The early experience with CD19-targeted CAR T-cell therapy included a recognition that patients with morphologic residual leukemia, defined as >5% blasts in their bone marrow, had higher-grade fevers for a longer duration than patients with minimal residual disease or remission. In addition, hypoxia and neurologic events were associated with a broad spectrum of features, from obtundation to seizures and cytokine release syndrome (CRS).
“When we looked into the serum of these patients, we were able to see between those who had no toxicity versus those who did, what was unique was a large upregulation of cytokines within their serum,” Dr Davila said. “We classify this toxicity as cytokine release syndrome.”
In addition to CRS, “on-target, off-tumor” toxicities were recognized, “meaning that the CD19-targeted T-cells are killing CD19-positive targets that aren’t malignant B-cells but are normal B-cells,” he said.
CRS is caused by immune activation of T-cells, resulting in elevated levels of inflammatory cytokines and activation of other immune cells. CRS and other neurologic adverse reactions normally occur early during the treatment cycle, within the first 7 days of CAR T-cell infusion, and typically peak within the first 14 days. Delayed-onset neurologic toxicity, including CRS, can sometimes occur, “and that’s one of the main reasons that we try to keep patients close to our center for the first 30 days,” he said.
Late events associated with CAR T-cell therapy are infections, prolonged cytopenia, and B-cell aplasia, which will most likely be managed by the primary medical oncologist, Dr Davila said.
CRS is potentially life-threatening, and deaths do occur despite the use of best standards of care. “We were able to recognize some factors that we can use to be able to identify patients who are at high risk for severe CRS,” Dr Davila said. “These include high disease burden.” Patients with early-onset CRS and with rapid and high T-cell expansion are also at high risk for severe CRS.
Recognizing the Signs
Preinfusion biomarkers that can identify patients at high risk for CRS are baseline levels of C-reactive protein, ferritin, and interleukin (IL)-6.
The clinical signs and symptoms of CRS can range from the constitutional to the specific, such as azotemia. Apart from fever, the most common side effects of CAR T-cell therapy are respiratory, including tachypnea and hypoxemia, and cardiovascular, including hypotension, tachycardia, and changes in cardiac output.
A CRS grading scheme of 1 to 4 was developed in 2014, and vigilant intervention was recommended for higher grades of CRS. This system has been replaced by a movement toward early intervention at grade 2, “with the goal of trying to prevent these patients from developing more severe CRS and mortality,” Dr Davila said.
A harmonized CRS grading scheme from the American Society for Blood and Marrow Transplantation has emerged, in which fever is no longer required to grade subsequent CRS toxicity; instead, it relies on hypotension and hypoxia as drivers of grading CRS severity.
Rates of CRS between the 2 CD19-targeted CAR T-cell therapies are similar among patients with acute lymphoblastic leukemia (ALL). The rate of grade 3 or 4 CRS in these patients is between 22% and 23%. For patients with non-Hodgkin lymphoma, the rates of severe CRS in clinical trials were 13% with axicabtagene ciloleucel (Yescarta), 22% with tisagenlecleucel (Kymriah), and 1% with lisocabtagene maraleucel, an investigational CAR T-cell therapy.
The goal of management with CAR T-cell therapy is to prevent life-threatening complications, while preserving its antitumor effects.
The mainstay of CRS management is IL-6 inhibition using tocilizumab (Actemra) or corticosteroids (dexamethasone or methylprednisolone) to suppress inflammatory responses.
IL-6 blockade demonstrates a rapid reversal of CRS symptoms in most patients. If no response is observed in 24 to 48 hours, consider a second dose of tocilizumab or the initiation of steroids, Dr Davila advised.
Additional Adverse Events
Additional toxicities associated with CAR T-cells are B-cell aplasia and hypogammaglobulinemia, which are “on target, off tumor” adverse events for which intravenous immune globulin replacement may be used to mitigate the risk for infection.
Patients with high grades of CRS are at increased risk for subsequent infection, Dr Davila said, highlighting the increased likelihood of B-cell aplasia as a result of rapid expansion and persistence of CAR T-cells.
Prolonged cytopenia after CAR T-cell therapy has also been documented. Day 90 neutropenia was observed in 11% of patients who received treatment with axicabtagene ciloleucel in a clinical trial of patients with diffuse large B-cell lymphoma and in 17% of pediatric patients and young adults with ALL who received treatment with tisagenlecleucel in the ZUMA-1 clinical trial. The 90-day rates of thrombocytopenia were 7% with axicabtagene ciloleucel and 38% with tisagenlecleucel in the JULIET clinical trial.