increasing up to 8 mg/kg/day. CSA is considered for early or steroid-resistant disease. Etoposide should be considered in refractory cases but can be problematic due to the already preexisting cytopenias in patients with sHLH/MAS following CAR-T cell therapy. Additionally, triggers, such as EBV, bacterial infection or underlying malignancy, particularly lymphoma, should be screened for and treated if adequately defined (Vatsayan et al. 2016).

Considerations for Patients Undergoing CAR-T Cell Therapy

  • Steroids remain the cornerstone for sHLH/MAS treatment, but 50% of patients are resistant.

  • A recent recommendation for HLH/MAS after CAR-T therapy:

    • Methylprednisolone 1 g/day for 3–5 days + IVIG 1 g/kg for 2 days, repeated on day 14.

    • In the case of deterioration, IV anakinra can be added up to 100 mg x 4/day.

    • Etoposide for refractory cases.

  • Other treatments for sHLH/MAS after CAR-T cell therapy.

    • Ruxolitinib: found to be effective in a case report and small phase 1 study

  • Cytokine blockers might be used

  • IVIG: might be effective, especially if the underlying cause is infection.

Key Points

  • Patients with persistent fever without an identified infection should be screened for sHLH/MAS.

  • Serum ferritin is a suitable and readily available biomarker of sHLH/MAS.

  • Corticosteroids are the cornerstone of induction treatment.

  • >50% of patients are steroid-refractory.

  • IV anakinra is the second line treatment.

  • Etoposide can be used in refractory sHLH/MAS.