Efficacy of BTK inhibitor administered for central high-risk systemic diffuse large B cell lymphoma and primary central nervous system lymphoma: A single-center retrospective study

doi:10.21203/rs.3.rs-3782984/v1

Purpose

This study was to explore the efficacy of Bruton's tyrosine kinase inhibitor (BTKi) in treating patients with central high-risk systemic diffuse large B cell lymphoma (DLBCL) and primary central nervous system lymphoma (PCNSL), while also assessing the influence of genomic variants on treatment outcomes.

Materials and methods

The safety, efficacy, and prognosis of patients treated with BTKi-containing regimens were analyzed. Genetic variants on treatment efficacy were analyzed using whole-exome sequencing (WES).

Results

Of the 10 patients with central high-risk systemic DLBCL, nine completed treatment and were available for efficacy evaluation. The overall response rate (ORR) was 55.6%. And the 1-year central nervous system infiltration rate was 11.1% (1/9) after receiving prophylactic treatment with BTKi. In a separate group of 16 patients with PCNSL, which included three patients with relapsed PCNSL, the median overall survival (OS) was 9 (9–16) months, and six patients with primary refractory disease had a median OS of 18 (2–31) months. Besides, seven patients with PCNSL newly treated with a combination of chemotherapy and BTKi, the ORR was 100% after two courses of treatment. WES was performed on 18 patients with PCNSL, including five with R/R PCNSL who received a BTKi-containing regimen. The median PFS of 7 (3–9) months and a median OS of 16 (9–29) months.

Conclusion

The findings of this study indicate that BTKi-containing regimens are safe and effective for treating central high-risk systemic DLBCL and PCNSL.

central nervous system lymphoma

diffuse large B cell lymphoma

genomic variants

zanubrutinib

orelabrutinib

DLBCL represents the most aggressive lymphomas, accounting for 30–40% of non-Hodgkin's lymphomas (NHLs) [1]. The standard initial treatment for DLBCL is the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. This regimen results in long-term remission for approximately 50–60% of patients[2]. However, approximately 5% of patients experience secondary central nervous system (CNS) infiltration. These patients have an extremely poor prognosis, with survival durations ranging from 2 to 5 months[3–5].

PCNSL is a rare extranodal NHL characterised by its high aggressiveness and unfavourable prognosis. Over 95% of PCNSL cases belong to the DLBCL subtype. Among adult CNS tumours, PCNSL accounts for approximately 2.4–3% of all primary brain tumours, comprising < 1% of NHLs[6]. The incidence of PCNSL has been increasing annually, particularly among the elderly population[7, 8]. Currently, methotrexate (MTX)-based chemotherapy regimens are the standard approach for treating patients with PCNSL[9]. However, more than 30% of patients experience relapse after initially responding to MTX-based therapy[10]. Additionally, approximately 10–15% of patients with PCNSL might exhibit primary resistance to MTX[11]. Patients with primary resistance or those who experience relapse or refractory (R/R) PCNSL have a very poor prognosis, with a median overall survival (OS) of 2 and 3.5 months, respectively[12]. Therefore, it is imperative to explore more potent therapeutic alternatives for R/R PCNSL.

Extensive evidence has demonstrated the effectiveness of Bruton's tyrosine kinase inhibitors (BTKi) against various B cell malignancies. Ibrutinib, a first-generation BTKi, has an overall response rate (ORR) of 23% in R/R DLBCL[13]. In comparison, the second-generation BTKi zanubrutinib (BGB-3111) has shown improvements in the efficacy and safety of Waldenström's macroglobulinaemia therapy[14]. A phase 2 study, BGB-3111-207, reported an ORR of 29.3% and a complete remission rate of 17.1 with zanubrutinib monotherapy, indicating excellent antitumour activity and an acceptable safety profile in R/R DLBCL. Orelabrutinib, on the other hand, exhibits excellent kinase selectivity, reduces off-target adverse effects, enhances blood-brain barrier permeability, and improves bioavailability[15]. It has demonstrated an acceptable safety profile and has shown antitumour efficacy in several studies[16, 17]. Additionally, studies have suggested a synergistic effect of orelabrutinib when combined with cluster of differentiation (CD) 20 monoclonal antibodies[18]. Therefore, a retrospective analysis of 26 patients with DLBCL was conducted, wherein the safety and efficacy of BTKi in 10 cases of CNS high-risk systemic DLBCL treated primarily with zanubrutinib-containing regimens and 16 cases of PCNSL treated primarily with orelabrutinib-containing regimens were studied and evaluated. Additionally, the molecular genetic features of PCNSL were explored.

Patients

This is a retrospective study that examines the use of BTKi (zanubrutinib/ibrutinib) in combination with conventional chemotherapy for treating patients with high-risk systemic DLBCL and PCNSL affecting the CNS. This study was conducted at the Second Hospital of Lanzhou University, with patient enrolment spanning March 2020 to March 2023. Clinicopathological data were collected using electronic medical records, while subsequent data points were collected through telephonic follow-up interviews.

In this study, patients with systemic DLBCL were eligible if they met the following three criteria: 1) age of ≥ 18 years; 2) histologically confirmed diagnosis of CD20⁺ DLBCL; and 3) the presence of at least one of the risk factors for CNS infiltration, such as involvement of high-risk sites (e.g., testis, uterus, kidney, adrenal glands, and spine); CD5 expression; or dual expression of Myc and B cell lymphoma 2 (Bcl-2) proteins resulting from MYC and Bcl-2 gene rearrangement/double-hit lymphoma. Patients who were human immunodeficiency virus-positive or had post-transplant lymphoid tissue proliferative disorders were excluded from the study. The diagnosis of PCNSL followed the criteria outlined in the National Comprehensive Cancer Network CNS Cancer Guidelines, involving: 1) confirmation of DLBCL through stereotactic biopsy of a brain lesion and 2) verification of no invasion outside the CNS through additional investigations (positron emission tomography [PET] and computed tomography [CT] examinations, ophthalmologic examination, and bone marrow aspiration biopsy). Refractory PCNSL was characterised by insufficient tumour shrinkage (< 50%) or disease progression after four cycles of chemotherapy, progression within 3 months after receiving standard chemotherapy and achieving complete remission (CR), or recurrence within 12 months of achieving CR or partial remission (PR) following chemotherapy or autologous haematopoietic stem cell transplantation (ASCT), with two or more relapses after CR. Patients with psychiatric disorders, immunodeficiency, pregnancy, incomplete baseline data, or those lost to follow-up were excluded from the study. The Medical Ethics Committee for Registered Clinical Trials in China (ethics approval number: ChiCTR2100047954) approved this retrospective study, and the research was conducted in accordance with the principles of the Declaration of Helsinki.

Therapy

Primary chemotherapy options for systemic DLBCL include the R-CHOP regimen, the rituximab, cyclophosphamide, liposomal adriamycin, vincristine, and prednisone regimen, and the salvage chemotherapy regimen comprising the isocyclophosphamide, carboplatin, and etoposide regimen, the gemcitabine, dexamethasone, and cisplatin regimen, the oxaliplatin and gemcitabine regimen, and BTKi. For primary chemotherapy in patients with PCNSL, clinicians typically consider patients the rituximab, methotrexate, and temozolomide regimen, the rituximab, methotrexate, and liposomal adriamycin regimen, and the rituximab, methotrexate, and BTKi (RM + BTKi) regimen. Salvage treatments encompass BTKi monotherapy, the RM + BTKi regimen, or radiotherapy. The choice of the treatment regimen is based on the patient's condition, drug sensitivity, and individual clinical considerations. In cases where patients have concurrent active hepatitis or experience intolerance of initial treatments, with a combination therapy involving rituximab and BTKi is considered once tolerance is established.

Clinical assessment and follow-up

In patients with systemic DLBCL, regular assessments of treatment response were conducted every two cycles[19]. The response following four treatment cycles and suspected CR were evaluated by employing 18F-fluorodeoxyglucose PET/CT. Thereafter, patients were followed up regularly every 3 to 6 months. In patients with PCNSL, tumour response was assessed using magnetic resonance imaging (MRI), PET, cerebrospinal fluid analysis, ocular slit lamp, and bone marrow biopsy according to the International PCNSL Collaborative Group guidelines[15]. MRI evaluations were performed every two cycles, with the possibility of extending this interval to three to six cycles after achieving CR. Efficacy was evaluated based on several key endpoints, including ORR, progression-free survival (PFS), and OS. ORR encompassed patients who achieved PR or CR. PFS was calculated from treatment initiation until disease progression or death. OS was defined as the time elapsed from treatment to death from any cause.

Whole-exome sequencing (WES)

Furthermore, WES analysis was conducted on tissue sections from 18 patients with PCNSL, including five patients with R/R PCNSL treated with BTKi-containing (orelabrutinib) regimens. This analysis aimed to investigate the potential association between genomic characteristics and patient responses to orelabrutinib.

The genomic deoxyribonucleic acid (DNA) of acceptable quality was subjected to random fragmentation into fragments measuring approximately 150–250 base pairs using an ultrasonic high-performance sample processing system (Covaris). Subsequently, exon enrichment was performed using the Agilent Sureselect Human All Exon V6 kit. High-throughput sequencing of qualified libraries was performed using the Illumina NovaSeq6000 platform to ensure that each sample met the specified data volume criteria, with a target average sequencing depth of > 100× across all regions. The entire WES process was outsourced to Kang Sheng Global Gene Technology Co.

The analysis of sequencing data involved multiple software tools and quality control steps. Initially, SOAPnuke software was used for image recognition, decontamination, and the removal of splice sequencing results. Subsequently, fastqc and ht-stat software were used to count the number of sequencing reads, data yield, sequencing error rates, etc., in the clean data. The clean data, which had undergone quality control, were compared to the reference genome hg19 using BWA software. Following this step, Picard, Genome Analysis Toolkit (GATK), and SAMtools software were employed to address issues such as tagging duplicates, local re-comparison, base mass value re-correction, etc. The mutect2 module within GATK4 was used for identifying somatic single nucleotide variants and somatic insertions and deletions. The mutations of all samples in the cohort were combined, and the Maftools software was used to map out the entire cohort of the mutation panorama.

Statistical analysis

Patient characteristics were summarised using descriptive statistics. Continuous variables are presented as means and medians (ranges), while categorical variables are expressed as numbers (proportions). Statistical analyses were performed using SPSS version 25.0. PFS was defined as the duration from chemotherapy initiation to disease progression or recurrence, death from any cause, or the last follow-up. OS was defined as the duration from the initiation of chemotherapy to death from any cause or the last follow-up.

Patient characteristics

From March 2020 to March 2023, 26 patients (16 males and 10 females) with a median age of 60 (27–70) years were included in this study. Among these patients, 10 were diagnosed with central high-risk systemic DLBCL and 16 patients had PCNSL, with three experiencing relapses, six classified as refractory cases, and seven categorised as primary PCNSL cases. All patients were confirmed to have the pathological subtype of DLBCL. The baseline data of these 26 patients are presented in Table 1 and Table 2.

Of the 10 patients with CNS high-risk systemic DLBCL, 70.0% (7/10) were males, with a median age of 60 (27–69) years, and 50% (5/10) were classified as elderly patients (aged ≥60 years old). Among these patients, 80% (8/10) had non-germinal centre B cell (GCB) subtypes according to Hans staging, and 20% (2/10) exhibited double-expressed patterns with Myc levels ≥40% and B cell lymphoma 2 (Bcl-2) levels ≥60%. Additionally, 20% (2/10) of patients exhibited CD5⁺ expression, 60% (6/10) of patients had Ki-67 levels of ≥80% and 90% (9/10) of patients were categorised as Ann Arbor stage IV. Notably, all patients did not manifest B-symptoms, 50% (5/10) of patients had Eastern Cooperative Oncology Group (ECOG) scores of >1, and 90% (9/10) of patients had elevated lactate dehydrogenase (LDH) levels. Among these patients, 50% (5/10) of patients had skeletal involvement, which was multifocal, while another 50% (5/10) exhibited adrenal involvement, and 10% (1/10) had testicular involvement. Prior to initiating BTKi treatment, the patients received a median of six (0–10) chemotherapy courses. Regarding the risk profile, among the 10 patients with systemic DLBCL, five were categorised as high risk based on the CNS International Prognostic Index (CNS-IPI) scores. Two patients were identified as CD5⁺ cases, with one of them also presenting with double-expressed lymphoma (DEL) and the other exhibiting multiple spinal infiltrations. Additionally, one patient had a large abdominal mass combined with spinal infiltration and DEL, while two patients developed CNS infiltration during treatment, with one being a primary case involving multiple spinal regions. The other patient did not exhibit recognised CNS risk factors and experienced disease progression despite third-line treatment, thus being classified as refractory DLBCL.

Among the 16 patients with PCNSL, 56.3% (9/16) were males, with a median age of 54 (31–70) years, and 25% (4/16) were classified as elderly patients (≥60 years). In terms of Hans typing, 81.2% (13/16) exhibited the non-GCB subtype, while 18.7% (3/16) of cases exhibited a double-expression profile. Additionally, 87.5% (14/16) of patients had Ki-67 levels of ≥80%. A significant proportion of patients, specifically 75% (12/16), had tumours involving deep regions of the brain, including the periventricular tissues, basal ganglia, corpus callosum, brainstem, and/or cerebellum. Furthermore, 68.8% (11/16) of patients had ECOG scores of >1, and 50% (8/16) of patients presented with elevated LDH levels. These patients received a median of 1 (0–8) cycle of chemotherapy before initiating BTKi treatment. In terms of disease status, 18.7% (3/16) were relapsed cases, 37.5% (6/16) were refractory cases, and 43.8% (7/16) were primary PCNSL cases.

Treatment outcomes

Ten patients with central high-risk systemic DLBCL underwent treatment involving a combination of R-CHOP therapy and BTKi, primarily zebutinib. In the case of 15 patients with PCNSL, the primary treatment comprised mainly of rituximab and MTX-based therapy combined with BTKi, primarily orelabrutinib. Additionally, one elderly patient with PCNSL received rituximab in combination with BTKi owing to renal function abnormalities. The specific treatment regimen and efficacy assessment are presented in Fig. 1. At the end of the follow-up period, the median duration of the BTKi application was 4 (1–24) months. Among the patients, nine continued to receive BTKi therapy, nine had to discontinue BTKi therapy due to financial constraints, and eight patients died due to disease progression.

Nine of the 10 patients with central high-risk systemic DLBCL received treatment with a BTKi-containing regimen for an average of 6 months. The final ORR was 55.6%, and the CR was 60%, comprising three CRs and two PRs. Notably, the best ORR (Fig. 2A) was 100% for patients with the GCB subtype compared with 63% for those with the non-GCB subtypes. Furthermore, a comparison of early- vs. late-stage dosing revealed an ORR of 67% in both groups. When examining the final ORR (Fig. 2B), patients with the GCB subtype received a 100% response rate, while those with the non-GCB subtype had an ORR of 50%. In terms of dosing, patients in the 1-3 line and late dosing groups had ORRs of 67% and 50%, respectively. Two patients with systemic DLBCL who developed CNS infiltration during treatment had a projected survival of <3 months. One of them received a combination of BTKi and salvage chemotherapy for 5 months, resulting in PFS and OS of 9 and 21 months, respectively. The other patient, previously treated with third-line therapy and diagnosed as refractory, developed CNS infiltration after 5 months of combination BTKi treatment and had an OS of 9 months. As of the follow-up period, only one out of 10 patients had died, while the remaining patients, including two with secondary CNS lymphoma (SCNSL), survived.

Sixteen patients with PCNSL were subjected to efficacy analysis, and they had a median maintenance time of 4 (1–24) months and a median follow-up duration of 9.5 (2–31) months for BTKi treatment. Among the nine patients with R/R PCNSL, three had experienced relapses and received BTKi single-agent salvage therapy (P1-P3), with a median BTKi maintenance time of 7 (1–8) months and a median OS of 9 (9–16) months. The remaining six were primary refractory cases, and they underwent salvage therapy with a BTKi-based regimen. Their median BTKi maintenance time was 3 (1–6) months and the median OS was 18 (2–31) months. Among these six primary refractory patients, three received early BTKi administration (P7, P10, and P16), while the other three initiated BTKi treatment after the course (P4-P6), with the early-administered patients showing a longer mean survival period compared with the late-administered patients (11 vs. 10 months). Furthermore, seven patients, all of whom were receiving their initial treatment and belonged to the non-GCB subtype, were treated with the RM+ BTKi regimen as their first-line treatment. They had a median BTKi maintenance time of 8 (2–24) months. Following two courses of treatment, they achieved an ORR of 100%, which included one case that achieved CR and six cases that achieved PR. The median follow-up duration was 5 (2–25) months, and the median PFS and median OS not remained undetermined.

Responses were observed across various subgroups of patients with PCNSL. The best ORR (Fig. 2D) differed between patients with GCB and non-GCB subtypes, with rates of 67% and 85%, respectively. Moreover, comparisons were made between patients with 1-3 lines of treatment vs. those receiving late-stage treatment, resulting in ORRs of 80% and 83%, respectively. Additionally, ORRs were analyzed for patients with different clinical histories, including those with relapse (67%), primary refractory cases (67%), and primary PCNSL (100%). Furthermore, ORRs were assessed in relation to the location of brain infiltration, whether superficial or deep, with rates of 50% and 83% for orelabrutinib and 86% and 50% for zanubrutinib. and the type of cranial lesion management was also considered, yielding ORRs of 50% and 83% for cranial lesion resection and biopsy, respectively. The final ORR demonstrated variations over time (Fig. 2C), reflecting subsequent disease progression in R/R patients, those receiving late-stage medication, and those with GCB subtypes (n=3). Furthermore, ORRs were analyzed in the context of brain infiltration location, revealing rates of 50% and 42% for superficial and deep brain infiltration, respectively. Similarly, for orelabrutinib and zanubrutinib, ORRs were 43% and 50%, respectively, and for patients undergoing brain lesion resection and biopsy, the ORRs were 40% and 50%, respectively.

Clinical response and genomic characterisation

In this study, genetic testing was performed on an additional 18 PCNSL cases. The analysis identified the top 15 high-frequency mutated genes in this cohort with the following prevalence rates: keratin-associated protein 4-1 (KRTAP4-1) (94%), pleckstrin and sec7 domain containing 3 (83%), stress-responsive DNAJB4 interacting membrane protein 1 (83%), AL450307.1 (78%), dual-specificity phosphatase 5 (78%), melanoma-associated antigen B16 (78%), telomere maintenance 2 (72%), flavin-containing dimethylaniline monoxygenase 2 (67%), transfer ribonucleic acid methyltransferase 13 homolog (67%), titin (67%), amine oxidase copper containing 1 (61%), phosphatidylinositol glycan anchor biosynthesis class Z (61%), Sushi, von Willebrand factor type A, epidermal growth factor, and pentraxin domain containing 1 (61%), inositol hexakisphosphate kinase 3 (56%), and T cell lymphoma invasion and metastasis 1 (56%). The distributions of high-frequency mutations are illustrated in the waterfall plot displayed in Fig. 3. It is worth noting that all 14 high-frequency mutated genes exhibited missense mutations, except for KRTAP4-1, which featured an in-frame deletion. Among the 18 cases, five were patients with R/R PCNSL who had received BTKi (orelabrutinib) treatment. The median duration of BTKi administration in this subgroup was 6 (1–8) months. These patients displayed a median PFS of 7 (3–9) months and a median OS of 16 (9–29) months. Their genetic mutations were characterised by Pim-1 proto-oncogene, serine/threonine kinase (PIM1) (100%), CD79B (60%), myeloid differentiation primary response 88 (MYD88) (40%), and PR domain zinc finger protein 1 (PRDM1) (40%), as shown in Fig. 4 (A). Additionally, the study examined five patients with R/R PCNSL and assessed their prognostic characteristics in relation to gene mutations, as presented in Fig.s 4B and 4C. The mean OS for individuals with the MYD88 mutation and deletion was 14 and 20 months, respectively. Similarly, the mean OS for those with the CD79B mutation and deletion was 14 and 22 months, respectively. Patients with the tumour necrosis factor alpha-induced protein 3 (TNFAIP3) mutation and deletion had a mean OS of 16 and 18 months, respectively. In terms of lymphoma subtype, the mean OS for the co-mutations in MYD88 and CD79B (MCD) subtype and non-MCD subtype patients was 14 and 20 months, respectively, while for the CD79B and/or PIM1 mutations (CDP) subtype and non-CDP subtype patients, the mean OS was 14 and 22 months, respectively. Regarding PFS, the mean values for MYD88 mutation and deletion were 5 and 10 months, for CD79B mutation and deletion were 6 and 11 months, for TNFAIP3 mutation and deletion were 4 and 10 months, for MCD subtype vs. non-MCD subtype were 5 and 11 months, and for CDP subtype vs. non-CDP subtype were 6 and 11 months.

DLBCL is the most prevalent form of lymphoma, constituting approximately 20% of all lymphoid malignancies[1]. The CNS-IPI score is one of the most well-established methods for assessing the risk of CNS infiltration, considering several risk factors, including age > 60 years, an ECOG score of > 1, elevated LDH levels, advanced (stage III to IV) disease, more than one site of extranodal involvement, and lymphoma infiltration in renal or adrenal regions[20]. The 2-year risk of CNS infiltration in patients with high CNS-IPI scores is 10.2–12.0%[20]. Once CNS infiltration occurs, treatment options are limited, and the prognosis is extremely poor. Some studies have recommended prophylactic treatment for CNS in the high-risk group. Risk factors associated with CNS infiltration in the 10 patients with systemic DLBCL in our study included high-risk sites of involvement, such as the testis, uterus, kidneys, adrenal glands, and spine, along with CD5 expression, the ABC subtype, and expression of Myc and Bcl-2 proteins (double-expression lymphoma, DEL) or the presence of gene rearrangements (double-hit lymphoma) [21, 22]. One of these patients was refractory to all three lines of therapy. Previous reports indicate that approximately 5% of patients with systemic DLBCL experience CNS infiltration, leading to a poor prognosis[3, 4]. A prospective study revealed that the rate of CNS infiltration was 10 times higher in the high-risk group classified by CNS-IPI scores compared to the low-risk group. However, the prophylactic use of high-dose MTX did not prove beneficial for high-risk patients[23]. Hence, effective treatment strategies for preventing CNS infiltration in DLBCL need further exploration. In this study, BTKi was employed as salvage therapy for SCNSL and as a prophylactic option for high-risk systemic DLBCL patients to evaluate whether this approach could improve clinical outcomes and prognosis and reduce the risk of CNS infiltration. Studies have demonstrated that patients with SCNSL have a median survival time of only 2–5 months[5]. Our study included two patients (20%) who were initially diagnosed with CNS high-risk systemic DLBCL but subsequently developed CNS infiltration during their treatment. One of them was diagnosed with SCNSL and rescued through BTKi combination chemotherapy (RM + BTKi regimen) and has now survived for 5 months. Another refractory patient who developed CNS infiltration after 5 months of BTKi monotherapy, this patient continued to receive combination salvage chemotherapy (including ASCT), demonstrating a total disease duration of 21 months. These instances suggest the potential efficacy of BTKi in prolonging the survival of patients with high-risk systemic DLBCL and secondary CNS infiltration. This conclusion requires further validation by expanding the sample size. Among the remaining eight patients in our study who were at a high risk of CNS infiltration but did not develop CNS infiltration during their treatment, they all underwent a median of 6 (1–10) cycles of chemotherapy with the R-CHOP regimen, followed by a mean of 6 months of BTKi maintenance therapy. The assessed efficacy indicated an ORR of 71.42% (5/7, 60% CR rate), including three cases of CR, two cases of PR, and two cases of PD. Among these, five patients exhibited high CNS-IPI scores, two had CD5⁺ lymphoma (combined DEL and spinal multiple infiltration), and one patient had a large abdominal mass combined with multiple spinal infiltrations and DEL. Some studies have reported that high-risk subtypes combined with secondary renal/adrenal involvement exhibit a higher risk of CNS infiltration, which is why these factors have been designated as independent risk factors based on the CNS-IPI score[24] [20]. In our study, the five patients at high risk for CNS infiltration (all with adrenal gland infiltration) had an ORR of 50% (2/4, one case not evaluated), with one case showing CR, one showing PR, and two cases showing progressive disease (PD), combined with bilateral testicular and thoracic and ascites infiltration, respectively, after an average of 6 months of BTKi maintenance. Despite the limited efficacy in these patients, none developed CNS infiltration during disease progression on treatment. The potential impact of BTKi addition on CNS infiltration reduction warrants further investigation through larger sample sizes. Two patients with CD5 + lymphoma were treated with BTKi treatment strategies: one underwent early combination chemotherapy and subsequent post-chemotherapy maintenance therapy, while the other patient received BTKi monotherapy maintenance therapy upon completing eight cycles of chemotherapy. Both patients have been closely monitored for 18 months, and their treatment efficacy has been assessed. Remarkably, the patient who received an early combination of chemotherapy and post-chemotherapy maintenance therapy achieved CR. On the other hand, the patient with a large abdominal mass in combination with multiple spinal infiltrations and DEL, who underwent BTKi monotherapy maintenance therapy following eight cycles of chemotherapy, exhibited PR. Furthermore, the timing of BTKi administration also affects the disease remission status (Fig. 2A and 2B). Although the early initiation of BTKi did not significantly increase the optimal efficacy, patients who received the medication early remained free of disease during the extended follow-up period, indicating that early application of BTKi might potentially prolong the duration of disease remission. In addition to the established risk factors for CNS infiltration, it is noteworthy that among the 10 patients with systemic DLBCL, 50% (n = 5) also presented with multifocal spinal infiltration. Previous studies have indicated that patients with multifocal bone infiltration in DLBCL might have a significantly poorer prognosis compared to those with unifocal bone infiltration. Specifically, the 5-year PFS rates for patients with multifocal bone infiltration were significantly lower (14%) than those with unifocal bone infiltration (75%), with corresponding 5-year OS rates of 47% and 92%, respectively. The more favourable prognosis in unifocal bone DLBCL cases might be associated with the GCB subtype[25], while patients with multifocal bone infiltration or spinal involvement are more likely to experience CNS infiltration[4]. Previous studies have reported a 2-year CNS infiltration rate of approximately 5% in systemic DLBCL and 12% in patients at high risk for CNS-IPI scores[3, 4] [20]. Another study showed no significant difference between prophylactic intrathecal and intravenous MTX for preventing CNS infiltration[26]. The present study focused on 10 patients at high risk of CNS infiltration. Among these patients, two still developed CNS infiltration despite the addition of BTKi therapy at different times. This suggests the importance of considering earlier initiation of BTKi therapy and exploring more effective combination treatment strategies. Compared to MTX prophylactic intrathecal injection, BTKi therapy showed good tolerability and demonstrated some efficacy in our small patient sample[26]. However, it did not significantly reduce CNS infiltration in patients with central high-risk DLBCL. It is important to note that this finding was based on a limited sample size and follow-up duration. Therefore, it emphasises the potential of molecular diagnostics in identifying high-risk patients. Screening for circulating tumour DNA in newly diagnosed patients could help identify those at very high risk and allow for more effective preventive treatment[27]. Early identification and prophylactic interventions for these high-risk patients are extremely important. CD5⁺ DLBCL has a poor prognosis and a high risk of CNS infiltration[28, 29]. In this study, BTKi treatment for patients with CD5⁺ DLBCL resulted in favourable efficacy and prolonged OS, with no CNS involvement observed during the follow-up period, This suggests that CD5 + patients could particularly benefit from BTKi therapy. This might be associated with distinct regulatory mechanisms of BTK in CD5⁺ and CD5⁻ B lymphocytes. BTKi can inhibit CD5⁺ B cell differentiation and the production of inhibitory mediators such as interleukin (IL)-10 and IL-35 in pancreatic cancer, thus improving the tumour microenvironment for therapeutic effects[30]. Additionally, BTKi activation of the B cell antigen receptor (BCR) signalling pathway was observed to induce apoptosis in CD5⁺ B cells[31]. However, further research is needed to elucidate any other potential regulatory mechanisms of BTK in CD5⁺ and CD5⁻ B lymphocytes. Furthermore, our study demonstrated that BTKi extended OS in patients with multifocal spinal infiltration and double expression. Early BTKi intervention, when combined with chemotherapy, in patients with high CNS-IPI scores might improve treatment outcomes. However, patients with a high disease burden exhibited poor responses to multiple therapies, possibly due to their unique characteristics[32, 33]. Patients with testicular involvement have specific immunophenotypic, genetic, and survival characteristics, which correlate with a high disease burden and poor prognosis[34]. This underscores the importance of considering the site, size, and number of extranodal involvements to further improve treatment efficacy. Fine-tuning risk assessment through scoring and stratification, coupled with timely administration of appropriate treatments, is crucial for improving patient outcomes.

Targeted BTK therapy has demonstrated promising outcomes in patients with PCNSL. Studies have reported ORRs of 44.4–77%, CR rates of 36–38.5%, median PFS of 3.1–4.54 months, and median OS of 3.1–11.5 months when using BTKi for treating R/R PCNSL[35–37]. Among the 16 patients with PCNSL included in this study, 56.3% (9/16) had R/R disease, and 43.7% (7/16) patients had primary disease, all with the pathological type of DLBCL. Among the nine R/R patients (three with relapsed disease and six with primary refractory disease), three patients achieved PR with first-line MTX-based chemotherapy but experienced disease relapse after salvage therapy with BTKi monotherapy, with a mean BTKi maintenance time of 5 (1–8) months. Unfortunately, they eventually succumbed to disease progression. This outcome is more favourable than previously reported survival for relapsed patients treated with chemotherapy, with an average extension of survival of 5 months[12]. For the six patients with primary refractory PCNSL-DLBCL who did not achieve PR after three courses of MTX-based chemotherapy, BTKi was administered as a second-line treatment, resulting in an average extension of survival by 12 (2–21) months compared with literature reports[12]. Among them, three received early administration of BTKi, while the other three received BTKi after the third course of chemotherapy. Notably, patients who received early BTKi had a longer mean survival than those who received late BTKi (11 months vs. 10 months). The remaining seven first-treatment patients, all of whom had the non-GCB subtype, received BTKi combination chemotherapy (RM + BTKi regimen) as first-line treatment, with a mean duration of 8 months. They achieved an ORR of 100% after two courses (one case showing CR and six cases showing PR), with a median follow-up of 5 (2–23) months. Median PFS and OS were not reached. Previous reports on BTKi as first-line treatment for PCNSL are limited; however, the addition of BTKi at the initial treatment stage improved treatment efficacy, resulting in early remission and longer median remission (5 months vs. 4 months) compared to MTX-based chemotherapy regimens. Further follow-up is necessary to confirm sustained benefits. Additionally, this study further analyzed the timing of BTKi administration in patients with PCNSL (Fig. 2D). Additionally, this study found that early administration did not demonstrate a higher remission rate, patients who received early BTKi treatment remained in disease remission during follow-up, whereas those receiving late BTKi treatment showed disease progression(Fig. 2D). However, this conclusion was limited by the sample size and follow-up duration. In conclusion, the addition of BTKi improves the outcomes of patients with PCNSL, and early administration shows a tendency to prolong overall survival. Furthermore, patients with deep brain infiltration exhibited a high response rate to early treatment; however, the long-term efficacy remained limited (Fig. 2C and 2D), consistent with previous reports[38]. Additionally, another study reported that the method of obtaining tumour tissues for diagnosis in patients with PCNSL also influenced treatment efficacy. Surgical resection was associated with longer PFS and OS compared with biopsy alone, Additionally, another study reported that surgical resection was associated with longer PFS and OS compared with biopsy alone, possibly due to the combination of stereotactic biopsy with multiple and deep lesions. Surgical resection could open the blood-brain barrier, potentially enhancing the penetration of certain chemotherapeutic agents[39]. However, it should be noted while stereotactic biopsy demonstrated superior short-term effectiveness, it still had a greater long-term recurrence rate and poorer prognosis compared to surgical resection.

With the development of high-throughput molecular technologies, previous targeted sequencing studies have identified several recurring mutations and copy number variants in PCNSL, including PIM1 mutations (41.4–100%)[40], MYD88 mutations (38–85.4%)[40–43], CD79B mutations (51.2%)[42], and PRDM1 mutations (19%)[44]. However, none of these mutation types were among the top 15 most frequently mutated genes observed in the cohort of 18 patients with PCNSL in this study. In this cohort, MYD88, PIM1, and PRDM1 mutations were identified as non-synonymous mutations in seven patients, all with a mutation frequency of 38.89%, and CD79B mutations were observed in six patients, with a mutation frequency of 33.33%. It is noteworthy that among these 18 patients, five patients had MCD, and five patients had co-mutations in MYD88 and PIM1, suggesting that MYD88 mutation might serve as a characteristic mutation in PCNSL and is frequently observed in combination with mutations in other genes. In particular, among the patients with R/R PCNSL treated with BTKi (orelabrutinib), five of them exhibited gene expression profiles showing 100% frequency of PIM1 mutations, 60% frequency of CD79B mutations, 40% frequency of MYD88 mutations, and 40% frequency of PRDM1 mutations. Furthermore, the study assessed the relationship between mutation profiles and the mean PFS and OS in R/R PCNSL patients (Fig. 4B and 4C). They suggested that mutations in MYD88, CD79B, and TNFAIP3 genes were associated with poor prognosis. Previous studies have demonstrated that MYD88 and CD79B are involved in the nuclear factor (NF)-kappa B (κB) signalling pathway, which promotes cytokinesis. MYD88, particularly in its most common mutated form (L265P), interacts with toll-like receptors and leads to increased NF-κB signalling[41, 45]. BTKi, on the other hand, inhibits NF-κB signalling downstream of the BCR pathway[46]. In a recent phase I/II clinical trial involving patients with R/R ABC-DLBCL, individuals with MCD exhibited sensitivity to ibrutinib[13]. MYD88^L265P mutation rates are higher in PCNSL compared with systemic DLBCL[47, 48]. While one study did not find an association between MYD88 mutations and PFS or OS[49], another study reported a poor prognosis associated with MYD88 mutations[50]. In our study involving five patients with R/R PCNSL, two patients had MYD88 mutations, three patients had CD79B mutations, and two patients had MCD, which was similar to previous findings[42]. Shorter PFS and OS were observed in patients with MYD88 mutations; however, no significant association was observed between CD79B mutation and longer OS, possibly due to the small sample size. Furthermore, Zhou et al. recently demonstrated that patients with CDP subtypes had a significantly longer 2-year OS (76% vs. 40%) compared to patients without CD79B or PIM1 mutations[42]. All five R/R patients in our study presented with CDP, with a mean OS of 17.8 months and an OS of approximately 2 years. Early WES testing and the timely addition of BTKi might further improve the prognosis of patients with the CDP subtype and prevent progression to R/R disease. This suggests that WES can effectively stratify patients for identification and guide treatment decisions. Additionally, 20% (1/5) of R/R patients in this study showed TNFAIP3 mutations. TNFAIP3 deletions led to increased expression of NF-κB target genes by enhancing MYD88^L265P driven NF-κB and p38 signalling[51]. BTKi could lower NF-κB signalling downstream of MYD88[46]; however, TNFAIP3 deletion resulted has been associated with ibrutinib resistance in ABC-DLBCL cell lines[13] [52–54]. In our study, one of the five R/R patients treated with BTKi had TNFAIP3 mutations, and the patient's prognosis was inferior to that of the four patients without TNFAIP3 mutations, with a mean OS of 15 and 23 months, respectively. In addition, Kuo et al. reported that the characteristic of ibrutinib resistance is Bcl-2 up-regulation and that combining ibrutinib with Bcl-2 inhibitors can overcome resistance in DLBCL[55]. In this study, one of the five R/R patients treated with BTKi had mutations in PIM1, TNFAIP3, and interferon regulatory factor 4 genes along with Bcl-2 up-regulation. This patient was salvaged with BTKi (ibrutinib) monotherapy for 8 months after disease progression, achieving an OS of up to 16 months, significantly surpassing expectations. Whether this outcome it is related to the specific mechanism of action of ibrutinib warrants further investigation. PCNSL exhibits genetic heterogeneity, and while WES was performed on a limited sample size of only (18 patients) in this study, the findings provide valuable insights for the development of clinical treatment strategies aimed at improving prognosis and mitigating drug resistance. It has been reported that patients with MCD are sensitive to ibrutinib[13]. However, the two co-mutated R/R patients in this study responded poorly to ibrutinib. Consequently, the question of whether the early administration of BTKi could enhance efficacy requires further validation. Patients with CDP have previously shown a favourable prognosis[42]. Nevertheless, the five R/R patients in this study, all of whom exhibited detectable PIM1 expression, demonstrated poor efficacy after BTKi application, with a median OS of 16 (9–29) months.

In conclusion, systemic DLBCL has a very poor prognosis with limited treatment options once CNS infiltration occurs. The need for prophylactic MTX therapy for patients at high risk of central infiltration has been a topic of debate in previous studies. In this study, prophylactic treatment with BTKi (zanubrutinib) for central high-risk DLBCL demonstrated a reduction in CNS infiltration rates. However, this finding was limited by a small sample size and warrants further investigation with a larger cohort. The underlying pathogenesis and molecular biological processes of PCNSL are yet to be elucidated. Although MTX-based therapy improves efficacy, treatment regimens for the long-term benefit of the patients are still lacking. Our study revealed that BTKi (orelabrutinib) treatment for R/R PCNSL can improve its efficacy and extend survival. Early administration of this drug can prolong OS, with first-line BTKi treatment leading to early remission and prolonged remission. In this study, the mutation characteristics of PCNSL were initially revealed through WES of 18 patients, and BTKi treatment was administered to five R/R patients. While it prolonged patient survival, the long-term prognosis remains unfavourable, particularly in patients with combined mutations in MYD88, CD79B, and TNFAIP3 genes. Our further efforts will focus on expanding the sample size to develop more effective and less resistant therapeutic strategies for PCNSL, incorporating a combination of treatment modalities such as targeted therapy and immunotherapy.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China [No.8226010026]; the Provincial Natural Science Foundation of Gansu Province [No.22JR11RA053]; and the “Cui Ying Postgraduate Tutor” training program of Lanzhou University Second Hospital [No.201710].

Declaration of interest statement

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in my product, service and company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.

Author contributions

Litian Zhang: Conceptualization, Methodology, Data curation, Visualization, Writing- Original draft preparation. Cuicui Li: Investigation. Ningning Yue: Supervision. Haoyun Jiang: Software, Validation. Qiqi Jin: Writing- Reviewing and Editing. Jiajia Cao: Writing- Reviewing and Editing. Chongyang Wu*：Conceptualization, Supervision，Project administration, Funding acquisition.

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Table 1. Demographics and baseline characteristics of systemic DLBCL.

Demographics or Characteristics		Case(%),n=10
Gender	Male		7	70.0%
	Female		3	30.0%
Age(years)at study entry	Median 60 (Range,27-69)
	＜60		5	50.0%
	≥60		5	50.0%
Hans classification	GCB		2	20.0%
	Non-GCB		8	80.0%
DEL	Yes		2	20.0%
	No		8	80.0%
CD5+	Yes		2	20.0%
	No		8	80.0%
Ki-67 (%)	＜80		4	40.0%
	≥80		6	60.0%
Ann arbor stage at diagnosis	Ⅰ-Ⅱ		1	10.0%
	Ⅲ-Ⅳ		9	90.0%
B symptom at diagnosis	Yes		0	0.0%
	No		10	100.0%
ECOG at study entry	0-1		5	50.0%
	2-4		5	50.0%
LDH at study entry	Elevated		9	90.0%
	Normal		1	10.0%
Extra-nodal disease	Bone		5	50.0%
	Adrenal gland		5	50.0%
	Testis		1	10.0%
Prior lines of therapy	1-3 lines		4	40.0%
	＞3 lines		6	60.0%
CNS-IPI risk factors	＜4		5	50.0%
	4-6		5	50.0%
Prior auto-SCT			2	20.0%
Prior CAR-T treatment			1	10.0%
Prior radiotherapy			1	10.0%

DLBCL，Diffuse large B-cell lymphoma；DEL，Double expression lymphoma ；GCB，germinal B cell-like；CAR-T，chimeric antigen receptor T-cell immunotherapy ；auto-SCT，Autologous Hematopoietic Stem Cell Transplantation.

Table 2. Demographics and baseline characteristics of PCNSL.

Demographic or Characteristic		Case(%),n=16
Gender	Male		9	56.30%
	Female		7	43.80%
Age(years)at study entry Median 54 (Range,31-70)
	＜60y		12	75.00%
	≥60y		4	25.00%
Hans classification	GCB		3	18.80%
	Non-GCB		13	81.30%
DEL	Yes		3	18.80%
	No		13	81.30%
Ki-67	＜80		2	12.50%
	≥80		14	87.50%
ECOG at study entry	0-1		5	31.20%
	2-4		11	68.80%
LDH at study entry	Elevated		8	50.00%
	Normal		8	50.00%
Prior lines of therapy	1-3 line		10	62.50%
	4- line		6	37.50%
Disease status	Hign risk		7	42.70%
	Primary refractory 37.5%		6	37.50%
	Relapsed		3	18.80%
Tumor location	Superficial brain		4	25.00%
	Deep brain		12	75.00%
Prior auto-SCT			1	6.30%
Prior CAR-T treatment			1	6.30%
Prior radiotherapy			3	18.80%

PCNSL，primary central nervous system lymphoma ；DEL，Double expression lymphoma ；GCB，germinal B cell-like；CAR-T，chimeric antigen receptor T-cell immunotherapy ；auto-SCT，Autologous Hematopoietic Stem Cell Transplantation.

No competing interests reported.

Efficacy of BTK inhibitor administered for central high-risk systemic diffuse large B cell lymphoma and primary central nervous system lymphoma: A single-center retrospective study

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