Case Presentation: A 53-year-old female with Stage IV diffuse large B cell lymphoma (DLBCL) with Myc and Bcl2 rearrangements. Chemotherapeutic regimens were initially successful at achieving remission, but her disease ultimately progressed. The patient elected to pursue CD19-directed Chimeric Antigen Receptor (CAR)-T therapy (axi-cel), and hospital admission was planned for the duration of therapy. The patient was admitted following lymphodepletion and CAR-T infusion was initiated on Day 0. Prophylactic anti-infectives were started for anticipated neutropenic fever. At Days +1 and +2, the patient developed Cytokine Release Syndrome (CRS) Grade 1 by temperature (Tmax: 105.4 F)1,2. Maximum doses of tocilizumab were given over these two days. At this point, temperature was better controlled but the patient still complained of rigors, fevers, and chills. IV Tylenol and crystalloid were given to address these symptoms.On the morning of Day +4, the patient’s temperature spiked again (Tmax: 105.2 F). 10 mg dexamethasone was given, but temperatures remained at 104 – 105 F. Temperatures only improved to < 100 F after 100 mg Anakinra was administered and remained stable throughout the day. In the evening, the patient rapidly deteriorated and Immune Effector Cell Encephalopathy (ICE) scores dropped to 0. This met criteria for Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Grade 4,1,2 and the patient was treated with methylprednisolone, Keppra, and supportive care in the ICU. ICE scores improved, with an eventual return to 10 on Day +6, and the patient was discharged in good condition on Day +12.
Discussion: CAR-T therapy utilizes adaptive immune response to customize lymphocytic attack of hematologic malignancies, often at the cost of systemic inflammatory syndromes. Typical latency of CRS is 2-3 days post-CAR-T; ICANS is 4-6 days, but both can take weeks to manifest.3 CRS onset was early in this patient, starting with high fever at Day +1. Initial improvement with IL-6 blockade was followed by breakthrough Grade 1 CRS that ultimately progressed to Grade 4 ICANS. Clinical trials have demonstrated that CD19-targeted axi-cel used to treat DLBCL is associated with a higher incidence of CRS and ICANS when compared to other CAR-T therapies.4 This, combined with the patient’s high tumor burden, may account for the abnormally early and intensely hyperthermic inflammatory response seen in this case.4It is also important to consider whether the timing and dosage of anakinra was appropriate. In this case, 100 mg anakinra was used as a fourth-line therapy. This is aligned with current guidelines that recommend anakinra for CAR-T-induced CRS/ICANS that is refractory to tocilizumab, corticosteroids, and supportive therapy.5 However, smaller studies report reduced rates of CRS/ICANS when anakinra is used as basal prophylaxis upon initiation of CAR-T therapy.6,7 Other studies also argue for the use of higher dose (8 mg/kg) anakinra, which yielded better outcomes than the lower-dose 100 mg used in this case.8 Had IL-1 blockade been administered earlier and/or at a higher dose, the patient might not have developed such severe CAR-T toxicity. However, this treatment did seem to help stabilize her course.
Conclusions: CAR-T cells are important in the treatment of B cell malignancies; however, their use is limited by immune-modulated toxicities. Anakinra may be used to mitigate these effects of CAR-T therapy, but further prospective data is needed on the timing, priority, and dosing guidelines for anakinra administration.