Multiple drugs

Abstract

Various toxicities: case report A 68-year-old woman developed immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) during treatment with axicabtagene-ciloleucel for diffuse large B-cell lymphoma (DLBCL) and subsequently developed gastrointestinal (GI) barrier damage causing septicaemia and disseminated candidiasis following treatment with axicabtagene-ciloleucel, cisplatin, cyclophosphamide, cytarabine, dexamethasone, fludarabine and tocilizumab [not all routes and dosages stated]. The woman with DLBCL had undergone five lines of therapy with axicabtagene-ciloleucel [Axicel]. She underwent leukapheresis and subsequently received bridging therapy comprising of two cycles of dexamethasone, high dose cytarabine [aracytine] and cisplatin, i.e. DHAP regimen for DLBCL that led to disease stability. Thereafter, lymphodepleting conditioning therapy with cyclophosphamide 500 mg/m2 per day and fludarabine 30 mg/m2 per day for three days was commenced. Her axicabtageneciloleucel infusion (2 × 106 CAR T cells per kilogram) was withheld and given five days after completion of lymphodepletion due to sudden onset of cauda equina syndrome secondary to lymphoma progression. Before the infusion of axicabtagene-ciloleucel, she underwent therapy with dexamethasone 40 mg/day for four days and radiotherapy. Subsequently, she developed grade 1 CRS on the following day of axicabtagene-ciloleucel infusion. The CRS evolved to grade 2 hypoxaemia on day 4. Hence, the woman required one dose of tocilizumab. On day 6 after axicabtagene-ciloleucel infusion, she developed grade 3 ICANS that required IV dexamethasone 10mg four times in a day. On day 8, her ICANS resolved with improvement in neutrophil count. Eventually, her dexamethasone tapered and stopped on day 13. On day 14 after administration of axicabtagene-ciloleucel, she had sudden onset of abdominal pain and diarrhoea along with cardiac arrest and hypotension requiring intensive care treatment in the hospital. But, she had a second cardiac arrest that required epinephrine [adrenaline]. Her peripheral blood cultures showed meropenem-sensitive Escherichia coli infection and CT scan demonstrated thickening of the large intestinal walls and nearly all the small loops. High dose norepinephrine [noradrenalin] was given and persistent inflammation markers and progressive procalcitonin decrease were noted. Her elevated serum levels β-(1,3)-D-glucan and mannan raised concern for invasive candida infection. Her serum galactomannan was found to be positive. But, negative DNAemia was noted for Aspergillus fumigatus. Subsequently, she died [cause of death not stated] on day 21 and autopsy was carried out. Her postmortem macroscopic findings revealed diffused petechiae suggestive of hypoxia. The sectioning of lungs showed a thickened and brown mucoid viscous bronchial secretion. Twoliter hemoperitoneum was noted in the peritoneal cavity and duodenal ulceration from upper GI tract to the Treitz ligament was found. The presence of pseudomembranous plaques on bowel serosa from Treitz ligament to anus was observed. Upon microscopic examination, the duodenal ulceration was confirmed with complete loss of mucous membrane reaching the musculosa. Her mucosae were replaced by pseudohyphae, hyphae and yeasts. Additionally, invasion due to fungal cells was noted in the stomach walls and the remaining bowels. Numerous fungi was present in the pseudomembranes and staining confirmed the mycelial agents. Presence of mycotic emboli were noted in the lungs and liver. Postmortem microbiological examination was also performed that showed numerous yeasts related to pseudomycelia and the culture grew Candida albicans. Further investigation showed Candida albicans. Bronchial mucus revealed growth of one colony of A. fumigatus. But, further investigation showed negative results for A. fumigatus in all postmortem samples. An abdominal effusion fluid showed positive results for galactomannan and mannan measurements. It was considered that her septicaemia and disseminated candidiasis were secondary to GI damage caused by axicabtagene-ciloleucel, cisplatin, cyclophosphamide, cytarabine, dexamethasone, fludarabine and tocilizumab [durations of treatments to reactions onsets not stated].