Anti-CD19 CAR transduced T-cells/cyclophosphamide/fludarabine
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Cytokine release syndrome: case report A 36-year-old man developed cytokine release syndrome (CRS) during treatment with cyclophosphamide, fludarabine and antiCD19 CAR-transduced T-cells for diffuse large B-cell lymphoma [DLBCL; not all dosages not stated]. The man had been diagnosed with DLBCL in 2003, for which he received various chemotherapeutic drugs with partial response. In May 2015, he underwent autologous stem cell transplantation. After 7 months, he experienced a relapse with involvement of multiple organs. He received palliative therapy, following which he received anti-CD19 CAR-transduced T-cells [CD19 targeted CAR-T cell therapy] infusion after cyclophosphamide and fludarabine lymphodepletion chemotherapy (ChiCTR-OCC-15007008). Subsequently, he exhibited a grade 2 CRS and obtained rapid remission. Additionally, he developed spontaneous terminal ileal perforation 38 days following anti-CD19 CAR-transduced T-cells infusion. The perforation was subsequently repaired with exploratory laparotomy. Five months after anti-CD19 CAR-transduced T-cells treatment, he reported fatigue, bone pain, decreased body weight, abdominal pain and distension. Follow-up positron emission tomography/CT (PET/CT) scan confirmed relapse of DLBCL. Flow cytometry was performed to evaluate the chimeric antigen receptor T-cell (CAR-T cell) amount in peripheral blood, and a percentage of 0.08% meant CAR-T cells decreased dramatically. Therefore, a second anti-CD19 CAR-transduced T-cells therapy was planned with deliberation. He received lymphodepletion chemotherapy with fludarabine 25 mg/m2 infusion on days 1–3 and cyclophosphamide 500 mg/m2 infusion on days 2–3. Surprisingly, on the day cyclophosphamide and fludarabine infusion was completed, he quickly developed persistent fever (39.5°C). Serum cytokines showed a remarkable elevation of IL-6, IL-10 and interferon-γ, even without new anti-CD19 CAR-transduced T-cells infusion. The peak serum levels of IL-6, IL-10, and interferon-γ were 32 pg/mL, 29 pg/mL and 345 pg/mL, respectively. The serum cytokine levels and high fever were similar to those during CRS, which developed the first time he received anti-CD19 CAR-transduced T-cells therapy. Investigations confirmed a grade 2 CRS. Flow cytometry on anti-CD19 CAR-T/CD3+ T-cell percentage in peripheral blood revealed a sudden rise from 0.08% to 19.8%. Quantitative PCR showed 438 copies/µg DNA in peripheral blood and 2950 copies/µg DNA in mass aspiration of the cervical lymph node. The man’s second anti-CD19 CAR-transduced T-cells infusion was cancelled due to the CRS. He suffered from fever for a period of 5 days and slowly recovered with supportive care. By day 9, a serum cytokine analysis showed normal interferon-γ and IL-6 concentrations. Around 20 days following the second CRS, a PET/CT scan revealed improvement with largely reduced lymphoma involvement. After 1 month, he developed fever as well as bone pain again. A PET/CT scan revealed diffused signs of lymphoma involvement, indicating a underlying disease progression. His dise
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