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Clinical Pharmacy Specialist, Leukemia
Department of Clinical Pharmacy
The University of Texas MD Anderson Cancer Center
Shilpa Paul, PharmD, BCOP, has no relevant conflicts of interest to report.
To date, the FDA has approved the CD19-directed CAR T-cell therapies tisagenlecleucel and axicabtagene ciloleucel (axi-cel) for several hematologic malignancies in the relapsed/refractory setting. These agents have demonstrated curative potential, yet they can sometimes cause severe acute and long-term toxicities. Below, I share my perspective on the key role of pharmacists in prevention, identification, and management of these toxicities.
The major acute toxicities associated with CAR T-cells are cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Toxicity risk factors include CAR T-cell design and dose along with patient factors such as tumor burden.
CRS is the most common acute event and is caused by cytokines (eg, IL-6, IFN-γ) released during CAR T-cell activation and tumor engagement, which activates macrophages and monocytes that further enhance the inflammatory process. CRS presentation ranges from fever, which is typically the most common and earliest sign, to rigors, arthralgias, myalgias, and finally to severe complications such as hypotension, hypoxia, and capillary leak syndrome, leading to multiorgan dysfunction. Although onset varies by type of CAR T-cell therapy, CRS usually occurs within the first week after infusion (median onset: 2‑3 days).
ICANS is the second most common acute event. Although its pathophysiology is still under investigation, ICANS appears to involve disruption or increased permeability of the blood–brain barrier due to the CAR T‑cell–related cytokine release. The clinical features of ICANS include agitation, delirium, somnolence, speech impairment, seizures, and even encephalopathy leading to coma. The median onset for ICANS is 4-6 days.
Pharmacist’s Role in Identification and Management of Acute Toxicities
The pharmacist’s role can differ among and within institutions. As a clinical pharmacist at MD Anderson Cancer Center, I am involved in ensuring that CRS or ICANS is graded according to our internal CAR T-cell therapy toxicity management algorithm, which closely follows the 2019 American Society for Transplantation and Cellular Therapy grading criteria. Accurate grading is vital to appropriate management. For instance, grade 1 CRS can be managed with supportive care whereas grade 3/4 involves admission to the intensive care unit and administration of high-dose steroids plus the IL-6 antagonist tocilizumab, if it has not already been given. Grade 1 ICANS can also be managed with supportive care, but as the grade/severity increases, management includes steroids, antiepileptic drugs, and other supportive measures. It should be noted that tocilizumab is ineffective against ICANS and should not be given to patients experiencing ICANS without concomitant CRS. My clinical role often involves ensuring early intervention, effectively managing toxicities with appropriate drugs and doses, and preventing drug misuse, such as premature steroid use for grade 1 CRS or ICANS, which may affect the efficacy of CAR T-cell therapy.
Staff pharmacists may largely focus on the critical duties of securing drugs for toxicity management, ensuring correct dosing, and verifying drug orders. When a patient is scheduled to receive CAR T-cells, pharmacists ensure that tocilizumab is sequestered for the patient. Ensuring tocilizumab availability is particularly important because this agent can be expensive and may not always be readily accessible; furthermore, the FDA mandates that certified facilities must have immediate, on-site access to a minimum of 2 doses of tocilizumab per patient within 2 hours of tisagenlecleucel or axi-cel infusion, if needed. At my institution, we help place tocilizumab orders at initiation of CAR T-cell therapy for physicians to sign. The tocilizumab order can then be activated in response to CRS at any time by the nurses on our CAR T-cell–dedicated floor. The pharmacist should also know appropriate dosing for tocilizumab as the dose for adults differs from that for pediatric patients. Pharmacists should also be familiar with the safety profile of these agents used to manage toxicity. For example, tocilizumab may elevate transaminases and lead to infusion‑related reactions or serious infections.
Like all clinicians involved in the CAR T-cell therapy process, pharmacists must receive FDA-mandated training in CRS and ICANS management. When my institution began our CAR T-cell program, we underwent education and certification for the approved CAR T-cell therapies.
To view individualized recommendations on CRS and ICANS management from a multidisciplinary panel of experts, please visit CCO’s Interactive Decision Support Tool: Assessment and Management of CAR T-Cell Toxicities.
Pharmacist’s Role in Management of Long-term Toxicities
CAR T-cell therapy is associated with several long‑term toxicities such as cytopenias, B-cell aplasia, and hypogammaglobulinemia. A report at ASH 2018 suggested that long-term neurologic and psychiatric events are rare but can occur.
If the patient is experiencing recurrent infections in the setting of hypogammaglobulinemia—not just hypogammaglobulinemia alone—then pharmacists have their standard role of supporting patients with intravenous immunoglobulin. Patients with cytopenias can be empirically managed with prophylactic antimicrobials until they have full count recovery.
For a nurse’s perspective on educating patients and caregivers about CAR T-cell–associated toxicities, please see this commentary from Alix Beaupierre, BSN, RN, OCN®, Transplant and Cellular Therapy Nurse Coordinator with Moffitt Cancer Center.
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