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Cyclophosphamide/fludarabine/her2-car-transduced-t-cells Various toxicities: case report

A 7-year-old boy developed lymphopenia, neutropenia and leucopenia during conditioning treatment with cyclophosphamide and fludarabine for lymphodepletion, and cytokine release syndrome during treatment with HER2-CAR-transduced-T-cells for metastatic rhabdomyosarcoma (RMS) [not all routes, dosages and durations of treatments to reactions onsets stated]. The child, who had metastatic RMS refractory to chemotherapies according to Children’s Oncology Group’s (COG) ARST0431 protocol and COG protocol ARST0921, was enrolled in clinical trial (NCT00902044). After a 4-week washout period and recovery from prior cytotoxic chemotherapy, he started receiving IV HER2-CAR-transduced-T-cells [autologous HER2 CAR T cells] infusions 1 × 108 cells/m2 ~10 weeks apart, each after lymphodepletion with cyclophosphamide and fludarabine. At the end of this induction phase, no morphologic or imaging evidence of RMS was noted. Thereafter, the same dose of HER2-CAR-transduced-T-cells was administered approximately every 10 weeks without cyclophosphamide and fludarabine for six additional months with the intent of consolidating the disease response. The cyclophosphamide and fludarabine regimen induced grade 4 lymphopenia and grade 4 leucopenia after each cycle of conditioning regimen. During induction with HER2-CAR-transduced-T-cells monotherapy, he developed grade 1 cytokine release syndrome (CRS) with fever, chills, malaise and nausea within 12 hours of each infusion. The CRS resolved completely with supportive care within 72 hours of onset. In addition to lymphopenia and leucopenia, the boy developed grades 3–4 neutropenia (grade 3 after first conditioning cycle and grade 4 after second and third conditioning cycle) lasting up to day 14 with each cyclophosphamide and fludarabine conditioning during induction. The bilateral bone marrow aspiration and biopsy following the third HER2-CAR-transduced-T-cells infusion showed recovery of trilineage haematopoiesis and no morphological evidence of RMS cells. He was considered to have a complete response (CR). Subsequently, he received four additional CAR T-cell infusions ~10 weeks apart without lymphodepletion over 6 months. The response was sustained for 12 months. Six months after the last dose of HER2-CAR-transduced-T-cells, recurrence of BM metastatic disease was noted. Therefore, the boy was re-enrolled on the trial and received IV HER2-CAR-transduced-T-cells 1 × 108 cells/m2 infusion after lymphodepletion with cyclophosphamide and fludarabine. Bilateral BMAB evaluation and PET-CT done 6 weeks after re-treatment showed CR. Subsequently, he completed re-induction with two additional cycles HER2-CAR-transduced-T-cells. Two weeks following the second infusion of HER2-CAR-transduced-T-cells, he concomitantly started receiving pembrolizumab every 3 weeks to promote the HER2-CAR-transduced-T-cells function. During consolidation of second CR, he received five additional HER2-CARtransduced-T-cells infusions