Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma. The predominant subtype is diffuse large B-cell lymphoma (DLBCL), and no systematic lesion is identified at diagnosis. BTKi (Bruton’s tyrosine kinase inhibitor) has demonstrated significant clinical activity in DLBCL. We retrospectively reported on 2 patients who began with memory deterioration or right limb movement disabilities. A cranial magnetic resonance imaging (MRI) scan and a brain biopsy were used to diagnose PCNSLs. Middle-dose methotrexate (MD-MTX) regimens were initiated for induction treatment. Zanubrutinib was chosen as the maintenance regimen due to the patients' inability to tolerate continuous MTX regimens. For 1 patient, he achieved sustained complete remission (CR) demonstrated by MRI. Another patient achieved partial remission (PR). The two patients are both alive until now. We successfully extended the PFS and OS in elderly PCNSL patients treated with zanubrutinib.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Primary central nervous system lymphoma (PCNSL) is a malignant lymphoma confined to the central nervous system [1]. Its prevalence increases with age. Typically, a cutoff of 60 years of age is used to define elderly PCNSL patients. However, many clinical trials prefer to enroll patients over 70. The median survival time for those patients is between 6 and 7 months, that has not resulted in a paradigm shift for decades [2].

Zanubrutinib is an orally available, second-generation Bruton’s tyrosine kinase inhibitor (BTKi), playing a crucial role in the B-cell receptor signaling pathway. Zanubrutinib was approved in the USA for the treatment of mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), and chronic lymphocytic leukemia (CLL) [3]. In this study, we reported two cases of elderly PCNSL patients whose methotrexate (HD-MTX)-based treatment was interrupted due to severe infections. As a result, zanubrutinib was introduced to substitute chemotherapy. The patients responded well to it.

Case PresentationCase 1

A 75-year-old man with deteriorating long- and short-term memory and personality changes was diagnosed with vascular dementia and cerebral infarction via brain magnetic resonance imaging (MRI). The fragile man had consciousness disturbance 1 year later. Bilateral radiative crowns, semiovale centrum, and paraventricular lesions were detected on MRI. Histological examination of a brain biopsy confirmed the diagnosis of DLBCL (shown in Fig. 1). Immunohistochemistry (IHC) analysis revealed that the tumor cells expressed CD20, CD79a, MUM1, CD5, and PAX-5 but did not express CD3, CD56, BCL-6, or CD10. The proliferation index of Ki-67 was approximately 80%. No other invasion was identified using positron emission tomography and computed tomography (PET/CT). An aspirate of the bone marrow and a lumbar puncture revealed no involvement. Lactate dehydrogenase concentration was 294 U/L, and serum HBV DNA concentration was below the detection limit. The left ventricular ejection fraction was determined to be 60%. A negative result was obtained using next-generation sequencing (NGS) technology for genetic abnormalities in peripheral blood. Due to a personal preference, fluorescence in situ hybridization (FISH) for immunoglobulin heavy chain and t (14; 18) translocation was not completed. The man was classified as a high-risk patient based on the International Extranodal Lymphoma Study Group (IELSG) [4].

Fig. 1.

Pathology of patient case 1.

The patient began induction treatment with a rituximab-MTX regimen (400 mg rituximab d1 and 1.5 g MTX d1). Consciousness recovery occurred quickly, and an MRI scan suggested that the lesion areas had shrunk. The patient was evaluated for complete remission (CR) via MRI after two consolidation treatments (500 mg rituximab d1 and 2.0 g MTX d1). Unfortunately, the treatment was halted for several months due to a massive pulmonary embolism and severe infection. Poor tolerability made further chemotherapy impossible, so zanubrutinib was chosen as the maintenance agent. The patient remained CR after receiving 160 mg twice daily for 9 months without experiencing adverse events. So far, the man stays alive (shown in Fig. 2).

Fig. 2.

MRI scans of the brain for patient one. a indicates the centrum semiovale and paraventricular violated at diagnosis. b shows tumor disappearing after one induction and two consolidation treatment based on MTX. c illustrates constant tumor negative after receiving zanubrutinib for 9 months.

Case 2

A 79-year-old woman complained of weakness, insomnia, and progressive loss of movement in her right limb. She was admitted to our hospital with zero-grade myodynamia in one limb and three-grade myodynamia in another. A 2.2 × 1.8 cm mass was detected on MRI in the right frontal cortex. Histology and IHC analysis revealed a DLBCL (shown in Fig. 3) with CD20, CD79a, MUM1 positive, Ki-67 positivity (approximately 60%), and BCL-6, CD21, and CD10 negative. Other systems involvement was ruled out using an enhanced CT scan and bone marrow aspirate. CSF was not performed at the time due to the patient’s intolerable conditions. Lactate dehydrogenase level was normal at 190 U/L, and serum HBV DNA level was normal. The ejection fraction of the left ventricle was determined to be 66%. The IELSG score showed an intermediate high risk.

Fig. 3.

Pathology of patient case 2.

The therapy began with rituximab-thiotepa-MTX (rituximab 300 mg d1, MTX 2g d1, and thiotepa 40 mg d1). Disabilities in the limb and arm were gradually eliminated so that the patient could hobble with assistance. Unfortunately, severe pneumonia developed following the second course of treatment (rituximab 400 mg d1, MTX 2g d1, and thiotepa 40 mg d1). She was then treated continuously with oral zanubrutinib 160 mg twice daily. Three months after treatment, an MRI estimated that the tumor had shrunk and the patient could walk independently (shown in Fig. 4). Zanubrutinib was well tolerated with no adverse events reported. The patient is still alive.

Fig. 4.

MRI scans of the brain for patient two. a indicates the right frontal cortex was violated at diagnosis. b shows tumor melting after one induction treatment. c illustrates cancer minimizing with 4 months of zanubrutinib treatment.

Discussion

PCNSL is an extranodal non-Hodgkin lymphoma that originates from the nervous system, accounting for only 1–2% of lymphomas with poor outcomes. The median overall survival time is 2 to 5 months individually [5]. The brain, eye, leptomeningeal, cranial nervous system, and spinal cord are involved significantly [6]. DLBCL, which expresses B-cell markers such as CD20, CD19, and CD79a, accounts for most PCNSL. Activated B-cell-like (ABC), which consists of the majority of the PCNSL, is found to be more toxic than other ABC-DLBCL [1].

Whole brain radiotherapy (WBRT), high-dose chemoautologous stem cell transplantation, and non-myeloablative chemotherapy are currently the treatment options for elderly patients with PCNSL [7]. The elderly patient’s eligibility for MTX treatment is determined by his or her physical condition and comorbidities, not by age alone. HD-MTX chemotherapy at doses up to 3.5 g/m2 was well tolerated in patients over 60 years of age with adequate status and improved renal clearance [8]. However, without consolidation treatment, the response is transient. New drugs offer frail patients a less toxic option for consolidation or maintenance treatment than chemotherapy or WBRT. Recently, new clinical trials involving novel agents targeting distinct mechanisms, including the CD20 antigen – rituximab, the BTK inhibitor – ibrutinib, and the immunomodulatory drug – lenalidomide, have been conducted in collaboration with various organizations worldwide [5].

Zanubrutinib is a second-generation BTKi with improved oral absorption and specificity for target kinases [9]. The drug is safe, and no dosage adjustments are recommended for patients based on their age, gender, race, body weight, mild or moderate renal impairment, or tumor type [10]. Clinical trials are desirable to evaluate zanubrutinib as a potential treatment option for patients with PCNSL. Yan Zhang et al. [11] confirmed for the first time the distribution of zanubrutinib in the CSF, estimating its highly effective, rapid blood-brain barrier (BBB) penetration, and estimating a CSF concentration greater than that of ibrutinib. Qiansong Cheng reported zanubrutinib successfully made tumor melting in a refractory PCNSL patient [12]. However, Haifeng Yu suggested zanubrutinib was inferior to ibrutinib and tirabrutinib to pass through BBB [13]. Yoshitaka Narita et al. [14] evaluated tirabrutinib, another highly selective oral Bruton’s tyrosine kinase inhibitor from the second generation. With forty-four r/r PCNSL patients included in the study, the overall response rate was 63.6 percent. Tirabrutinib's CSF/plasma concentration ratio was greater than that of ibrutinib.

In elderly patients, maintenance therapy acts a key role in avoiding rapid relapse. However, it is difficult for physicians to choose a more effective and safer maintenance strategy based on individual circumstances. Glass et al. and Nordic et al. [15] suggested that maintenance therapy regimens containing temozolomide are safely used in patients with PCNSL. Rituximab is frequently used with other agents during the induction or maintenance phase. Ney et al. [16] demonstrated that rituximab at a dose of 750 mg/m2 had a distinct benefit for fragile patients at high risk of relapse. James L. et al. [17] concluded that an increasing dose of lenalidomide enhanced the CSF concentration of lenalidomide. Lenalidomide was effective in patients with r/r PCNSL at the dose of 10 mg/d on days 1–21 of 28-day cycles as maintenance therapy. Due to the low prevalence of PCNSL in clinical trials, all maintenance regimens are highly empirical in terms of dose and schedule. Well-designed trials are required to select optimal maintenance agents with long-term follow-up in elderly PCNSL patients.

This report describes how we treated two elderly patients unwilling to continue with reduced consolidation therapy. After 9 and 4 months of treatment with zanubrutinib (160 mg twice daily), the tumors remained in remission and shrank. No infections, nausea, or any grade of thrombocytopenia or leukopenia were observed throughout the treatment. The two individuals remain alive until now. It’s a pity we did not evaluate the CSF concentration of zanubrutinib. However, we successfully extended the OS and PFS of elderly PCNSL patients, who could not receive chemotherapy, with zanubrutinib. Additional clinical evidence should be accumulated to understand the drug’s responses and toxicity better, regardless of whether it is used in the induction or maintenance phase. The CARE Checklist has been completed by the authors for this case report, attached as supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529315).

Acknowledgments

The authors would like to thank the Second People’s Hospital of Guiyang, which provided a platform for coordinating this project. Thanks to the Second People’s Hospital of Guiyang Institutional Review Board for permission to use the data for this analysis.

Statement of Ethics

The Second Guiyang People’s Hospital’s Institutional Review Board reviewed and approved the studies involving human participants on April 8th, 2022. Written and informed consent was obtained from the patients’ next of kin for publication of the details of their medical cases for the 2 patients. The patient in case 1 remained unconscious except for a while after induction treatment; it was impossible to obtain the consent from the patient, so we obtained the consent from his son for publication. We obtained the consent for publication both from the second patient herself and her daughter.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

There were no funding sources for this study.

Author Contributions

This report was conceptualized and designed by Ying Liu and Kangxin Tuo. Kangxin Tuo gathered clinical data. This report was written by Ying Liu and Jie Sun. Each author contributed to this report and approved the final version submitted for publication.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary materials. Additional questions may be directed to the corresponding author.

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.