Zanubrutinib-induced aseptic meningitis: a case report and literature review

Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor used in B cell malignancy treatment and is generally well tolerated in most patients. Zanubrutinib-induced aseptic meningitis is currently not reported. Herein, we present the first case of zanubrutinib-induced aseptic meningitis. A 33-year-old woman was diagnosed with relapsed/refractory follicular lymphoma and subsequently developed aseptic meningitis after receiving zanubrutinib treatment. We reviewed the literature and uncovered the lack of current reports on zanubrutinib or other BTK inhibitor-induced aseptic meningitis. Moreover, we summarized cases on aseptic meningitis induced by common chemotherapy and targeted drugs used for hematological diseases. Drug-induced aseptic meningitis (DIAM) is a drug-induced meningeal inflammation. The possible pathogenesis is the direct stimulation of the meninges via intrathecal injection of chemotherapy drugs and immune hypersensitivity response caused by immunosuppressive drugs. It is more common in women with immune deficiency and mainly manifests as persistent headache and fever. Cerebrospinal fluid examinations mainly demonstrate a significant increase in cells and proteins. DIAM diagnosis needs to exclude bacterial, fungal, viral, and tuberculosis infections; neoplastic meningitis; and systemic diseases involving the meninges. The prognosis of DIAM is usually favorable, and physicians should detect and stop the causative drug. In conclusion, zanubrutinib-induced aseptic meningitis is a rare but serious complication, and physicians should be promptly aware of this adverse event to avoid serious consequences.


Introduction
Bruton tyrosine kinase (BTK) is a nonreceptor kinase that plays a crucial role in oncogenic signaling for leukemic cell proliferation and survival in multiple B cell malignancies (Pal Singh et al., 2018).BTK inhibitors form a covalent bond with a cysteine residue  in the kinase domain to inactivate BTK, which further restrains the B-cell antigen receptor pathway activation and blocks malignant B-cell proliferation and survival (Kim, 2019).Zanubrutinib is a next-generation BTK inhibitor that has presented promising antitumor activities in both preclinical models and clinical studies (Syed, 2020).Zanubrutinib monotherapy is generally well tolerated in patients with B cell malignancies.A pooled safety analysis of zanubrutinib reports that the common grade

Case presentation
A 33-year-old Chinese woman presented to our department with the chief complaint of headache, fever, tremors, and unstable gait for 10 days in November 2020.She had a known history of relapsed/refractory follicular lymphoma (FL) for 2 years.Two years ago, she presented with multiple lymph node enlargement and splenomegaly a few months after giving birth.She had no symptoms of fever, night sweats, and weight loss.She visited a local hospital.The left armpit lymph node biopsy indicated FL (grade II).Positron emission tomography/computed tomography (PET/ CT) revealed lymph node enlargement of ≥3 cm diameter and increased β-2-[18F]-Fluoro-2-deoxy-D-glucose (FDG) uptake in the neck, armpits, mediastinum, abdominopelvic cavity, and groin.Additionally, the FDG uptake was increased in both breasts, spleen, and multiple bones.Therefore, she was diagnosed with FL (stage IV, grade 2, group A, FLIPI 3 points).Considering the history of giving birth, she received four courses of R2 chemotherapy (rituximab and lenalidomide) for 4 months at the local hospital.However, remission was not achieved; thus, she was prescribed four courses of standard R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 months, and she achieved partial remission.Afterward, she received maintenance therapy with rituximab every 2 months.However, 5 months ago, she experienced recurrent lymphadenopathy and hepatosplenomegaly, and she visited our hospital.The PET/CT confirmed lymphoma relapse.Considering that new targeted drugs, including obinutuzumab and phosphoinositide 3-kinase inhibitors, have not yet been marketed in China and this patient could not be a candidate in the clinical trial of FL at our hospital because of hepatitis B virus infection, she was scheduled to receive zanubrutinib treatment (560 mg per day) after obtaining informed consent.She re-achieved partial remission after taking zanubrutinib for 4 months, and oral zanubrutinib was continued.However, 10 days ago, the patient developed neurological symptoms, including headache, fever, hand tremors, and unsteady gait.The laboratory examination revealed negative results for serum procalcitonin, C-reactive protein (1,3)-β-D-glucan and galactomannan test, tuberculosis antibody, and interferon-gamma release assay.Then, a lumbar puncture was performed, and the opening pressure of cerebrospinal fluid (CSF) was 210 mmH2O.The cell count, protein, and glucose were 300 × 10 6 /L (normal range: 0-10 × 10 6 /L), 690 mg/dL (normal range: 15-45 mg/dL), and 42.84 mg/dL (normal range: 45-79.2mg/dL), respectively (Figure 1A).The ink stain, herpesvirus type II DNA, mycobacterium tuberculosis DNA, tuberculosis antibody, culture of bacteria, fungi, and mycobacterium, exfoliated cells, metagenome, autoimmune encephalitis-related antibodies, paraneoplastic syndrome-related antibodies, and flow cytometry were negative.Brain magnetic resonance imaging (MRI) enhanced scan illustrated meninges thickening, cistern narrowing, third ventricle and bilateral lateral ventricle enlargement and hydrocephalus, and CSF exudation (Figures 1B, C).Zanubrutinib-induced aseptic meningitis diagnosis was highly suspected based on clinical manifestations and laboratory findings.Therefore, zanubrutinib was stopped and mannitol (125 mL, once every 12 h) was given for dehydration.The patient's neurological symptoms significantly improved, and headache, fever, hand tremors, and unsteady gait disappeared after stopping zanubrutinib for 2 months.The cell count and protein by the CSF analysis significantly decreased (Figure 1A).Enhanced brain MRI scanning revealed that the enhancement degree of intracranial pia mater and hydrocephalus was reduced (Figures 1D, E).We used another BTK inhibitor orelabrutinib to fight the lymphoma and the patient was well tolerated 4 months later.Up to now, the patient's lymphoma has been well controlled, and no CNS symptoms have reappeared after 3 years of follow-up.The therapeutic course is summarized in Figure 1F.

Discussion
Herein, we report a Chinese female patient with relapsed/ refractory FL who developed aseptic meningitis after receiving zanubrutinib treatment for 4 months.The diagnosis of zanubrutinib-induced aseptic meningitis was established in our case according to the temporal association between zanubrutinib exposure and the development of CNS symptoms, clinical and laboratory findings, and typical MRI of meningitis.Currently, different BTK inhibitors, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, pirtobrutinib, and nemtabrutinib, have been approved or used in the later stage of clinical development for B cell malignancy treatment, such as mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström's macroglobulinemia, and FL.Among these BTK inhibitors, except for acalabrutinib, which is prone to causing headaches, other BTK inhibitors rarely cause CNS symptoms (Lipsky and Lamanna, 2020).To the best of our knowledge, no cases of zanubrutinib-or other BTK inhibitorinduced aseptic meningitis have been reported, and this is the first case of zanubrutinib-induced aseptic meningitis.We reviewed the literature on the pathogenesis, clinical  In DIAM, drug intake history is crucial because no specific characteristics are associated with a specific drug.Nonsteroidal antiinflammatory drugs, intravenous immunoglobulins, antibiotics, monoclonal antibodies, anticonvulsants, vaccines, and intrathecal drugs are common causes of DIAM (Yelehe-Okouma et al., 2018).
To date, no study on the mechanism of BTK inhibitor-induced aseptic meningitis has been published.The mechanisms of aseptic meningitis caused by other drugs may include direct meningeal irritation by intrathecal drug injection and immunologic hypersensitivity reaction caused by systemic administration (Yelehe-Okouma et al., 2018).We speculate that the mechanism of zanubrutinib-induced aseptic meningitis may be the immune hypersensitivity response caused by zanubrutinib that inhibits the activation of the B-cell antigen receptor pathway.Moreover, the patient did not develop DIAM with orelabrutinib; thus, we speculated whether it was related to the differences in CNS permeability between different BTK inhibitors.Currently, no study has compared head-to-head CSF concentrations under treatment with different BTK inhibitors.Three studies have reported that CSF concentrations of three BTK inhibitors (ibrutinib, zanubrutinib, and orelabrutinib) were 1.65, 2.94, and 20.10 ng/mL, respectively (Grommes et al., 2017;Song et al., 2021;Zhang et al., 2021).Therefore, high CSF concentrations of both zanubrutinib and orelabrutinib indicate that DIAM may not be related with the differences in CNS penetration between the different BTK inhibitors.In addition, BTK is the only kinase targeted by orelabrutinib (with >90% inhibition) (Dhillon, 2021), which may explain that aseptic meningitis developed with zanubrutinib rather with orelabrutinib.DIAM symptoms mainly include headache, fever, neck stiffness, nausea, photophobia, disoriented, and short-term memory deficits.The CSF analysis showed high cell and protein and normal glucose levels.MRI of the brain appeared to be normal or displayed signs of meningitis.DIAM is an exclusionary diagnosis, which requires exclusions of bacterial, fungal, viral, and tuberculosis infections, neoplastic meningitis, and systemic diseases involving the meninges (Tattevin et al., 2019).DIAM should be distinguished from these diseases, and we summarized the etiology, clinical features, CSF characteristics, treatment, and prognosis of these diseases in Table 1, which helps the doctors detect and identify DIAM promptly in clinical practice.Overall, no significant difference was found in the clinical symptoms between DIAM and other meningitis.The CSF analysis of DIAM showed high cell count, which may be confused with infectious meningitis and neoplastic meningitis.However, the CSF of DIAM does not present any pathogens or tumor cells, which can be distinguished from infectious meningitis and tumor meningitis.DIAM management mainly includes discontinuing the causative drugs and symptomatic treatments.Most patients can recover after stopping medication for approximately 1 week.Physicians must recognize and accurately discontinue relevant pathogenic drugs.Our patient with FL received immunosuppressive therapy, and CSF examination demonstrated a significant increase in cell and protein levels as previously reported.However, her glucose level was slightly lower than normal, and the brain MRI revealed typical signs of meningitis.In addition, her symptoms significantly improved after discontinuing zanubrutinib for approximately 2 months, which was longer than that previously reported.
Despite the lack of studies reporting aseptic meningitis induced by zanubrutinib and other BTK inhibitors except for our case, BTK inhibitors may cause some other serious and rare CNS AEs, including progressive multifocal encephalopathy (PML) and posterior reversible encephalopathy syndrome (PRES) (Zukas and Schiff, 2018).The mechanism may be associated with impaired cellular immunity caused by BTK inhibitors (Fugate and Rabinstein, 2015;Tattevin et al., 2019;Cortese et al., 2021;Zou et al., 2023).To distinguish aseptic meningitis from other rare complications induced by BTK inhibitors, Table 2 summarizes the pathogenesis, clinical manifestations, imaging features, CSF analysis, diagnostic criteria, treatment strategies, and prognosis of these three rare CNS complications to provide information regarding their management.PML is caused by the reactivation of John Cunningham polyoma virus in the presence of cellular immune impairment.PRES involves perfusion imbalance and reversible vascular edema.DIAM is caused by T cell-mediated immune hypersensitivity and meningeal direct inflammation caused by intrathecal injection of antimetabolic drugs.These three complications occur following immunosuppressive drug therapy, and physicians should promptly identify these rare complications and discontinue relevant suspected immunosuppressive drugs.
This study has some limitations.First, zanubrutinib was not rechallenged to deeply determine this adverse reaction in our patient.Additionally, this is the first case of zanubrutinib-induced aseptic meningitis, and further observation and the mechanism of zanubrutinib-induced aseptic meningitis should be explored in the future.

Conclusion
Zanubrutinib-induced aseptic meningitis should be considered a potentially serious adverse drug reaction, and whether other BTK inhibitors can cause aseptic meningitis remains unclear.Physicians, especially hematologists, should be aware of this potential AE.Relevant suspicious drugs should be promptly and effectively discontinued when suspected of DIAM because the symptoms of DIAM are severe and most patients can quickly recover after discontinuing the causative drugs.
FIGURE 1 (A) Changes in various cerebrospinal fluid indicators before and after zanubrutinib discontinuation in the patient (B-C) Brain MRI of the patient before zanubrutinib discontinuation.(B) T1 enhancement; (C) T2.(D-E) Brain MRI after the patient stopped using zanubrutinib for 4 months.(D) T1 enhancement; (E) T2.(F) Detailed time course of the patient's clinical course and therapeutic regimen.

TABLE 1
Main criteria for DIAM differential diagnosis.

TABLE 2
Clinical characteristics of rare central nervous system complications induced by drugs in hematological malignancies.Summary of all published cases reporting DIAM in hematological diseases.

TABLE 3 (
Continued) Summary of all published cases reporting DIAM in hematological diseases.