Cytokine Release Syndrome after Tisagenlecleucel Infusion in Pediatric Patients with Refractory/Relapsed B-Lineage Acute Lymphoblastic Leukemia: Is there a Role for Diclofenac?

Research Article

Austin Crit Care J. 2021; 8(1): 1035.

Cytokine Release Syndrome after Tisagenlecleucel Infusion in Pediatric Patients with Refractory/Relapsed B-Lineage Acute Lymphoblastic Leukemia: Is there a Role for Diclofenac?

Napolitano S1*, Ottaviano G2, Bettini L3, Russotto V4, Bonanomi S1, Rovelli A1, Biondi A1,5, Ronad R4 and Balduzzi A1,5

1Department of Pediatric, Hematology-Oncology and Bone Marrow Transplantation Unit, Monza and Brianza Foundation for Children and their Mums, San Gerardo Hospital, Italy

2Molecular and Cellular Immunology Unit, University College of London, Great Ormond Street Institute of Child Health, United Kingdom

3Monza and Brianza Foundation for Children and their Mums, Tettamanti Laboratory, Italy

4Department of Emergency and Intensive Care, University Hospital San Gerardo, Italy

5University of Milan-Bicocca, Italy

*Corresponding author: Sara Napolitano, Pediatrician, Clinica Pediatrica, Università’ degli Studi di Milano Bicocca, Monza, Italy; Contact Information: Fondazione MBBM / Ospedale San Gerardo, Via Pergolesi 33, 20900 Monza (MB), Italy

Received: April 12, 2021; Accepted: May 11, 2021; Published: May 18, 2021


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.


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 conditions [1]. 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-1 [2]. In a cohort of consecutive unselected Intensive Care Unit (ICU) patients (including children) with fever (38.90C - 41.30C) 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 effects [3]. Continuous infusion of low-dose diclofenac allows to achieve fever control with no major cerebral or systemic side effects [4,5]. 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 lowdose 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 response [6-8]. 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 edema [10,11]. The severity of symptoms may correlate with serum cytokine concentrations and duration of exposure to the inflammatory cytokine storm [12]. Finally, sever neurological symptoms can occur with and, less often, without CRS, since some interleukins could drive trafficking of immune cells in central nervous system [7,9].

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 Grading [9,11,13,14]. 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.