Page 73 - 2020_02-Haematologica-web

Management of patients undergoing CAR T-cell therapy
infusion of CAR T-cell products, especially given the likely cytokine-driven exacerbation of inflammatory processes. The presence of fever should prompt blood and urine cul- tures, a chest radiograph, and, depending on symptoms, respiratory viral screening, cytomegalovirus and Epstein- Barr virus nucleic acid testing, computed tomography imaging, lumbar puncture, and/or brain magnetic reso- nance imaging. Empiric antimicrobial therapy based on symptoms and institutional protocols should not be delayed based on the presumption of CRS and clinicians should consider the prior duration of neutropenia.43
To reduce the time from recognition of suspected sepsis to treatment with antimicrobial medications, institutions may consider the use of patient group directives or condi- tional orders. These orders allow nursing staff to respond rapidly to signs and symptoms of infection, an example being the automatic administration of specific intravenous antibiotics following the detection of a fever.
Cytokine release syndrome
CRS is a form of systemic inflammatory response fol- lowing the infusion of CAR T cells. However, CRS has also been described following the administration of vari- ous monoclonal antibodies including bi-specific antibod- ies and anti-lymphocyte globulin and as a complication of haploidentical transplantation.44-48 CRS is the most com- mon complication after CAR T-cell therapy. Depending on the type of CAR T-cell therapy, the disease characteristics and the grading system which has been used, the reported incidence has ranged from 30-100% and for CRS grade 3 or 4 from 10-30%.49
The activation of CAR T cells is the triggering event of CRS. This leads to the release of effector cytokines such as interferon-γ, tumor necrosis factor-α and IL-2. These mol- ecules are, in turn, capable of activating the monocyte/macrophage system and inducing the produc- tion of a broad spectrum of pro-inflammatory cytokines (including IL-1, IL-6, IL-10, interferon γ and monocyte chemoattractant protein-1) leading to a raised level of C- reactive protein and sometimes hyperferritinemia. In pre- clinical models (humanized immunodeficient mice), it has been shown that human monocytes are the main source of IL-1 and IL-6 during CRS. The syndrome can be pre- vented by monocyte depletion or by blocking the IL-6 receptor with tocilizumab. Tocilizumab does not, howev- er, protect mice against late lethal neurotoxicity character- ized by meningeal inflammation. In contrast, an anti-IL-1 receptor antagonist (anakinra) appeared to prevent CRS and neurotoxicity in animal models.36,50,51
Severe CRS shares clinical features with macrophage activation syndrome, including fever, hyperferritinemia and multi-organ dysfunction. CRS usually occurs between 1 and 14 days after the CAR T-cell infusion and can last from 1 to 10 days.11,52 Its severity is variable and is evalu- ated according to a novel grading scale recently proposed by an American Society for Transplantation and Cellular Therapy (ASTCT) consensus panel.38 Rare but fatal cases with neurological involvement have been reported in the literature.11 Risk factors for CRS include tumor burden, the presence of active infection at the time of the infusion, the dose of infused CAR T cells, the type of CAR T-cell con- struct and the choice of LD regimen.37,53-55
The treatment for severe cases, in addition to sympto- matic measures, consists of the administration of tocilizumab (a monoclonal antibody against IL-6 receptor)
and, sometimes, corticosteroids. Tocilizumab should be administered no more than four times during one episode of CRS. Siltuximab (monoclonal antibody against IL-6) can be used as a second-line treatment (Figure 1).
An algorithm outlining the management of CRS is shown in Figure 1.
Neurological toxicity
The neurological toxicity seen in CAR T-cell recipients, previously called CAR-related encephalopathy syndrome (CRES), has recently been termed immune effector cell- associated neurotoxicity syndrome (ICANS).38 This is the second most common adverse event following CAR T-cell infusion and its incidence has been reported at rates vary- ing from 12% to 55%. In a recent study of 100 patients, the median time-to-onset of the first neurological symp- toms was 6 days (range, 1-34 days) after the CAR T-cell infusion.57 The duration of symptoms is generally between 2 and 9 days although late complications may occur.11,38,57 In general, it develops either at the same time as or following resolution of CRS. Deterioration in hand- writing has been shown to be an early predictor of central neurotoxicity. Therefore, daily writing tests over the first months following the CAR T-cell infusion can be used as a simple tool to detect incipient ICANS.
The spectrum of symptoms and signs is non-specific, ranging from confusion, headaches, tremors, hallucina- tions and abnormal movements to seizures, papilloedema and coma. Any neurological symptom occurring after the CAR T-cell infusion must therefore be considered as CAR T-related until proven otherwise. However, the ASTCT consensus panel recommended excluding non-specific symptoms such as headache, tremor, myoclonus, asterix- is, and hallucinations as they are usually managed symp- tomatically and do not generally trigger specific interven- tions.
Severe cases have been reported, occasionally leading to death, due to multifocal hemorrhage, cerebral edema and laminar cortical necrosis. The severity is correlated with the increase in specific biomarkers such as C-reactive pro- tein, ferritin and IL-6.11,58-60 Close monitoring of patients using validated nursing tools is necessary to identify early manifestations of neurotoxicity. This requires serial cogni- tive testing.
Rapid access to neurological expertise is needed. Cross- sectional imaging (computed tomography, magnetic reso- nance imaging), electroencephalography, and cerebro- spinal fluid examination may all be required in the man- agement of these complex patients. Anti-epileptic prophy- laxis with agents such as levetiracetam is not routinely recommended except in patients with a history of seizures or central nervous system disease.
Pre-existing neurological comorbidities may be a risk factor for the development of ICANS. Disease-associated factors include ALL, tumor burden, history of meningeal involvement and prior central nervous system-directed therapies.11,58-60 The intensity of ICANS has been correlated with the depth of lymphopenia and the homeostatic expansion of CAR T cells. Moreover, the severity of ICANS has also been found to be associated with the severity and early onset of CRS as measured by the extent of fever within 36 h of the infusion, hemodynamic insta- bility, tachypnea and hypoalbuminemia reflecting loss of vascular integrity and capillary leakage.
The CARTOX scoring system was updated by the
haematologica | 2020; 105(2)
307