Central nervous system aspergillosis complicating ibrutinib chemotherapy: A case series

ABSTRACT

Content Introduction: Ibrutinib is a small molecule Bruton's tyrosine kinase (BTK) inhibitor which has revolutionised treatment of chronic lymphocytic leukaemia (CLL). BTK is involved in B-cell receptor signalling regulating normal B-cell activation, interactions and survival. Ibrutinib use can predispose to invasive fungal infections (IFI), via dysregulation of the innate immune system. We report three patients exhibiting central nervous system (CNS) aspergillosis as a complication of Ibrutinib therapy. Case 1 A 73-year-old man diagnosed with TP53-deleted CLL commenced second-line ibrutinib after initial bendamustine therapy. Five months after starting ibrutinib, he presented with confusion and worsening mobility. Ring-enhancing lesions suggestive of cerebral abscesses were identified on CT and were aspirated. Aspirate confirmed Aspergillus fumigatus and he completed a three-month course of voriconazole. Despite successful treatment of IFI, his CLL progressed and alternative chemotherapy was no-longer suitable. He died six months after discharge from pneumonia. Case 2 A 64-year-old woman with CLL diagnosed in 2020 commenced second-line ibrutinib two months after progression through one FCR cycle. Three weeks into cycle three of ibrutinib, at a time of clinical remission, she presented with a one week history of lethargy, confusion and ataxia without fever or lateralising neurological signs. MRI head demonstrated two large ring-enhancing lesions. In view of aspergillosis risk, empirical voriconazole was initiated. Aspergillus fumigatus was isolated following abscess drainage and voriconazole treatment continued with clinical improvement. She remains well three months after discharge and is planned to re-commence ibrutinib. Case 3 A 61-year-old woman with a background of Crohn's disease on long term prednisolone was diagnosed with TP53-mutated CLL in 2005 and commenced ibrutinib in 2020. COVID-19 pneumonitis was diagnosed three months prior to presentation which was treated with dexamethasone (without IL-6 inhibition). In January 2021 she was admitted with a three-week history of worsening headache, visual field defect and pyrexia. MRI imaging indicated cerebral abscess. She underwent drainage and Aspergillus fumigatus was grown. She made good clinical progress with voriconazole, although her admission was complicated by Pneumocystis jirovecii pneumonia. Discussion: CLL is a haematological malignancy with low incidence of IFI. Cerebral aspergillosis is uncommon, even amongst immunosuppressed individuals, however literature reports have indicated an association with ibrutinib. The first two cases had no other clear predisposition for IFI and are likely attributable to ibrutinib. Case 3 had additional risk factors of long-term and acute steroid use. Onset of ibrutinib-induced CNS IFI can occur early in treatment without any other risk factor and presentations may be atypical, such as the absence of fever in Case 1, or with non-specific symptoms as in Case 2. Ring-enhancement on MRI was present in all three cases. Increased awareness of the potential for IFI, particularly CNS infection, in patients taking ibrutinib is crucial with its increasing use. Clinical suspicion is needed for any patient treated with BTK inhibitors presenting with neurological symptoms or undifferentiated fever. Further research is required to determine if the incidence of invasive aspergillosis in ibrutinib recipients warrants routine antifungal prophylaxis.