CAR T-cell treatment and related toxic response
She first underwent T-cell collection via apheresis, followed by T-cell engineering and expansion. She received lymphodepleting chemotherapy, including fludarabine 25 mg/m2 for 3 days and 250 mg/m2 cyclophosphamide for 3 days before infusion. Then, she was administered a dose of CD19+CAR Ts (a total of 2.97 × 106 cells/kg). The BM morphology before reinfusion showed 11% malignant cells, and FCM showed 6.01% CD19+ malignant cells expressing CD19+, CD34part+, CD10+, CD123+, CD58+, CD38, and+CD20+.
On day 1 after reinfusion, the patient started having fever, with a continuous high temperature of up to 39.7 °C, accompanied with dizziness and hypotension refractory to fluid boluses. Her condition was graded as grade 2 CRS, and she was administered with tocilizumab (8 mg/kg) and dopamine (5 ug/kg/min). Her blood pressure (BP) was maintained at 90/40 mmHg. Meanwhile, here IL-6 level rapidly rose to 874 pg/mL, but her heart function remained normal. From day 2 to day 4, the patient was continuously febrile, and her temperature was up to 39.7 °C, with hypotension, dizziness, lassitude, and edema of the limbs. Her BP ranged 85–101/33–64 mmHg. Multiple vasopressors, including dopamine and dobutamine, were used, and the condition was evaluated as grade 3 CRS. Routine blood tests showed that the white blood cells, hemoglobin, and platelet decreased at a very low level (Table 1), and the IL-6 level was over 5000 pg/mL (Figure 1A). The patient was administered with a total of seven doses of tocilizumab (8 mg/kg/dose) and 5 mg dexamethasone every 12 h to control sCRS. Albumin, platelets, and red blood cells were administered as supportive treatments. Meropenem, vancomycin, and voriconazole were used against infection. On day 5, the patient presented with disseminated intravascular coagulation (DIC). Blood products, including fibrinogen, plasma, and platelets, were provided to treat DIC and capillary leakage. On day 6, the patient suddenly felt depressed, she was unarousable, and her physical examination showed chemosis. Then, she developed seizure three times, lasting approximately 2–3 minutes every time. Computerized tomography (CT) showed diffuse cerebral edema (Figure 2). She was classified as grade 4 ICANS with elevated intracranial pressure. Diazepam was given to control the seizure, and sufficient mannitol and methylprednisolone (25 mg/kg) pulse therapy was administered. However, the patient’s condition still deteriorated. On day 8, she was in a comatose state, with a Glasgow coma scale of 6. She also developed acute kidney injury (AKI) with oliguria, dyspnea, heart failure, cerebral edema, and DIC. Laboratory examination showed that the IL-6 level was more than 5000 pg/mL, and the creatinine clearance rate (Ccr) decreased to 38 ml/min/1.73m2, classified as grade 3 AKI, while the CAR-T cell reached 6990 copies/μg DNA.
She was immediately administered with invasive mechanical ventilation due to her deep coma state and dyspnea. The B-type natriuretic peptide increased to more than 35000 pg/mL. Echocardiography showed 51% left ventricle ejection fraction. Chest CT showed pulmonary edema. Abdominal CT showed intestinal wall thickening. Dexamethasone and methylprednisolone were continuously provided to control sCRS. Levetiracetam was used to prevent symptomatic epilepsy. TPE was also used continuously for 2 days at 2000 ml (50 mL/kg) plasma once a day to remove cytokines. The blood pump flow rate was 100 ml/min, and the flow rate of replacement fluid was 1000 mL/h, lasting for 2 h every day. On day 9, the patient still had fever, and her maximum body temperature was 38.6 °C (Figure 1B). Thus, ruxolitinib (RUX, 0.25 mg/kg, every 12hour) was used to inhibit the immune response. The patient’s condition still deteriorated, and she had continuous oliguria (less than 1 mL/kg/h). The Ccr decreased to 25.9 mL/min/1.73m2 . Creatine kinase increased to 1208 U/L, considering rhabdomyolysis. CRRT was administered as the patient presented with acute kidney injury, oliguria, edema, and heavy volume load. However, she had low coagulation function and could not tolerate systemic anticoagulant therapy. Thus, regional citrate anticoagulation (RCA) was administered for the increased bleeding risk. The dialysate was formulated without calcium. The initial RCA flow rate was 120 ml/h [calculated using the formula (1.5–2.0) × blood pump flow rate every minute]. The initial blood pump flow rate was 80 ml/min (2 mL/kg/min). Initial 10% calcium gluconate flow rate was 10 mL/h [calculated using the formula (0.1–0.2) × blood pump flow rate every minute]. The Ca2+ concentration of external circulation was maintained at 0.25–0.35 mmol/L, while that of internal circulation was 0.8–1 mmol/L, as shown by the dynamic determination of arterial blood gas. Interleukin and renal function were tested before and after plasma exchange and CRRT. On day 10, the IL-6 and creatine levels obviously decreased (Figure 1A). Due to economic reasons, the patient’s guardian refused continuing CRRT. Afterwards, by continuing to administer RUX and Dex, the patient’s consciousness gradually recovered, with only with a continuously high level of creatine (Figure 1C). On day 28, the BM smear achieved CR, and FCM was negative. As of now, she is still in complete CR 3 months after CAR-T treatment, and CAR-T cell could be still found in PB (Figure1D).