A 55-year-old man was diagnosed with stomach lymphoblastic lymphoma at the IB stage (Ann Arbor staging system) 2 years ago. He received six cycles of standard-dose R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone). Positron emission tomography-computed tomography (PET-CT) scan showed multiple mass with elevated metabolic activity in the cervical and peritoneal cavities, right clavicula fossa, mediastinal region. Bilateral renal tumor invasion was also detected (Deauville score 5). Progressive disease was considered and rebiopsy of the renal mass was performed. Pathology indicated relapse of the primary disease. The patient then received three cycles of R-IMED/DHAP (rituximab, ifosfamide, methotrexate, etoposide,dexamethasone, cytarabine, and cisplatin) therapy. Posttreatment PET-CT reanalysis suggested partial remission as the metabolic activity of the stomach was significantly repressed (Deauville score 1).
The patient had previous history of HBV infection, and blood test on initial admission indicated positive results for HBsAg, antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B e antigen (anti-HBe), while the serum HBV DNA level was undetectable. His results for human immunodeficiency virus (HIV) and anti-hepatitis C virus (HCV) antibody detection were negative. As for his liver function, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were within the normal range, and no abnormal ultrasound findings were identified suggesting chronic hepatitis. On admission to our clinical center, the patient was required to receive anti-HBV prophylactic treatment with entecavir (0.5 mg/day) during his entire treatment.
Lymphoma of the patient progressed after multiline chemotherapy. In order to control his present conditions, we selected CAR-T cocktail therapy with anti-CD19 and anti-CD22 CAR T-cell infusion. The patient was enrolled in our trial and agreed to receive CAR-T treatment. Informed consent was provided by the patient. Peripheral blood mononuclear cells (PBMCs) were harvested and CAR T cells were constructed and cultured for 14 days by Bio-Rad Corporation (Hercules, CA, USA). Then, standardized FC (fludarabine and cyclophosphamide) regimen was conducted for lymphodepletion (25 mg/m2 fludarabine and 20 mg/kg cyclophosphamide on days -4 to -2). Sequential infusion strategy was planned as follows: anti-CD19 CAR-T infusion 2 x 106/kg on days 1 and 3 and anti-CD22 CAR-T infusion 2 x 106/kg on days 0 and 2. The patient gradually developed cytokine release syndrome (grade 1), with peak ferritin level of 952.1 mug/L and interleukin-6 (IL-6) level of 118.50 pg/ml ( Figures 2A-C ). Lentiviral copy surveillance conducted with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) suggested that CAR T-cell expansion reached a maximum point +9 days post-infusion (copy numbers for CD19 27297 and CD22 6212) ( Figure 2D ).
Although this patient continuously received entecavir (0.5 mg, q.d.) antiviral treatment, he suffered from vomiting and stomach discomfort +11 days post-CAR-T infusion. The liver function assay indicated elevated ALT and AST levels, combined with increased levels of total bilirubin (TBIL) and direct bilirubin (DBIL) ( Figure 2E ). After exclusion of other potential causes of acute liver injury, we examined his HBV DNA copy level, and the results indicated that HBV reactivation was highly possible (+16 days HBV DNA, 2.58 x 102) ( Figure 2E ). Therefore, we quickly implemented combinatory rescuing anti-HBV treatment with entecavir and tenofovir. Reexamination suggested that the patient's HBV DNA and abnormal liver function recovered on +24 days.