Abstract
Background/Aim: Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based drug therapy and whole-brain radiation therapy. However, there are many cases in which these standard treatment options are not tolerated for various reasons. In the present study, five cases of refractory/relapsed PCNSL that are difficult to treat with standard treatment were successfully treated by tirabrutinib. Patients and Methods: A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The reasons why standard treatment cannot be given to these patients are the low KPS, renal dysfunction, and resistance to HD-MTX. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube. Results: Imaging findings showed that the patients achieved a 100% response rate to tirabrutinib, with a median survival of 8 months. As symptoms improved, 2 of the 3 patients who were initially administered tirabrutinib via a nasogastric tube were able to receive the drug via the oral route. Three patients developed adverse reactions; however, treatment was not interrupted because they were manageable. Conclusion: Tirabrutinib was effective in the treatment of patients who were unable to receive standard treatment options. Tirabrutinib may be considered one of the novel treatment strategies that could improve the prognosis of PCNSL patients in the future.
Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based systemic chemotherapy and whole-brain radiation therapy (WBRT) (1-3). More recently, multi-drug chemotherapy regimens that are more potent systemic chemotherapies are being developed as a way to avoid late adverse events associated with WBRT (4-7). The overall treatment success rate for PCNSL has improved as these novel treatment options have become available, and the median survival increased from 12.5 months in the 1970s to 26 months in the 2010s (8). However, these advanced treatment options have little benefit for elderly patients with PCNSL, and the median survival of patients over the age of 70 years has remained at 6 months since the 1970s (8). Poor outcomes in the elderly PCNSL population may be attributed to poor performance status (PS) and intolerability to more potent systemic chemotherapy due to the presence of comorbidities (9-12). WBRT is considered the primary treatment option for PCNSL patients below the age of 70 years if they are known to have a poor response to HD-MTX or have renal dysfunction and are not candidates for HD-MTX therapy. However, WBRT monotherapy reportedly only prolongs median survival to 11.6 months, which is not considered satisfactory (13). Thus, although recent improvements in treatment outcomes can be attributed to the development of potent systemic chemotherapy regimens, overall survival for patients who cannot receive such regimens has remained unchanged since the 1970s. In 2020, tirabrutinib was introduced in Japan as a new treatment for PCNSL. Tirabrutinib is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor that can be administered orally (14). In the present study, the outcomes of tirabrutinib treatment in five patients who were unable to receive standard treatment options are reported.
Patients and Methods
A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The pathological diagnosis of diffuse large B-cell lymphoma (DLBCL) was confirmed in all five cases. In three patients with refractory PCNSL, standard treatment options were considered unsuitable due to resistance to HD-MTX, low KPS, and renal dysfunction. Two patients with relapsed PCNSL had previously received standard treatments, and low KPS was the primary reason why standard treatment options were not considered. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube (15). The patients’ characteristics are summarized in Table I.
Patient characteristics.
Results
Tirabrutinib at 480 mg/day was given to all patients. Imaging findings obtained within 2-4 weeks of the start of the treatment showed that all patients had achieved a partial response. Median survival after the administration of tirabrutinib was 8 months (range=4-17 months). Three patients developed adverse events, which included headache (n=1) and erythema (n=2). These adverse events were all mild and were treated with analgesics and topical steroids. As KPS improved, 2 of the 3 patients who were initially administered tirabrutinib in suspension via a nasogastric tube were able to receive the medication orally. Table II summarizes the treatment outcomes. Two representative cases are described below.
Summary of results.
Case 3. The patient was a 62-year-old man with refractory PCNSL. Diffuse lesions were found primarily in the ventricular walls of the lateral ventricles, and the patient had severe cognitive impairment (Figure 1A and B). Neuroendoscopic biopsy was performed to confirm the histopathological diagnosis of DLBCL, and the treatment options were considered. Estimation of renal function showed that the patient had severe renal dysfunction, with serum creatinine (Cr) at 2.42 mg/dl, blood urea nitrogen (BUN) at 49 mg/dl, and an estimated glomerular filtration rate (eGFR) of 23. Thus, the standard treatment with HD-MTX was contraindicated. The option of WBRT monotherapy was also considered; however, due to severe cognitive impairment, the patient would have required intense sedation to stay still during WBRT. Thus, tirabrutinib was selected as the treatment strategy. His symptoms gradually improved following the administration of tirabrutinib, and imaging performed two weeks after the start of the treatment clearly showed reduction in tumor size (Figure 1C and D). He did not develop any adverse events or any worsening of renal function.
Diffusion and fluid-attenuated inversion recovery magnetic resonance images. (A, B) Pre-tirabrutinib administration. Tumors are located in the ventricular walls of bilateral lateral ventricles. (C, D) At two weeks post-tirabrutinib administration. Tumors are mostly reduced (partial response).
Case 4. The patient was a 77-year-old woman with relapsed PCNSL. She was initially treated with three courses of rituximab (375 mg/m2) + HD-MTX (3.5 g/m2) followed by WBRT, and she achieved complete remission on imaging. However, she developed recurrence and was readmitted to our hospital (Figure 2A and B). At the time of readmission, her KPS was 40, and she was unable to receive anything orally. Thus, tirabrutinib was administered via a nasogastric tube. Her symptoms improved after two weeks, and she was able to receive tirabrutinib orally. Imaging also clearly showed that the size of the tumor was reduced (Figure 2C and D). She developed erythema, which was successfully treated with topical steroids.
Axial and coronal contrast-enhanced magnetic resonance images. (A, B) Pre-tirabrutinib administration. Tumors are located in the paraventricular areas of bilateral lateral ventricles. (C, D) At two weeks post-tirabrutinib administration. Tumors are mostly reduced (partial response).
Discussion
Tirabrutinib is a second-generation molecular-targeted drug that targets Bruton’s tyrosine kinase (BTK) in B cells, and is indicated for most cases of PCNSL, since over 90% of PCNSL cases are DLBCL (16). Whereas ibrutinib is a potent inhibitor of multiple off-target kinases and can cause severe toxicity, tirabrutinib is a highly selective, less toxic, and irreversible oral BTK inhibitor (15). A phase I/II trial of tirabrutinib was conducted in Japan (14). The trial included patients over the age of 20 years with relapsed/refractory PCNSL, and a total of 44 patients were enrolled. The overall response rate was 63.6%, and median progression-free survival was 2.9 months. With the standard dose of 480 mg, the response rate was 52.9%, and median progression-free survival was 5.8 months. Adverse events were assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events v4.0 Japan Clinical Oncology Group version. Grade 3 or higher adverse events included neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each); these incidence rates were comparable to those of other drug therapy regimens. The trial therefore demonstrated that tirabrutinib is a novel and effective treatment option against relapsed/refractory PCNSL (14). However, indications for tirabrutinib were limited to patients with KPS ≥70 and creatinine clearance ≥50 ml/min (Cockcroft–Gault formula) or ≥50 ml/min/1.73 m2 (Modification of Diet in Renal Disease formula). Patients in the present study did not meet these criteria because they had KPS <70 and/or renal dysfunction. Though these patients would receive best supportive care as the standard therapy, all patients achieved partial response to tirabrutinib, and adverse events were manageable. It was also demonstrated that tirabrutinib can be administered in suspension via a nasogastric tube to achieve sufficient effects (15). Collectively, these findings indicate that tirabrutinib can be considered a relatively safe first-line therapy in patients with poor KPS. Furthermore, treatment with tirabrutinib may be considered an initial option to improve KPS, such that patients can then be switched to standard treatment options such as HD-MTX. Other than the low KPS, renal dysfunction also makes it challenging to administer standard treatments. Since HD-MTX is contraindicated, WBRT monotherapy is considered the standard of care in this patient population. However, the median survival of patients treated with WBRT monotherapy is limited to less than 1 year. Since tirabrutinib is metabolized in the liver, it may be an effective treatment option for patients with renal dysfunction and may improve their prognosis. Therefore, tirabrutinib is a novel treatment option for PCNSL and may be selected in the treatment of patients who are unable to receive standard treatment options.
Acknowledgements
The Authors received no financial support for the research, authorship, and/or publication of this article.
Footnotes
Authors’ Contributions
Design of the study: HY, TO. Data collection: HY, TO, TN. Data analysis: HY, TO, MF, JT. HY and TO wrote the first draft, and all Authors contributed to improving the paper. All Authors approved the final version.
Conflicts of Interest
All Authors have no conflicts of interest to disclose in relation to this study.
- Received May 20, 2022.
- Revision received June 11, 2022.
- Accepted July 8, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
