A 46-year old woman was diagnosed with diffuse large B-cell lymphoma 6 months ago (stage IIB). The MRI scan indicated that the lymphoma invaded her liver, pancreas, stomach, and right kidney. She received one cycle of R-CHOP, three cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, oncovin, cyclophosphamide, and hydroxydaunorubicin), one cycle of large-dose methotrexate (MTX), and one cycle of R-DHAP plus Bruton's tyrosine kinase (BTK) inhibitor chemotherapy. Posttreatment evaluation indicated that the remaining tumor (13 mm x 10 mm) resided in her lower common bile duct.
This patient had previous history of HBV infection and took entecavir treatment before chemotherapy initiation. On her first admission into our center, serum test indicated that she had positive results of HBsAg, anti-HBe, and anti-HBc. The results for hepatitis C virus (HCV) and HIV antibodies were negative. Her HBV DNA level was undetectable. Her initial liver function test result was quite abnormal as serum AST was 121 U/L and ALT was 190 U/L. Her TBIL level reached 223.9 mumol/L, and the DBIL level was 212.1 mumol/L. We then performed magnetic resonance cholangiopancreatography (MRCP), and the results demonstrated tumor nodule localizing in the lower common bile duct, with notable dilation of the bile duct and pancreatic duct. As her tumor caused serious obstruction, percutaneous transhepatic cholangial drainage (PTCD) was conducted and her liver function quickly recovered.
Because the patient had suffered rapid progression of lymphoma and obstructive jaundice during chemotherapy, chemotherapy resistance was considered. In order to control her pancreatic tumor progression, we performed CAR-T cocktail therapy with anti-CD19 and anti-CD22 CAR-T therapy. Her CAR-T culturing and lymphodepletion chemotherapy were the same as those of case 1. Sequential infusion strategy was planned as follows: anti-CD19 CAR-T infusion 2 x 106/kg on days 1 and 5 and anti-CD22 CAR-T infusion 2 x 106/kg on days 0 and 2. The patient developed mild nausea, vomiting, and fever post-infusion, with peak ferritin level of 2,583 mug/L and IL-6 level of 197.7 pg/ml ( Figures 2A-C ). Lentiviral copy surveillance conducted using qRT-PCR suggested that CAR T-cell expansion reached a maximum point +10 days post-infusion (copy numbers for CD19 6541 and CD22 3602) ( Figure 2D ).
Her liver function remained steady under entecavir treatment until +14 days post-CAR-T infusion. Blood test on +14 days indicated elevated ALT (53 U/L)/AST (66 U/L), with mild elevations of TBIL (22.5 mumol/L) and DBIL (20.7 mumol/L) ( Figure 2E ). After ruling out possibilities of obstruction of the PTCD tube and a retest of HBV copy (+14 days, 2.25 x 102 IU/ml) ( Figure 2E ), reactivation of HBV was suspected. We quickly implemented combinatory rescuing anti-HBV treatment with entecavir and tenofovir. As a result, her HBV DNA copy and her AST/ALT levels returned to normal at +21 days.