ABSTRACT
Background: Cytokine release syndrome (CRS) is a major complication
after chimeric-antigen receptor (CAR) T cell treatment, characterized by
an uncontrolled sistemic inflammatory reaction. The potential role of
diclofenac in the management of CRS has been investigated in five
pediatric patients treated for relapsed/refractory B-lineage acute
lymphoblastic leukemia.
Procedure: in case of persistent fever with fever-free intervals shorter
than 3 hours, diclofenac continuous infusion was initiated, at the
starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose, in
our experience, possibly escalated up to 1 mg/Kg/day, as per
institutional guidelines. Vital signs, O2 requirement, SpO2/FiO2 ratio
and dosage of diclofenac and vasopressors until CRS resolution were
recorded.
Results: CRS occurred at a median of 20 hours (range 8-27) after
tisagenlecleucel infusion. Diclofenac was started at a median of 20
hours (range 13-33) after fever onset. A mean of 3,07 febrile peaks
without diclofenac and 0,95 with diclofenac were reported (p-value
0.02). A clinical benefit was achieved by hampering the progression of
tachypnea and, mainly, tachycardia. Despite fever control, CRS
progressed in four of the five patients and hypotension requiring
vasopressors, fluid retention, besides hypoxia, occurred. Vasopressors
were followed by 1-2 doses of tocilizumab (one in patient 2 and two in
patients 3, 4, and 5), plus steroids in patients 4 and 5.
Conclusion: based on a limited number of patients, diclofenac leads to a
better fever control, which translates into symptom relief and
improvement of tachycardia, but could not prevent the progression of
CRS.
INTRODUCTION
Diclofenac is a commonly prescribed non-steroidal anti-inflammatory drug
(NSAID) with analgesic, anti-inflammatory, and antipyretic properties,
which has been proven effective in a variety of acute and chronic pain
and inflammatory
conditions1. The
principal mechanism of action is the inhibition of prostaglandin
synthesis by the inhibition of cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) with relative equipotency. The binding of
NSAIDs to COX isozymes inhibits the synthesis of prostanoids
(prostaglandin PGE2, PGD2, PGF2, prostacyclin PGI2 and thromboxane
TXA2). PGE2 is the dominant prostanoid produced in inflammation and the
inhibition of its synthesis is considered the main mechanism of the
potent analgesic and anti-inflammatory properties of these agents.
Moreover, it has been demonstrated that diclofenac has higher
selectivity for COX-2 than COX-12. In a cohort of
consecutive unselected Intensive Care Unit (ICU) patients (including
children) with fever (38.9°C - 41.3°C) not responsive to paracetamol,
diclofenac sodium (starting dose 0.2 mg/kg intravenous - i.v.) was
effective in reducing body temperature in the majority of the
investigated patients, with no major side
effects3. Continuous
infusion of low-dose diclofenac allows to achieve fever control with no
major cerebral or systemic side effects4,5.
Renal function impairment represents a potential side effect, but it is
expected to be transient/reversible, preventable by fluid optimization
and infrequent in pediatrics.
The aim of this study is to describe the possible role of low-dose i.v.
continuous infusion diclofenac in the management of cytokine release
syndrome (CRS). CRS is an uncontrolled systemic inflammatory reaction
resulting from a massive release of cytokines due to the interaction
between tumor and immune effector
cells6. The initial
source of cytokines can be either the target cells themselves or the
immune cells that have been recruited to the tumor site. This condition
leads to excessive activation of immune cells, especially macrophages,
which induces a further release of cytokines, like IL-1, IL-6, IL-8,
IL-10, and MCP-1, culminating in a cytokine storm with an enhanced
inflammatory response6,7,8.The clinical pattern of CRS ranges from mild to severe life-threatening
symptoms (grade 1 -
4)9. Patients with CRS
frequently present with fever, shivers, tachycardia, dyspnea,
hypotension, fluid retention, malaise, headache, nausea, vomiting, rash,
myalgia, arthralgia, and rigor. Respiratory symptoms such as dyspnea,
tachypnea, and hypoxia occur frequently and severity may vary. Cardiac
complications include tachycardia, hypotension, and sudden cardiac
dysfunction. In addition, vascular leakage is common and presents as
peripheral and pulmonary
edema10,11.
The severity of symptoms may correlate with serum cytokine
concentrations and duration of exposure to the inflammatory cytokine
storm12. Finally,
sever neurological symptoms can occur with and, less often, without CRS,
since some interleukins could drive trafficking of immune cells in
central nervous system7,9.
Multiple grading systems have been used to clinically classify the
severity of CRS, including the National Cancer Institute Common
Terminology Criteria for Adverse Events, the Penn Grading Scale, the Lee
Grading Scale, which, more recently, were merged into the ASTCT
Grading9,11,13,14.
Criteria for severe or life‐threatening CRS differ among these grading
systems, in terms of dose and numbers of vasopressors and type and
extent of O2 support requirement. In all of these scales, severe and
life‐threatening grades of CRS require advanced supportive care.
The purpose of this study is to investigate the impact of diclofenac in
the management of CRS occurring after tisagenlecleucel infusion.
PATIENTS AND METHODS
All patients scheduled for receiving tisagenlecleucel were admitted in
the Pediatric Transplant Unit for lymphodepleting chemotherapy and CAR-T
cell infusion. In case CRS occurred, patients were managed in the ward,
with the collaboration of the ICU medical staff, whenever appropriate.
In case of life-threatening CRS, when respiratory management included
the possibility of invasive mechanical ventilation, patients were
transferred to ICU.
For the purpose of this study, CRS was graded according to the ASTCT
grading, but also according to the two alternative main scoring systems,
namely U-Penn and Lee classifications, all summarized in Table 1.
In case of persistent fever with fever-free intervals shorter than 3
hours, diclofenac continuous infusion was initiated, at the starting
dose of 0.5 mg/Kg/day, the lowest effective pediatric dose, in our
experience, possibly escalated up to 1 mg/Kg/day, as per institutional
guidelines.
Peripheral oxygen saturation (SpO2), heart rate (HR), noninvasive blood
pressure (NBP), respiratory rate (RR) and body temperature (Temp) were
recorded at least every 3 hours, more frequently or continuously if
clinically appropriate. Blood tests (CBC, CRP, biochemistry,
coagulation) were performed daily to assess and monitor CRS. Vasopressor
use and doses and respiratory support parameters, which ranged from
oxygen support through nasal cannula to continuous positive airway
pressure (C-PAP) helmet, were recorded.
FiO2 (Fraction of inspired Oxygen) values were estimated as follows:
FiO2 24, 28, 32 and 36% for nasal cannulae with oxygen flow of 1, 2, 3
and 4 L/min respectively; FiO2 40% for aerosol mask with oxygen flow of
8 L/min; FiO2 from 24 to 50 % for Venturi mask; FiO2 100 % for
non-rebreathing mask with reservoir bag; FiO2 as set according to
manufacturer instructions for helmet C-PAP.
The SpO2 to FiO2 ratio was calculated as a useful tool for
stratification of hypoxia severity in the pediatric population. As
previously reported, in the absence of an arterial access, directly
measuring PaO2 (Partial Pressure of Oxygen), the SpO2 to FiO2 ratio
shows a good correlation with the FiO2 to PaO2
ratio15,16.
Mann-Whitney statistical test was used for p-value calculation of the
efficacy of diclofenac based on the number of febrile peaks during 24
hours with and without diclofenac (the results are shown in table 3).
RESULTS
Five out of the first 10 patients treated with tisagenlecleucel for
chemorefractory or post-transplant relapsed B-lineage ALL in our
institution, from August 2016 to August 2019, experienced some grade of
CRS. Characteristics of the five patients (3 males; median age 5 years,
range 3-21 years) are reported in Table 2. Briefly, patients 1, 3, and 4
had relapsed after stem cell transplantation, whereas patient 2
presented with a chemorefractory relapse and patient 5 with a second
refractory relapse. Bone marrow blasts upon screening ranged from 15%
to 70% and at lymphodepletion initiation ranged from 48% to 70% in
this patient series.
Vital signs monitoring (heart rate, respiratory rate, temperature, blood
pressure, SpO2/FiO2) as well as CRP levels, diclofenac, dopamine and
noradrenaline doses from the time of CAR-T cell infusion until
resolution of CRS have been plotted for each patient in Figure 1 and
scored according to three different grading systems Penn, Lee and ASCTC.
Grade 3-4 CRS was observed in four patients, while only one patient
presented with grade 1 CRS. Fever, consistently defined as grade 1 CRS
among the different grading systems (even if low-grade, i.e.
<37.5°C) was almost invariably associated with shivers,
tachycardia, tachypnea and hypotension. Moreover, the maximum interval
elapsing between spikes, despite the use of i.v. paracetamol, rarely
exceeded three hours.
Patient 1 experienced maximum grade I CRS, according to Penn, Lee and
ASCTC, consisting of fever only, requiring antipyretic, including
diclofenac. No need for oxygen support, vasopressors nor tocilizumab
occurred within the duration of CRS (14 days).
Patient 2 experienced maximum grade 4 CRS, according to Penn and grade 3
according to Lee and ASCTC grading. High-dose oxygen (high-flow nasal
cannula, HFNC) with FiO2 45% for almost 5 days (89 hours) and dopamine
10 mcg/kg/min for 24 hours were required.
Patients 3, 4, and 5 presented CRS maximum grade IV, according to Penn,
Lee and ASCTC, and required high-dose dopamine (10-12 mcg/kg/min), plus
norepinephrine in patient 5, C-PAP in patient 3 and 5 and intubation in
patient 4.
Median time to fever onset was 20 hours (range 8-27) after CAR-T
infusion, whereas treatment with diclofenac was initiated at a median of
20 hours (median, range 13-33) after fever onset. The starting dose of
diclofenac i.v. continous infusion was 0.5 mg/kg/day, and the dose was
escalated/adjusted according to the temperature curves, with a maximum
dose of 1 mg/kg/day.
In order to assess the impact of diclofenac in the management of CRS,
firstly, its effectiveness in controlling sustained fever within the
first 24 hours after the start of the therapy, compared with the 24
hours prior to diclofenac initiation, was assessed. A decline in fever
peaks as compared to baseline was observed in all patients during the
first 24 hours after starting treatment with diclofenac (Figure 1).
Specifically, the highest median body temperature was significantly
lower within 13-24 h after diclofenac infusion started as compared to
the early hours of fever onset, where patients remained febrile despite
standard anti-pyretic drugs (e.g. paracetamol). Furthermore the efficacy
of diclofenac has been assessed as the number of febrile peaks during 24
hours with and without diclofenac: a mean of 3,07 febrile peaks without
diclofenac and 0,95 with diclofenac with a p-value of 0,02 (Table 3)
have been observed.
Moreover, we hypothesized that fever control by means of diclofenac
could provide a beneficial effect on vital parameters and hemodynamic
functions. Although some patients still presented with fever, within the
first 48h hours after starting the infusion of diclofenac a clinical
benefit was obtained by hampering progression of tachycardia and
tachypnea. Heart rate and respiratory rate were significantly reduced
after 48 hours of diclofenac therapy, as compared to the same baseline
parameters, just before starting treatment (Figure 1). Conversely, no
direct detrimental effect of diclofenac on blood pressure was observed.
Whenever diclofenac had to be discontinued (4 events in 3 patients), due
to drug infusion incompatibilities in patients with venous access
issues, fever invariably occurred, but was promptly controlled upon
diclofenac resumption. However, despite fever control, in the following
days, four patients presented with severe hemodynamic instability, with
hypotension and oliguria, which required vasopressors: four patients
received dopamine 5-12 mcg/kg/day, and one patient received also i.v.
norepinephrine at 0,1 mcg/kg/min for less than 48 hours.
Vasopressors were followed by the administration of tocilizumab (1 dose
in patient 2 and two doses in patients 3, 4, and 5), the recombinant
humanized monoclonal antibody, directed against the interleukin‐6
receptor, approved by the FDA for treatment of severe or
life-threatening CAR-T cell induced CRS. Tocilizumab binds both soluble
and membrane‐bound IL‐6 receptor and inhibits IL‐6‐mediated signaling
through these receptors17.
The SpO2/FiO2 ratio consistently varied along with the severity of CRS,
with lower SpO2/FiO2 values in patients with higher body temperature,
heart rate, respiratory rate and CPR values.
A SpO2/FiO2 ratio below 200 was considered among the clinical indicators
of severe respiratory distress leading to the decision of ICU admission
and invasive mechanical ventilation in patient 4. Patient 5 was
transferred to ICU due to long-lasting refractory fluid overload,
jeopardizing his cardio-respiratory dynamics.
Furthermore, a significant increase of CRP was observed in all patients,
but rising with different kinetics, according to the evolution of CRS.
The highest CRP was reached at a median of 4 days (range 4-8 days), with
decreasing values thereafter. However it was not possible to attribute a
role to the anti-inflammatory effect of diclofenac, compared with the
powerful effect of tocilizumab, in reducing CRP to normal levels.
Eventually, CRS resolved at a median of 10 days (range 9-15) and no
major sequelae were observed in the follow-up.
DISCUSSION
NSAIDs have antipyretic, analgesic and anti-inflammatory effects. They
are used in pediatrics, even if less frequently than in adults, and have
multiple therapeutic indications, the most common ones being fever, pain
after surgery, and inflammatory
disorders18,19.
In this study we described the course of CRS in five patients who have
been treated with diclofenac for CRS-related fever after
tisagenlecleucel infusion for relapse or chemorefractory B-lineage ALL.
The reported incidence of CRS after CAR-T cell therapy overall is highly
variable and ranges from 35% to
93%20,21,22.
In the pediatric ALL population CRS was reported in the 77% of the
patients treated with tisagenlecleucel, with 22% and 27% presenting
grade III and IV,
respectively23. Time
to CRS onset after CAR-T infusion was 3 days (range 1-22) and the median
duration 8 days (range 1-36); 39% of the patients required tocilizumab
(23% only one dose and 13% two doses), with 50% of the patients being
transferred to the ICU and 15% requiring
intubation24.
CRS treatment included antipyretics for fever, intravenous fluids and
vasopressors for hypotension, besides supportive care for respiratory
distress, ranging from low flow oxygen to mechanical ventilation.
Vasopressors were reported in the 53% of the patients enrolled in the
expanded access, with 24% requiring
high-doses24.
Corticosteroids could mitigate the cytokine storm, but their use was
limited due to the risk that the clinical effectiveness of CAR-T cell
therapy could be potentially jeopardized by the blocking of T cell
activation, function, and
proliferation8,25.
In the original trial with tisagenleclaucel corticosteroids were
administered in 20% of the treated patients (16/79)24.
The high-grade CRS occurring in our series of patients was not
surprising, due to the high disease burden at the time of
lymphodepletion. In the management of fever unresponsive to paracetamol
or other NSAIDs, diclofenac i.v. continuous infusion from 0,5 mg/kg to 1
mg/kg was planned, according to our standard practice for persistent or
refractory fever. Diclofenac was able to control fever, occurring
between 12 and 72 hours after tisagenlecleucel infusion and
characterized by a very severe profile, sometimes with spikes up to
39-40°C every 3-4 hours. In all the 5 patients diclofenac allowed
prolonged control of tachycardia and tachypnea, on top of fever control.
Despite the initial hemodynamic stability, diclofenac could not prevent
CRS progression in 4 out of 5 patients.
We can conclude from our experience that the use of diclofenac had
improved patient symptoms and decreased the complexity of patient
management, by means of fever control and the consequent improvement of
vital parameters, up to the progression of CRS. No toxic effects
associated with diclofenac were
observed26. Moreover
diclofenac might have limited / delayed the use of other drugs in the
management of CRS by getting rid of fever-associated vital sign
impairment.
Mild to severe respiratory failure is among the hallmarks of CRS.
Capillary leak is the mechanism underlying hypoxia and lung opacities.
CRS-associated fever, however, has a major role in increasing minute
ventilation and respiratory distress. We may argue that, in a
significant proportion of patients, the increased respiratory workload
driven by fever may prompt the decision to proceed with endotracheal
intubation and invasive mechanical ventilation.
Low-dose
diclofenac infusion, through its effect in reducing oxygen consumption,
may contribute to reduce non-invasive ventilation failure and prevent
ICU admission. We cannot prove or rule out that diclofenac could have
had any impact on CRS evolution in our series of patients. The patients
in our series, with a high disease burden, became unstable shortly after
CAR-t cell infusion and, in the absence of diclofenac, their CRS
management would have required to anticipate the subsequent steps.
Therefore diclofenac serves as first step in CRS management in our
institution and may allow subsequent steps to be delayed. We cannot
speculate whether the chance to delay tocilizumab could be of some
benefit, allowing prolonged IL-6 effects.
In conclusion, the use of diclofenac relieved patient’s symptoms and
decreased the complexity of management by limiting the increased
cardio-respiratory workload secondary to fever. Despite CRS progression,
fever control and the reduction of its detrimental effect on vital
parameters decreased patient discomfort. No conclusions on CRS hampering
could be drawn based on this limited series of patients.
ACKNOWLEDGMENTS
The authors wish to thank the clinical and the laboratory team and are
grateful to the Comitato Maria Letizia Verga per lo Studio e la Cura
della Leucemia del Bambino for their continuous support of clinical and
research activities.
CONFLICT OF INTEREST
The author certify that there are no conflicts of interest in the
subject matter or material discussed in this manuscript.
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LEGENDS
TABLE 1 Synopsis of CRS grading according to the U-Penn, Lee and ASTCT
classifications
TABLE 2 Characteristics of the five patients with relapsed/refractory
B-ALL experiencing CRS after tisagenlecleucel
TABLE 3 Number of febrile peaks/24 hours measured since the fever
started up to the initiation of diclofenac and throughout diclofenac
treatment up to tocilizumab, if any: a mean of 3,07 febrile peaks/24
hours without diclofenac and 0,95/24 hours with diclofenac were observed
FIGURE 1 CRS course overtime in the five patients
Diclofenac mg/Kg: intravenous continuous infusion (i.v. c.i.) daily dose
is indicated; body temperature (°C); CRP levels (mg/dL);
Dopamine infusion;
HR: heart rate; RR: breath rate; SBP: systolic blood pressure; DBP:
diastolic blood pressure; SpO2/FiO2 ratio