mAbs could represent a therapeutic option for the
management of CRS. 3,6 Tocilizumab, a humanised
mAb, blocks the IL-6 receptor and subsequent
signalling. This results in decreased production
of anti-inflammatory mediators. Its use as a rescue
medication for severe CRS due to CAR T-cell
therapy, has been associated with near-immediate
reversal of CRS symptomatology (for example,
fever, hypotension, respiratory distress). 3
Dosages for tocilizumab can range from 4mg/
kg to 8mg/kg (maximum of 800mg per dose) for
patients ≥30kg. Tocilizumab is infused
intravenously over 60 minutes. 3 A subsequent
dose can be considered for patients with
persistent symptoms after 12–24 hours. The
acquisition of tocilizumab should be considered
for all patients undergoing CAR T-cell therapy. 3
Pharmacists and clinicians must ensure that
tocilizumab (or other anti-cytokine therapy) is
available on site and available for administration
prior to CAR T-cell infusion so that patients can
receive the drug as quickly as possible when
needed. Because of the high cost and the potential
of severe adverse events (for example, infections,
reactivation of viruses, tuberculosis, and
hepatotoxicity), the use of tocilizumab should be
limited strictly to critically ill patients. 1
The use of corticosteroids remains
controversial. Administration of high-dose
corticosteroids in the treatment of CRS results
in decline in detectable CAR T-cells via
apoptosis. 3 Dosing of steroids (intravenous
methylprednisolone and dexamethasone)
should be performed on protocol-specific
recommendations and characteristics of the
individual patient. Dexamethasone is the
preferred agent, due to superior central nervous
system penetration. 4,7 The corticosteroids should
be tapered quickly based on symptom resolution
to diminish the CAR T-cell effect.
Other agents that have been considered or used
in the management of CRS are siltuximab,
etanercept, infliximab and anakinra; however,
there are limited data so far. 4,6,7
Macrophage activation syndrome/
haemophagocytic lymphohistiocytosis
Some patients might experience CRS with
symptoms similar to macrophage activation
syndrome (MAS) or haemophagocytic
lymphohistiocytosis (HLH). 3,7
Studies have shown that tocilizumab does not
prevent the development of MAS/HLH and its
complications. 3
Central nervous system toxicities
Patients may also experience severe neurological
toxicities such as altered mental status,
confusion, aphasia, delirium and even seizures
and coma. 7 It remains important to monitor
the degree of confusion, somnolence and
encephalopathy to determine appropriate
management of symptoms (CAR T-cells detectable
in the cerebrospinal fluid). 6 Some case-reports
of lethal cerebral oedema in patients treated
with CAR T-cells have been described. 12 The
pathophysiology of these neurotoxic effects is
still unclear but inflammatory cytokines seem
to be involved. 1,7
Because dexamethasone has excellent CNS
penetration, its use can considered in cases of
severe and life-threatening neurologic symptoms
requiring urgent medical intervention. 3,6
Antiepileptic prophylaxis, such as levetiracetam,
can be given to patients at risk of seizures.
Tumour lysis syndrome
Tumour lysis syndrome (TLS) has been reported
in patients treated with CD19-targeted cells,
especially in patients with chronic lymphocytic
leukaemia. 7,13 TLS complications are usually
managed as per standard of care, that is,
prophylactic allopurinol, fluids and rasburicase
as needed. 7,13
Neutropenia
Following administration of chemotherapy
followed by CAR T-cells, patients frequently
become neutropenic and lymphopenic. This can
predispose patients to opportunistic infections.
The degree and rates of neutropenia vary
depending on the conditioning regimen received.
Prophylaxis with granulocyte colony-stimulating
factors may be initiated 24 hours after completion
of the conditioning regimen and continued until
neutrophil recovery. Prophylactic antimicrobials
may also be considered for patients with
neutropenia.
Fever
Nearly all patients develop fever after CAR T-cell
infusion with 80–100% having grade 3 or greater
fever. Supportive treatments include use of
acetaminophen for all patients who develop fever.
Non-steroidal anti-inflammatory drugs should be
avoided. 6
Hypogammaglobulinaemia
This is a common condition observed with the
profound and prolonged B-cell aplasia that occurs
following anti-CD19 CAR T-cell infusions.
Pharmacists and physicians
must ensure that anti-cytokine
therapy is available on site prior
to CAR T-cell infusion
Replacement therapy with intravenous
immunoglobulins has been used. 6,7
Conclusions
CAR T-cell therapy is a powerful new tool in the
oncologist’s arsenal and can induce remissions
(CD19 CAR T-cell) in otherwise refractory children
and young adults with acute lymphoblastic
leukaemia. Recently, tisagenlecleucel (Kymriah ®
Novartis) and axicabtagene ciloleucel (Yescarta ® ,
Kite Pharma) have been FDA approved. CAR
T-cells bring spectacular opportunities, but also
challenges, for pharmacists, especially in the
management of side effects and toxicities.
Supportive care and early anti-cytokine therapy
is absolutely required to mitigate the life-
threatening consequences of severe CRS.
Education of pharmacists involved in CAR T-cell
infusion and knowledge of potential side effects
is important.
21
HHE 2018 | hospitalhealthcare.com
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