CRP levels signal cytokine storm in CAR therapy

C-reactive protein levels can serve as a reliable indicator for severe cytokine release syndrome in patients receiving chimeric antigen receptor T-cell therapy, according to additional analyses from a phase I trial.

"We have found that daily monitoring of CRP [C-reactive protein] in combination with simple clinical parameters allows us to identify patients in need of intensive medical monitoring and potentially pharmacologic management," reported Dr. Marco Davila in Science Translational Medicine.

Dr. Marco L. Davila

The observations were based on analysis of clinical data and serum cytokine levels over the first 21 days after infusing CD19-targeted 19-28z chimeric antigen receptor (CAR) T cells into 16 patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) (Sci. Transl. Med. 2014;6:1-9).

CAR therapy has demonstrated activity against several treatment-refractory leukemias, but in some patients has induced cytokine release syndrome (CRS), a clinical syndrome of fevers, hypotension, hypoxia, and neurologic changes including seizures.

Patients with CRS typically have fevers that start about 24 hours after infusion with 19-28z CAR T cells and can persist for several days. These fevers, however, aren’t always the harbinger for more clinically relevant toxicities, and premature intervention to curb the CRS can diminish T-cell persistence or efficacy, explained Dr. Davila of Memorial Sloan-Kettering Cancer Center in New York.

In an effort to distinguish between patients whose fevers would spontaneously resolve and those with clinically meaningful or severe CRS, the investigators retrospectively analyzed cytokine increases in serum samples from all 16 patients on the phase I trial. Of the 39 cytokines screened, 7 inflammatory cytokines correlated with pretreatment tumor burden and severe CRS. They are interferon-gamma, interleukin-5, IL-6, IL-10, Flt-3L, granulocyte-macrophage colony-stimulating factor, and fractalkine.

In addition, patients requiring intensive medical intervention had a 75-fold increase over pretreatment baseline levels in two of the seven cytokines, and universally exhibited at least one clinical sign of toxicity such as hypotension, hypoxia, or neurologic disorders.

"Thus, on the basis of the combined clinical and cytokine data, we could accurately define a severe CRS in those patients with the triad of persistent fevers (38° C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity," Dr. Davila reported.

CRP as a surrogate

Cytokine monitoring, however, is unlikely to be performed daily because of cost and time constraints. CRP was selected as a surrogate for cytokine elevation based on the well-known association between CRP levels and IL-6 and the clinical amelioration of severe CRS afforded by IL-6 receptor blockade.

"We observed a clear difference between the CRP levels of patients with a severe CRS vs. patients classified as having either mild or no CRS," he noted.

Only those patients who met the criteria for severe CRS had a CRP level of 20 mg/dL or more. Patients whose CRP exceeded this threshold were at particularly high risk for CRS (sensitivity, 86%; specificity, 100%).

"CRP, a routinely available lab test, can serve as a surrogate for predicting development of the CRS," coauthor and colleague Dr. Renier J. Brentjens said in an interview. "This allows for sensitive day-to-day assessment of cytokine release in treated patients, which will allow for better management of CRS in CAR T-cell-treated patients," said Dr. Brentjens, director of cellular therapeutics at Memorial Sloan-Kettering Cancer Center.

Dr. David L. Porter, director of blood and marrow transplantation at the University of Pennsylvania Hospital, Philadelphia, said they too have found that CRP tracks with severity of CRS. However, at least at this point, while it may help predict which patients have a more severe reaction, it does not allow for early or different intervention.

"It remains completely unknown whether early intervention for CRS will inhibit the T-cell activity," he said in an interview. "We have developed a grading system for CRS that was designed to help determine when patients require intervention for CRS based on clinical criteria rather than laboratory values. But ultimately, if CRP or other measurements predict when intervention is appropriate, this will be a very useful assay."

CRS intervention

Treating severe CRS with high-dose steroids resulted in rapid reversal of fevers, cytokines, and other clinical symptoms, but abrogated T-cell expansion and persistence, whereas IL-6 receptor blockade with tocilizumab (Actemra) did not, Dr. Avila reported. Indeed, two patients demonstrated an almost 7,000-fold expansion after first-line tocilizumab.

In addition, the manner of treating severe CRS may affect clinical outcomes. All three patients treated with high-dose steroids relapsed despite previously achieving a complete molecular remission whereas untreated patients or those treated with tocilizumab alone had no evidence of recurrent disease after achieving a complete molecular remission.