Page 350 - Read Online

Page 8 of 12 Sharma et al. Neuroimmunol Neuroinflammation 2018;5:43 I http://dx.doi.org/10.20517/2347-8659.2018.51

Table 3. Cytokine release syndrome and chimeric antigen receptor-T cell related encephalopathy syndrome*
Grade CRS CRES
Grade 1 Non-life threatening symptoms (includes fever, nausea, fatigue, CARTOX-10 score 7-9 (mild impairment)
headache, myalgias, grade 1 organ toxicity)
Grade 2 Symptoms require moderate intervention (Oxygen requirement < CARTOX-10 score 3-6 (moderate impairment)
40%, hypotensive but responsive to fluids or low dose pressors,
grade 2 organ toxicity)
Grade 3 Symptoms require aggressive intervention (Oxygen requirement ≥ CARTOX-10 score 0-1 (severe impairment), intracranial
40%, hypotensive requiring high dose or multiple pressors, grade 2 pressure as noted by papilledema or CSF opening pressure <
organ toxicity or grade 4 transaminitis) 20 mmHg, partial seizures or non-convulsive seizures on EEG
responsive to benzodiazepines.
Grade 4 Life-threatening symptoms (ventilator support, grade 4 organ Obtunded, high grade papilledema or CSF opening pressure ≥
toxicity) 20 mmHg or cerebral edema on imaging, generalized seizures
or status epilepticus, new motor weakness
Grade 5 Death
*Adapted from Neelapu et al. [23] and Lee et al. [32] . CAR: chimeric antigen receptor; CRS: cytokine release syndrome; CRES: CAR-T related
encephalopathy syndrome; CSF: cerebrospinal fluid

cytokines by infused T-cells plays a significant role in this syndrome. A variety of inflammatory cytokines
have been found to be elevated in the serum of patients experiencing CRS, including interleukin(IL)-6,
interferon-gamma, IL-15, IL-8, IL-10, and IL-2. Higher disease burden has been predicted to lead to more
toxicity, but other factors continue to be explored. Various organ systems have been noted to be impacted by
CRS to varying degrees [23,31] [Figure 2]. CRS is generally seen within the first week after infusion of CAR-T
cell therapy and the peak risk is within the first two weeks of administration - thus, patients are typically
monitored in the acute inpatient setting (with access to an intensive care unit), and with frequent monitoring
of vital signs and laboratory parameters including blood counts, coagulation factors, measures of organ
function, and inflammatory markers [23,31] .

Various grading systems to evaluate CRS have been developed including one by Lee et al. which has been
[32]
[32]
used at various centers where the therapy is offered . The group modified a National Cancer Institute
Common Terminology Criteria for Adverse Events or CTCAE to define mild, moderate, severe and life-
threatening degrees of CRS. Grade 1 symptoms are mild, requiring supportive treatment, and include fever,
nausea, headache, etc. The grading is subsequently raised based on the degree of organ toxicity noted and
the level of intervention required to maintain a stable hemodynamic status, with grade 5 toxicity translating
to death [Table 3] .
[32]
Neurological toxicity is the other well-described and important phenomenon seen in these patients and
has been noted from the very onset of CAR-T trials. A wide spectrum of symptoms have been reported
including headaches, global encephalopathy, seizures, tremors, ataxia, hemiparesis, aphasia, ataxia, apraxia,
dysmetria, and cranial nerve palsies. In very rare cases, diffuse cerebral edema has been noted, which has in
some cases been fatal. Elevated cytokine levels are implicated although it is not yet completely clear what is
the mechanism of neurological dysfunction observed across patients. The role of endothelial activation and
increased blood-brain barrier permeability as well as role of IL-1 have been recently described in association
[33]
with neurotoxicity . Evaluation of several cases has demonstrated anti-CD19 CAR T cells may be found at
a higher level in the CSF of patients who experience neurotoxicity, and these patients may also have higher
levels of IL-6 in the CSF [32,34] . While the initial neurotoxicity is seen early in the course with concurrent CRS,
delayed neurological toxicity up to several weeks after infusion has also been noted, though the mechanism
for this remains unclear.

[23]
Neelapu et al. have described the neurological toxicity seen with CAR-T infusions and developed the
term CAR-T related encephalopathy syndrome (CRES), and have provided a helpful grading system for
[23]
this entity . Similar to CRS, Grade 1-4 are assigned based on a combination of a neurological assessment