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VOLUME 13 | ISSUE 3
symptomatic management with antipyretics and analgesics.8 A
full infectious workup, including blood cultures and appropriate
imaging, followed by prompt initiation of empiric antibiotics is
recommended, especially in the setting of concurrent neutropenia
due to limited ability to separate CRS from infection. Grade 2
CRS is characterized by symptoms requiring moderate intensity
interventions, including hypotension requiring fluid resuscitation
or one low-dose pressor, hypoxia requiring the addition of up to
40% oxygen, or the presence of a specific grade 2 organ toxicity.
Patients with grade 3 CRS require more than one pressor or high
titration of a single pressor (i.e., > 20 mcg/kg/min norepinephrine)
for hypotension and must have an oxygen requirement of > 40%
or a specific grade 3 organ toxicity. Blinatumomab has a short half
life of approximately 2 hours, which grants tight control of drug
levels throughout the treatment course. In the setting of grade 3
CRS, the infusion should be discontinued and may be restarted at
9 mcg/day once symptoms resolve.1 Dexamethasone is crucial in
attenuating the excessive inflammatory cascade during blinatum-
omab-related CRS, yet the optimal regimen remains to be deter-
mined. One published recommendation includes a tapered regimen
of dexamethasone 24 mg IV divided every 8 hours on day 1, 16 mg
divided every 12 hours on day 2, followed by 8 mg daily on days 3
and 4, but the rapidity of the taper depends on the patient’s clinical and are associated with CRS.15 CRP originates from the liver as
status.9 Because blinatumomab relies on T-cell activation for
efficacy, there is a theoretical concern that dexamethasone might
impair efficacy. Low doses of dexamethasone suppress cytokine
release without impairing in vitro cytotoxic effect,10 and receipt of
dexamethasone did not impair outcomes in a large phase 2 study11;
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nevertheless the absence of randomized data warrants judicious
use of dexamethasone. The IL-6 receptor antagonist tocilizumab
(Actemra®) is rarely needed for blinatumomab-related CRS, in con-
trast to CRS following CAR T cells (as discussed below). However, a
case of steroid-refractory blinatumomab-related CRS complicated
by macrophage activation syndrome that was responsive to
tocilizumab has been reported.12 Grade 4 CRS is characterized by
life-threatening symptoms or ventilator-dependent respiratory
failure, for which permanent discontinuation of blinatumomab
is recommended along with the aforementioned supportive care
strategies.1
CRS is a common and clinically significant AE following CAR
T cells, with a variable onset following infusion and a reported
all-grades incidence as high as 100% in ALL.13, 14 Despite increases
in numerous cytokines, the key mediator of CRS following CAR T
cells appears to be IL-6, an acute-phase reactant producing both
anti- and pro-inflammatory effects, dependent on the level and
signaling pathway involved. IL-6 is normally produced in response
to infection, trauma, or immunological challenge, and contributes
to a clinical syndrome mirroring sepsis.8 C-reactive protein (CRP)
and ferritin frequently are measured following CAR T-cell infusions
an acute phase reactant and can be used as a surrogate marker
for IL-6, given IL-6 monitoring can be a challenge with limited
assay availability and slow turnaround time.16 Significant ferritin
elevations (sometimes > 300,000 ng/m), may occur in the setting
of CRS, mimicking hemophagocytic lymphohistiocytosis with
associated hepatosplenomegaly and hypofibrinogenemia.
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