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).