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Delayed neurotoxicity after axicabtagene ciloleucel therapy in relapsed refractory diffuse large B-cell lymphoma

Bone Marrow Transplantation volume 56, pages 683–685 (2021)Cite this article

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Chimeric antigen receptor T-cell (CAR T-cell) therapy has transformed the treatment landscape of relapsed refractory (RR) diffuse large B-cell lymphoma (DLBCL). Axicabtagene ciloleucel and tisagenlecleucel are the two currently approved CD19 directed CAR T-cell therapies in RR DLBCL [1, 2]. While CAR T-cell therapy has significantly improved response rates in patients with RR DLBCL, its safe application is hindered by potentially serious complications, such as cytokine release syndrome (CRS) and neurotoxicity (now termed as immune effector cell therapy-associated neurotoxicity syndrome [ICANS]) [3,4,5]. A wide range of neurotoxicity symptoms have been described in literature, including confusion, expressive aphasia, seizures, coma, and potentially death [1]. In the CD19 CAR T-cell pivotal trials for RR DLBCL, grade 3–4 neurotoxicity was seen in 12–28% of patients [1, 2]. The median time to the onset of neurotoxicity was 5–6 days (range, 1–17) post CAR T-cell infusion [1]. While mild symptoms are self-limiting, severe symptoms require supportive care with or without dexamethasone. Usually neurotoxicity, secondary to CAR T cells, resolves within 4 weeks but on occasions it can be fatal [1, 6]. Here in, we report a case of delayed recurrent neurotoxicity after axicabtagene ciloleucel CAR T-cell administration in a patient with RR DLBCL.

The patient was 76-year-old female with medical history significant for hypothyroidism, chronic obstructive pulmonary disease, hypertension, stage III adenocarcinoma colon, and lobular carcinoma in situ of breast. She was initially diagnosed with DLBCL (stage IV) on biopsy of an enlarged left inguinal lymph node. Due to multiple malignancies, patient was seen in high-risk genetic clinic and no further testing was recommended. Subsequently, patient received upfront R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemo-immunotherapy for six cycles and post treatment PET scan showed a complete response. Three months later the patient had a biopsy proven recurrence of disease, which did not respond to salvage chemotherapy (GDP; gemcitabine, dexamethasone and cisplatin). Due to the refractory nature of the disease, she received commercial axicabtagene ciloleucel CAR T cell at a dose of 2 × 106 cells/kg with fludarabine/cyclophosphamide lymphodepletion chemotherapy. On day 2 of CAR T-cell infusion, patient developed grade 3 CRS, requiring five doses of tocilizumab for resolution of symptoms, although tocilizumab package insert recommends use of up to four doses. On day 6, patient developed altered mental status and agitation, consistent with grade 3 neurotoxicity, and was treated with intravenous (IV) dexamethasone (10 mg every 6 h). Initial taper and transition to oral steroids, led to recurrence of neurological symptoms (on day 33), requiring re-initiation of high dose IV steroids. CT scan of the brain without contrast, as well as a CT angiogram of head and neck was unremarkable. The patient responded again to higher doses of corticosteroids with a slow steroid taper, and was discharged on oral steroids on day 47 of CAR T-cell therapy. On a follow-up clinic visit (after 2 weeks), patient was doing well and was able to function independently. Follow-up PET scan at ~4 months post CAR T-cell therapy showed a partial response. Off note, CD4 count at 3 months post CAR T-cell infusion was 136 cells/µL and IgG level was 725 mg/dl. At day 172 post CAR T-cell therapy, patient was readmitted to the hospital with confusion, disorientation followed by expressive aphasia. Extensive work up was done including stroke protocol CT brain that ruled out cerebral ischemia or intracranial hemorrhage. MRI brain was also normal. EEG showed generalized slowing but no epileptiform discharge. CSF analysis was negative for lymphoma involvement and bacterial cultures were negative. BioFire infectious panel on CSF to check for HHV6, cryptococcus, varicella zoster virus, human parechovirus, herpes simplex virus 1/2, enterovirus, cytomegalovirus (CMV), Streptococcus pneumoniae, Streptococcus group B, Neisseria meningitidis, Listeria monocytogenes, Hemophilus influenza, and Escherichia coli, was negative. Fungal serologies and cultures from CSF were also negative. CSF protein level was normal at 43 mg/dl. Systemic infectious work up, including blood cultures, urine cultures, viral nucleic-acid amplification tests (including CMV, EBV, HHV6, Adenovirus), and galactomannan antigen, were negative as well. Metabolic work up revealed normal ammonia, vitamin B12, folate and TSH levels. CRP level and DIC panel were within normal limits. Peripheral blood analysis by flow cytometry using Protein L staining revealed 3.5% CAR T cells. The patient’s neurological status did not improve after 11 days of IV dexamethasone, and consequently, received one dose of cyclophosphamide 750 mg/m2 for refractory ICANS. She had gradual improvement of neurological symptoms after 48 h of cyclophosphamide and was subsequently discharged on slow steroids taper. At the time of discharge, 8 days after cyclophosphamide, she had no signs of ICANS. During this presentation, patient had no CRS. Interestingly, CT scans done locally shortly before this presentation showed that PR had spontaneously converted CR. Approximately, 10 months after CAR T-cell therapy, patient died due to septic shock secondary to pseudomonas bacteremia.

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  1. BMT and Cellular Therapy Program, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Talha Badar, Bryon D. Johnson & Mehdi Hamadani

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Correspondence to Mehdi Hamadani.

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MH reports: Research Support/Funding: Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma. Consultancy: Janssen; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Magenta Therapeutics, Omeros, AbGenomics, Verastem, TeneoBio. Speaker’s Bureau: Sanofi Genzyme, AstraZeneca.

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Badar, T., Johnson, B.D. & Hamadani, M. Delayed neurotoxicity after axicabtagene ciloleucel therapy in relapsed refractory diffuse large B-cell lymphoma. Bone Marrow Transplant 56, 683–685 (2021). https://doi.org/10.1038/s41409-020-01029-4

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