Management of Cytokine Release Syndrome (CRS) in Patients Undergoing Chimeric Antigen Receptor Modified (CAR) T-Cell Therapy Following Autologous Stem Cell Transplant (ASCT)

Background: CAR Modified T-Cell therapy is an engineered immunotherapy that harnesses the power of the patient's immune system to fight cancer.   Although trials in this therapy have been small to date, encouraging results have been reported from phase I trials in acute lymphoblastic leukemia and chronic lymphocytic leukemia.

Poor risk relapsed or refractory diffuse large B cell lymphoma (rel/ref DLBCL) is a novel area of investigation for the use of CAR T-cell therapy. It is hypothesized that cellular therapy can be optimized by giving CAR T-cells immediately after a patient has received high-dose chemotherapy followed by ASCT.

Patients undergoing CAR T-cell therapy are prone to CRS which can be fatal.  C-reactive protein (CRP) has been identified as a surrogate marker for CRS.

Intervention:  Patients with aggressive rel/ref DLBCL receive BEAM conditioning followed by ASCT on day 0 and CAR T-cell infusion on days +2 and +3 per institutional protocol 12-117.  CRP levels are monitored daily for trends, and close surveillance for signs/symptoms of CRS is performed.  An algorithm to guide management of CRS is included in all our CAR T-cell therapy protocols (Fig. 1).

Findings:  To date, six patients have been treated on this protocol.  Two of the six patients had CRS and were treated according to the management guideline, and both patients had a peak CRP >20 (Fig. 2).  All patients had neutrophil engraftment at the expected time point and remain in remission at a median follow-up of 6 months.

Discussion & Implications:  Preliminary findings based on limited data show encouraging results for use of CAR T-cell therapy in this patient population.  A correlation was seen in incidence of CRS when CRP was >20.  This has been seen in previous studies and may help to better identify patients at risk for developing CRS.  The CRS management algorithm serves as a guideline: the immunomodulatory agents (specifically dexamethasone) included in the algorithm run the risk of muting the action of the CAR T-cells.  Thus, the risk of implementing this algorithm needs to be weighed against the risk of progression of lymphoid malignancy.  In this protocol, a lower threshold for activating the management algorithm is utilized as the risk of death from CRS exceeds that of death due to primary disease.  This trial is ongoing, and updated results are forthcoming.

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