Cytokine Release Syndrome With the Novel Treatments of Acute Lymphoblastic Leukemia: Pathophysiology, Prevention, and Treatment

Abstract

Purpose of Review T cell-based therapies (blinatumomab and CAR T cell therapy) have produced unprecedented responses in relapsed and refractory (r/r) acute lymphoblastic leukemia (ALL) but is accompanied with significant toxicities, of which one of the most common and serious is cytokine release syndrome (CRS). Here we will review the pathophysiology, prevention, and treatment of CRS. Recent Findings Efforts have been initiated to define and grade cytokine release syndrome (CRS), to identify patients at risk, to describe biomarkers that predict onset and severity, to understand the pathophysiology, and to prevent and treat severe cases to reduce T cell immunotherapy-related morbidity and mortality. Summary Optimizing the timing of T cell-based therapies in ALL, identifying new biomarkers, and investigating novel anticytokine agents that have anti-CRS activity are likely to be fruitful avenues of study.

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management

“…Cardiotoxicity is frequently a sequela of CRS, so understanding risks that may predispose to CRS should be considered in patients, especially those with pre-existing cardiovascular disease. Patients that are at risk of developing CRS are patients with high disease burden, an older age at the time of infusion, higher-intensity lymphodepleting regimen, utilization of fludarabine and cyclophosphamide during lymphodepleting chemotherapy, higher infused CAR T-cell doses, use of unselected bulk CD8 + T cells, high levels of CTL019 + CD8 and CD3 cells, the presence of inflammatory markers including a higher peak of C-reactive protein, and severe thrombocytopenia [25,27,33,34] (Table 7).…”

Cardiovascular Complications of Chimeric Antigen Receptor T-Cell Therapy: The Cytokine Release Syndrome and Associated Arrhythmias

“…Proposed risk factors for CRS are T-cell therapy targeting CD19 or CD22, [23] high disease burden, severe thrombocytopenia, higher infused CAR T-cell doses, higher-intensity lymphodepletion doses, addition of fludarabine to cyclophosphamide during lymphodepletion, use of unselected bulk CD8 þ T cells, high levels of CTL019 þ CD8 and CD3 cells, higher peak of C reactive protein (CRP), inflammatory markers, and patient factors, like older age. [5,24] Burstein et al [25] found, in a study of pediatric patients with ALL, that personal history of systolic or diastolic dysfunction, abnormal electrocardiogram findings, and having more than 25% blasts in the bone marrow were associated with a higher incidence of hypotension needing vasopressors. Although there is no available clinical data with regard to how cardiovascular risk factors and presence of cardiomyopathy could influence adverse cardiovascular outcomes during CAR T-cell treatment, it is reasonable to obtain a thorough cardiovascular risk assessment and baseline echocardiogram in those with significant cardiovascular risk burden prior to treatment with CAR, particularly in those patients who have previously received anthracycline chemotherapy.…”

CAR T cells better than BiTEs

“…This is of particular importance for older patients and their ability to tolerate severe CRS and ICANS, both of which occur more frequently with CAR T-cell therapy. 35 Furthermore, a benefit of blinatumomab is the ability to stop the infusion in response to toxicity, which is not a possibility with CAR T cells. Although the increased risk of severe CRS (8.3% to 43% depending on CD19 CAR construct and grading system) remains a major concern with CD19 CAR T cells, early mitigation strategies with tocilizumab and/or corticosteroids that have not decreased CAR efficacy impaired engraftment or persistence or increased risk of serious infection 36 and improved the safety profile.…”