2026 年 13 巻 p. 445-450
Tirabrutinib, a second-generation Bruton tyrosine kinase inhibitor, has shown promising efficacy in patients with relapsed or refractory primary central nervous system lymphomas. However, its clinical effectiveness after a rechallenge remains largely unknown. This case report described a 59-year-old woman with primary central nervous system lymphoma who initially achieved a complete response with tirabrutinib, after discontinuing methotrexate-based chemotherapy due to treatment-related toxicity. The disease relapsed 2.5 months later, and subsequently followed a refractory course. Even high-dose chemotherapy with autologous stem cell transplantation and additional chemoradiotherapy produced only short-lived responses with repeated relapses. Tirabrutinib was re-administered as a rechallenge therapy and resulted in a fourth complete response. The patient experienced sustained complete response for 20 months while under ongoing tirabrutinib monotherapy. This case illustrates that tirabrutinib rechallenge may represent a feasible therapeutic option for select patients with recurrent primary central nervous system lymphoma, who previously received Bruton tyrosine kinase inhibitor therapy. The biological mechanisms underlying renewed drug sensitivity remain uncertain. In carefully selected cases, there may be resultant clinical benefits. Further studies are warranted to clarify the molecular and clinical determinants associated with successful tirabrutinib rechallenge in patients with primary central nervous system lymphoma.
Primary central nervous system lymphoma (PCNSL) is a highly aggressive B-cell neoplasm that is most commonly classified as the activated B-cell-like subtype. Chronic activation of the B-cell receptor (BCR) signaling pathway plays a key role in the survival of patients with PCNSL.1) Bruton tyrosine kinase (BTK) is a central enzyme in the BCR signaling pathway.2) It is a recognized therapeutic target in this neoplasm. Tirabrutinib (TIR) is a second-generation BTK inhibitor that irreversibly and selectively binds to Cys481 of BTK. Compared to the first-generation agent (ibrutinib), TIR exhibits reduced off-target kinase inhibition, thereby improving safety and tolerability.3,4) Clinical studies of TIR in patients with relapsed or refractory PCNSL have demonstrated clinical efficacy with an overall response rate of approximately 60% in both phase I/II trials and in post-marketing surveillance.5,6) In the long-term follow-up of the phase I/II study, the median duration of response was 9.2 months. In contrast, the progression-free survival remained limited at 2.9 months,7) indicating that disease relapse during or after TIR treatment is common.
Although TIR has become an important treatment option in the salvage and refractory settings, its optimal use remains unclear. In particular, the clinical value of TIR rechallenge after prior exposure has not yet been established, and real-world evidence is scarce. Here, rechallenge is defined as the re-administration of the same agent after disease progression on prior therapy, regardless of whether intervening treatments are administered. In other malignancies treated with tyrosine kinase inhibitors (TKIs), such as epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), re-administration of the same TKI, including rechallenge, after systemic therapy, can provide clinical benefits in selected cases.8,9) Considering this, a BTK inhibitor rechallenge in cases of PCNSL may offer potential clinical benefits, although this approach has not yet been proven.
In this case report, we described a woman with recurrent PCNSL, in whom a rechallenge with TIR achieved a durable response after multiple prior therapies. Our findings highlight the potential of a TIR rechallenge in carefully selected patients.
A 59-year-old woman presented with disorientation, urinary incontinence, and bilateral frontal lobe lesions. Magnetic resonance imaging revealed gadolinium-enhancing masses extending across the bilateral frontal lobes and corpus callosum, with surrounding fluid-attenuated inversion recovery hyperintensity (Figure 1A, B, C, D, E and F). Histopathological examination of the tumor specimen obtained via craniotomy suggested diffuse large B-cell lymphoma. Immunohistochemistry was positive for cluster of differentiation 20 (CD20), CD79a, B-cell lymphoma 2 (BCL-2), and BCL-6, but was negative for CD3, CD5, CD10, CD30, and glial fibrillary acidic protein. The Ki-67 labeling index was approximately 80%. In situ hybridization for Epstein–Barr virus–encoded ribonucleic acid yielded negative results. The bone marrow and ophthalmological examinations revealed no evidence of malignancy. Whole-body screening using diffusion-weighted whole-body imaging with background body signal suppression demonstrated no extracranial lesions. Based on these findings, PCNSL was diagnosed.
Magnetic resonance imaging at the initial presentation demonstrates a tumor extending across the bilateral frontal lobes and corpus callosum. The lesion shows: (A) faint hypointensity on T1-weighted imaging (T1WI); (B) mixed hypointensity and faint hyperintensity on T2-weighted imaging; (C) signal ranging from faint hypointensity to hyperintensity on fluid-attenuated inversion recovery; (D) faint hyperintensity on diffusion-weighted imaging; (E) faint hyperintensity on T2*-weighted imaging; and (F) homogeneous enhancement on gadolinium-enhanced T1WI.
Following the biopsy, corticosteroid was administered, which partially improved the patient's neurological symptoms (Figure 2A). Before systemic therapy, the patient's mini-mental state examination (MMSE) score was 12/30 and the Karnofsky Performance Status (KPS) score was 50. Two cycles of rituximab, high-dose methotrexate, procarbazine, and vincristine (R-MPV) therapy resulted in tumor reduction (Figure 2B). However, treatment was interrupted because of coronavirus disease 2019 and drug-induced hepatitis (Common Terminology Criteria for Adverse Events [CTCAE] [version 4.0] grade 4), during which the tumor increased in size (Figure 2C). Rituximab, methotrexate, and vincristine therapy was initiated. However, the patient developed renal dysfunction (CTCAE grade 3). Continuation of methotrexate-based chemotherapy was deemed unfeasible. TIR, at a dose of 480 mg once daily, was introduced as salvage therapy for refractory disease. This therapy achieved a complete response (CR), but an early relapse occurred 1.5 months later (Figure 2D and E). Given the limited tumor burden at relapse, the patient's relatively young age, and improvement indicated by a KPS score of 70, high-dose chemotherapy with busulfan and thiotepa (Bu/TT), followed by autologous stem cell transplantation (HDC/ASCT), was performed, resulting in a second CR (Figure 2F). However, the lymphoma relapsed 3 months later (Figure 2G). After the recovery of organ function, remission induction with six additional cycles of R-MPV therapy achieved a third CR (Figure 2H). Consolidation therapy with reduced-dose whole-brain radiotherapy (23.4 Gy in 13 fractions) was administered followed by high-dose cytarabine (HD-Ara-C). However, the disease relapsed shortly thereafter (Figure 2I and 3A, B, C, D, E and F).
Clinical course of the patient on axial gadolinium-enhanced T1-weighted imaging. (A) Tumors involving the bilateral frontal lobes and corpus callosum before initiation of chemotherapy. (B) Tumor reduction after two cycles of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy. (C) Tumor progression following treatment interruption due to coronavirus disease 2019 (COVID-19) infection and drug-induced liver injury. (D) Complete response (CR) after one cycle of rituximab, methotrexate, and vincristine (R-MV) therapy followed by tirabrutinib (TIR). (E) Progressive disease (PD) 1.5 months after achieving a CR during continued TIR treatment. (F) CR after high-dose chemotherapy with busulfan and thiotepa followed by autologous stem cell transplantation (HDC [Bu/TT]/ASCT). (G) PD 2 months after achieving CR following HDC (Bu/TT)/ASCT. (H) CR after six cycles of R-MPV therapy. (I) Early PD after consolidation therapy with reduced-dose whole-brain radiotherapy (rdWBRT) and two cycles of high-dose cytarabine (HD-Ara-C). (J) CR after TIR rechallenge. (K) Chronological illustration of the clinical course, including treatment and tumor status, of this case.
Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events (version 4.0)
Additional magnetic resonance imaging sequences before and after tirabrutinib (TIR) rechallenge (axial-gadolinium enhanced T1-weighted imaging [T1WI] shown in Figure 2). (A-F) Recurrent tumor in the right cingulate gyrus before TIR rechallenge; (G-L) complete response (CR) after TIR rechallenge. The lesion (arrowheads) shows: (A) faint hypointensity on T1WI; (B) mixed hypointensity and faint hyperintensity on T2-weighted imaging (T2WI); (C) signal ranging from faint hypointensity to hyperintensity on fluid-attenuated inversion recovery (FLAIR); (D) mixed isointensity and faint hyperintensity on diffusion-weighted imaging (DWI); (E, F) homogeneous enhancement on coronal and sagittal gadolinium-enhanced T1WI, respectively. At CR, (G) T1WI; (H) T2WI; (I) FLAIR; (J) DWI; (K) coronal; and (L) sagittal gadolinium-enhanced T1WI.
When TIR was re-administered at the same dose as the rechallenge therapy, we achieved a fourth CR (Figure 2J and 3G, H, I, J, K and L). TIR was continued for 20 months thereafter, during which sustained remission was maintained. At the last follow-up, the patient demonstrated a KPS of 70 and a MMSE of 26/30. During the ongoing TIR therapy, neutropenia (CTCAE grade 3) occurred 5 months after initiation, and an elevation of serum amylase (CTCAE grade 4) developed at 17 months, prompting temporary treatment interruption. No radiological pancreatic abnormalities were observed. The causal relationship with TIR administration remains uncertain. Laboratory values were normalized after treatment interruption, and TIR was resumed at the original dose. The overall clinical course is summarized in Figure 2K.
This study was approved by our institutional review board (approval number: 23022-4). Informed consent was obtained from the patient for publication of the patient's information and images, which were recorded.
TIR rechallenge after systemic chemotherapy can achieve renewed and durable disease control in selected patients with relapsed PCNSL. In our patient, the disease followed a refractory course with multiple relapses, despite several salvage regimens. However, a TIR rechallenge led to a CR that was maintained for 20 months to date.
PCNSL is associated with a high relapse rate and limited salvage options. Moreover, the outcomes in recurrence/refractory settings remain poor.10) The findings reported in this case report may provide new insights into the use of TIR in specific clinical settings. There are few reports on the clinical use of TIR. Hence, many aspects of its optimal clinical use remain unclear. Questions remain regarding the best sequencing or combination strategies, the role of maintenance therapy, and the management of resistance, including whether and how to rechallenge using TIR after relapse. No standard approach to BTK inhibitor rechallenges exists for PCNSL. Current practice is guided by individual cases and extrapolations from other malignancies. Therefore, clinicians must individualize the use of TIR in patients with relapsed PCNSL. TIR represents a promising PCNSL therapy option. However, its full potential, including the optimal strategy for BTK inhibitor rechallenge, is only beginning to be understood.
Reports describing TIR rechallenge in PCNSL are scarce. More broadly, there is a marked paucity of evidence supporting rechallenge with BTK inhibitors, including the first-generation agent, ibrutinib. In contrast, evidence demonstrating the effectiveness of BTK inhibitor re-administration has been reported for ibrutinib, with most studies describing clinical responses following reinitiation after temporary interruption owing to planned treatment or treatment-related toxicity.11,12) This should be distinguished from rechallenge, which refers to re-administration following disease progression during ongoing BTK inhibitor therapy. Kawauchi et al.13) (2025) recently reported a similar case in which TIR was re-administered as a rechallenge therapy. In their report, the patient achieved CR with TIR that lasted for 6 months before relapse. After salvage treatment with R-MPV therapy and HD-Ara-C, TIR was rechallenged, and CR was induced again. However, disease progression recurred within 5 months,13) in contrast, our patient experienced long-term remission following the TIR rechallenge. A pivotal phase I/II study of TIR reported that 80% (12 of the 15) of patients with CR/ Complete Response unconfirmed continued treatment for ≥12 months and that a subset of patients remained in prolonged remission (~14% were progression-free at 3 years, with a median response duration of ~9.2 months).7) Considering these findings, TIR can lead to long-term remission in a subset of patients. Our case report further demonstrates that durable remission can be attained after a TIR rechallenge.
The underlying biological mechanism of the restored sensitivity to BTK inhibitors remains unclear. Multiple malignancies exhibit tumor regression upon reintroduction of a previously failed therapy after a break.9,14) This paradigm is well-established for EGFR-mutant NSCLC. Clinical experience shows that after progression to first-line EGFR TKI therapy, switching to non-TKI chemotherapy may reduce or eliminate TKI-resistant clones, allowing rechallenge with EGFR TKI to produce renewed responses.8,9) A similar resensitization phenomenon may have occurred in our patient with PCNSL. In PCNSL, numerous driver gene mutations, most notably in MYD88 and CD79B, have been identified within key signaling pathways involved in cellular proliferation and survival, including the Janus kinase–signal transducer and activator of transcription, nuclear factor kappa B, and BCR pathways.15) Furthermore, recent single-cell and spatial transcriptomic analyses have demonstrated that PCNSL harbors transcriptionally and spatially distinct malignant subclones, underscoring the marked intratumoral heterogeneity and supporting ongoing clonal evolution.16) If intratumoral heterogeneity drives clonal selection during BTK inhibitor therapy, leading to the expansion of BTK-independent clones, alternative or combinatorial therapeutic strategies are likely required to effectively target these resistant populations. In this setting, treatment modalities other than BTK inhibitors may reduce the number of BTK-independent clones, with occasional re-expansion of BTK-dependent clones. In our case, TIR was introduced early in the overall treatment course; therefore, following relapse after initial TIR therapy, multiple treatments, including HDC/ASCT, re-administration of R-MPV, whole-brain radiotherapy, and HD-AraC, were administered sequentially prior to TIR rechallenge. These sequential treatments may have promoted a clonal shift from BTK-independent to BTK-dependent clones, potentially accounting for the durable response observed upon TIR rechallenge. The use of cycling-targeted therapies to exploit clonal shifts is an emerging therapeutic strategy in oncology.17) Future research to identify the mechanisms underlying the efficacy of TIR rechallenge is warranted. Furthermore, the evaluation of paired specimens at initial diagnosis and subsequent relapse may provide new insights into clonal selection and help identify the underlying mechanism of this phenomenon.
A limitation of this report is that it described a single case. Therefore, the efficacy and safety of TIR rechallenge cannot be generalized. The observed durable remission may be largely dependent on individual factors, including patient characteristics, biological features of the tumor, specific therapies administered, and the sequence of administration.
In conclusion, TIR rechallenge is a feasible therapeutic option for recurrent PCNSL in carefully selected patients who previously received BTK inhibitor therapy. Further accumulation of clinical experience, ideally supported by molecular profiling at relapse, is required to define the patients most likely to benefit from a TIR rechallenge and the appropriate clinical context in which to apply this strategy.
The authors also thank Editage (www.editage.jp) for the English language editing.
All authors have no conflict of interest.
