Credit: MSKCC
Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.
However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).
With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).
But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.
Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.
Response, bridge to allo-SCT
Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.
After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.
Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.
Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.
Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.
“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”
CRS diagnosis, stratification
In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.
Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).
Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.
The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.
Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.
Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.
Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.
