CNS Aspergillosis Following BTK Inhibitors Mimicking Secondary CNS Lymphoma – A Case Series
Naina Murthy1, Maria Martinez-Lage2, Jeremy Abramson3, Andrew Branagan3, Yongli Ji3, Yi-Bin Chen3, Alyssa Letourneau4, Brian Nahed5, Thomas Nelson6, Isabel Arrillaga-Romany1, Nancy Wang1, Jorg Dietrich1
1Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital, 2Department of Pathology, Massachusetts General Hospital, 3Department of Medicine, Division of Hematology & Oncology, 4Department of Medicine, Division of Infectious Diseases, 5Department of Neurosurgery, Massachusetts General Hospital, Massachusetts General Hospital, 6Department of Neurology, Division of Neuro-Oncology, Dana-Farber Cancer Institute
Background:
BTK inhibitors are commonly used in malignant B-cell lymphomas but can be associated with fungal infections, in part driven by altered platelet functions that diminish anti-fungal immune mechanisms. We describe four unique patients treated for B-cell malignancies (B-cell lymphoma, CLL, mantle cell lymphoma, and Waldenstrom’s disease) with progressive neurological deficits initially thought to represent secondary CNS lymphoma but on further diagnostic workup identified as CNS Aspergillosis.
Design/Methods:
Retrospective review of patients managed for B-cell hematological malignancies with BTK inhibitors associated with CNS Aspergillosis.
Results:
Four male patients (age 61-74) were treated with ibrutinib or zanubrutinib at a dose ranging from 160-560 mg daily (range 3-12 months) when developing new neurological symptoms and imaging findings were suggestive of recurrent lymphoma with CNS involvement. However, subsequent brain biopsies revealed invasive cerebral Aspergillosis in all cases with pulmonary involvement in three out of the four cases. Symptom presentation included headache and seizures (n=4), paresthesias (n=1) and expressive aphasia (n=1).
Initial anti-fungal treatment consisted of voriconazole at a dose of 200-500 mg twice daily and subsequently posaconazole in three out of four patients. Additionally, three patients underwent surgical resection. Two patients remained stable without fungal disease progression for more than a year. One patient stopped taking voriconazole after 6 months due to side effects (decreased appetite, fatigue, lethargy, weight loss, and night sweats) and was eventually lost to follow-up. One patient had recurrent Aspergillosis and passed away following antifungal treatment for over two years.
Conclusions:
BTK inhibitors can be associated with fungal infections, including CNS involvement. These four cases illustrate the challenge in establishing a correct diagnosis and highlight the importance of considering atypical and fungal infections in individuals treated with BTK inhibitors.