CLINICAL NEWS
Predicting the Risk and Severity of Cytokine Release Syndrome
in Patients Receiving CAR T-Cell Therapy
While treatment with CD19-directed chimeric
antigen receptor (CAR) T cells has demonstrated
impressive response rates of over 80% in select
patients with B-cell malignancies, the associ-
ated toxicities – including severe neurotoxicity
and cytokine release syndrome (CRS) – are
serious concerns.
To better understand the kinetics of CRS and
identify biomarkers of its severity, Kevin A. Hay,
MD, MSc, from the Clinical Research Division
at the Fred Hutchinson Cancer Research
Center in Seattle, Washington, and researchers
conducted a phase I/II study of patients who
received lymphodepletion followed by anti-
CD19 CAR T-cell therapy to treat relapsed/
refractory B-cell malignancies. Their analysis,
published in Blood, identified several indepen-
dent predictors of CRS, including lymphodeple-
tion using cyclophosphamide and fludarabine,
higher CAR T-cell dose, and the presence of
thrombocytopenia before lymphodepletion.
The study enrolled 133 adult patients
(median age = 54 years; range = 43-62 years)
with CD19-positive B-cell malignancies,
including acute lymphocytic leukemia (n=47),
non-Hodgkin lymphoma (n=62), and chronic
lymphocytic leukemia (n=24). Patients had
received a median of four prior therapies (range
= 1-11 therapies); 25 (19%) had undergone
allogeneic hematopoietic cell transplantation
(HCT), 22 (17%) had undergone autologous
HCT, and three (2%) had undergone both.
Patients received lymphodepletion che-
motherapy with a cyclophosphamide-based
regimen with (n=104; 78%) or without (n=29;
22%) fludarabine. Two to four days later, they
received an infusion of CD19-directed CAR T
cells (formulated in a 1:1 ratio of CD4+:CD8+)
at one of three dose levels:
• 2×10 5 cells/kg (n=35; 26%)
• 2×10 6 cells/kg (n=86; 65%)
• 2×10 7 cells/kg (n=12; 9%)
The researchers collected blood samples before
lymphodepletion, on day zero before CAR T-
cell infusion, and at regular intervals after CAR
T-cell infusion to evaluate CAR T-cell counts
and serum biomarkers.
A total of 93 patients (70%) developed
CRS, graded according to modified National
Cancer Institute Common Terminology
Criteria for Adverse Events. Most patients
had grade 2 CRS (32%; defined as symptoms
that require or respond to moderate inter-
vention), followed by grade 1 (26%; defined
as symptoms that are not life-threatening
and require symptomatic treatment only)
and grade 3 (4.5%; defined as symptoms that
require or respond to aggressive intervention).
Ten patients (7.5%) developed grade ≥4 CRS
with life-threatening symptoms, half of whom
(n=5) died within the first 30 days after CAR
T-cell infusion because of complications associ-
ated with CRS and/or neurotoxicity. Another
ASHClinicalNews.org
patient died four months after treatment
because of irreversible neurotoxicity.
Neurologic adverse events (AEs) were also
common: 53 patients (40%) experienced one or
more grade ≥1 neurologic AE, and the severity of
those events was associated with the severity of
CRS (p<0.0001). All patients with grade ≥4 CRS
developed grade ≥3 neurotoxicity, which typically
presented after CRS (p=0.003), with the first
neurologic AE presenting a median of four days
(range = 2-7 days) after CAR T-cell infusion.
“Fever [≥100.4°F] was the first objective
sign of CRS,” the authors noted, “with the
exception of one patient who presented with
hypotension without fever.”
Fever occurred a median of 2.2 days (range
= 0.9-5.6 days) after CAR T-cell infusion and
lasted for a median of three days (range = 1.2-
4.8 days). Compared with patients with grade
1-3 CRS, patients who developed grade ≥4 CRS
had fevers that presented earlier after infusion
(p<0.001), peaked earlier (p=0.001), reached a
higher maximum temperature (p<0.0001), and
lasted longer (p=0.03).
Most patients (n=109; 82%) received both
lymphodepletion chemotherapy and CAR T-
cell infusion in the outpatient setting and were
only admitted at the onset of fever. Seventeen
patients (13%) required admission to the in-
tensive care unit (ICU) because of CRS and/or
neurologic AEs, with a median length of stay of
three days (range = 2-7 days).
The authors noted that, because CRS
reached peak severity a median of 3.4 days
after onset of fever (range = 1.4-4.7 days),
“there was sufficient time for hospital admis-
sion and therapeutic interventions to mitigate
CRS progression.” Twenty patients with CRS
and/or neurotoxicity were treated with both
tocilizumab and dexamethasone, five received
dexamethasone alone, and one received tocili-
zumab alone. Fever resolved within a median
of 0.4 days (interquartile range = 0.2-2.0 days)
after the first dose of either drug.
Multivariable analyses revealed several risk
factors for CRS (see TABLE 1 ), including those
indicative of more robust CAR T-cell expansion
(such as a higher bone marrow CD19+ tumor
burden), and baseline and treatment-related
factors that could be addressed early to reduce
the risk of CRS (such as the presence of throm-
bocytopenia and CAR T-cell dose level).
Many patients who developed grade
≥4 CRS presented with vascular instability,
TABLE 1. Univariate
capillary leak, and consumptive coagulopa-
thy, suggesting that “endothelial activation or
dysfunction coincides with severe CRS,” the
authors wrote.
“The risks of [anti-CD19] CAR T-cell
therapy could potentially be reduced by iden-
tifying patients who are at high risk of devel-
oping CRS before therapy and modifying the
treatment regimen, or early after CAR T-cell
infusion when preventative interventions could
be instituted,” the authors wrote. “A logical
approach to reducing the risk of severe CRS is
to reduce the CAR T-cell dose in patients with
high tumor burden.”
“[Our] data provide
a framework for
early intervention
studies to facilitate
safer application of
effective anti-CD19
CAR T-cell therapy.”
—KEVIN A. HAY, MD, MSc
The study is limited by its single-center
design, and the authors noted that they were
not able to identify the exact mechanisms
that led to endothelial activation in CRS or
an optimal approach to reducing CAR T-cell
dose while maintaining efficacy. However, they
concluded, “[our] data