Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis.

doi:10.21203/rs.3.rs-5025573/v1

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Research Article

Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis.

https://doi.org/10.21203/rs.3.rs-5025573/v1

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Purpose

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignant tumor with poor prognosis. Orelabrutinib, a highly selective BTK inhibitor, has demonstrated promising clinical effectiveness in patients with relapsed and refractory PCNSL. The purpose of this study was to evaluate the effectiveness and safety of orelabrutinib, rituximab, temozolomide and high-dose methotrexate (RMOT) regimen in the treatment of patients with newly diagnosed PCNSL.

Method

Patients diagnosed with PCNSL were included in this retrospective study. All patients received at least 4 cycles of RMOT regimen (rituximab 375 mg/m² iv day 1; MTX 3.5 g/m² iv day 2; temozolomide 150 mg/m² po day 1 to day 5; orelabrutinib 150 mg qd po; 4 weeks per cycle), and autologous stem cell transplantation (ASCT) or whole brain radiation therapy (WBRT) was used as consolidation therapy. All patients were proposed to receive orelabrutinib as maintenance therapy for a maxium duration of 2 years.

Results

16 treatment-naive PCNSL patients were treated with RMOT regimen. The CRR and ORR were 87.5% and 93.75%, respectively. The median follow-up time was 18.7 months. The median PFS and OS was not achieved. The 1-year PFS and OS rates both reached 90%. The most common adverse reaction was anemia, most adverse reactions were grade 1–2, and only 1 patient (6.25%) occurred grade 3 adverse reactions.

Conclusion

This retrospective data suggested that RMOT had an encouraging anti-tumor activity in newly diagnosed PCNSL patients, with a toleratable safety profile. Further perspective studies are warranted to validate its effectiveness in untreated PCNSL.

primary central nervous system lymphoma (PCNSL)

bruton tyrosine kinase

orelabrutinib

rituximab

temozolomide (TMZ)

This is the first report that demonstrate RMOT regimen has better effectiveness and lower adverse reactions than previous research, and has the potential to be the standard care for untreated PCNSL patients. Our study also suggests that maintenance therapy with orelabrutinib may provide a new treatment for patients intolerant to consolidation therapy. Furthermore, our study found orelabrutinib remains effectiveness in PCNSL patients with GCB subtypes, the specific mechanism needs to be explored and discussed.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignant tumor arising in the brain, spinal cord, eyes, or leptomeninges with an unfavorable prognosis[1]. The optimal standard treatment for PCNSL has yet to be defined. HD-MTX-based regimens remain the first option for newly diagnosed PCNSL due to high response rates as demonstrated by numerous studies[2]. The incorporation of additional chemo-therapeutic agents has been explored in various trials, demonstrating significant improvements in patient outcomes[3–6]. Despite these advances, approximately half of patients experience relapse or develop refractory disease within a short period of time[7–8].

Bruton’s tyrosine kinase (BTK) plays a crucial role in the B-cell receptor signaling pathway[9], genetic alterations often occur in the chronic active B-cell receptor signaling featured by MYD88 and CD79B which mediate the response to BTK inhibition (BTKi) in PCNSL[10]. Ibrutinib, a first-in-class BTKi, exhibits the ability to effectively penetrate the blood-brain barrier, and has shown high response rates in both newly diagnosed or relapsed/refractory (R/R) patients with PCNSL. However, the durability of these responses has been limited[11–13]. Orelabrutinib is a novel, potent, highly selective second-generation BTK inhibitor with a high CSF concentration[14]. Several clinical trials have reported the efficacy and safety of orelabrutinib in r/r PCNSL, and its potential use in combination with chemotherapy, molecular targeted drugs, immune-checkpoint inhibitors is also being explored[15–17]. In light of the encouraging results from these trials, we have adopted the combination therapy of orelabrutinib, rituximab, temozolomide and HD-MTX in our daily practice for treating newly diagnosed PCNSL.

This study retrospectively analyzed the clinical characteristics, outcomes and adverse reactions in newly diagnosed PCNSL patients who were treated with RMOT therapy,.

Patients

All patients diagnosed with PCNSL between February 2021 and July 2023 were retrospectively reviewed from Sun-Yat Sen Cancer Center. The enrolled patients fulfilled the following criteria: (a) the disease was pathologically diagnosed as DLBCL; (b) complete clinical and treatment information were available; (c) the patients were between 18 and 80 years old; (d)there was no involvement of sites other than the central nervous system; and (e) no antitumor treatment was received before RMOT therapy. The exclusion criteria were as the following: (a) concurrent with other types of malignancy and (b) patients with any immunodeficiency disease.

Treatment

All patients received at least 4 cycles of RMOT regimen (rituximab 375 mg/m² iv day 1; MTX 3.5 g/m² iv day 2; temozolomide 150 mg/m² po day 1 to day 5; orelabrutinib 150 mg qd po; 4 weeks per cycle) as the first-line induction therapy. To minimize potential adverse reactions, orelabrutinib was given untile the concentration of MTX was less than 1 × 10^− 7 mol/L. When patients received complete response (CR), autologous stem cell transplantation (ASCT) or whole brain radiation therapy (WBRT) was recommended as consolidation therapy. After 6 cycles, if the patients received partial response (PR), WBRT was used as consolidation therapy. For patients had stable disease (SD) or progressive disease (PD), after the induction therapy, salvage treatment was given. All the patients received orelabrutinib monotherapy as maintenance treatment for a maxium duration of 2 years.

Clinical assessment and follow-up

Treatment responses were assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. Response evaluation includes CR, PR, PD, and SD. Once the maintenance therapy was finished, the patients were evaluated by contrast-enhanced MRI scan of the brain every 3 months for the first 2 years and then every 6 months for years 3–5[18]. Overall survival (OS) was the time from treatment to death for any cause. Progression-free survival (PFS) was calculated from the time of treatment initiation until disease progression or death. Treatment-related adverse reactions were evaluated with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

Statistical software SPSS 21.0 (IBM, Chicago, IL) was used for data analysis. Descriptive statistics were used to analyze means, standard deviations, and medians for continuous variables and proportions to summarize discrete variables. Survival was estimated with the Kaplan-Meier method. Response at the end of treatment were reported as proportion (95% CI) calculated using the Clopper-Pearson method. The patient characteristics and treatment responses of the groups were compared using the chi-square or Fisher’s exact tests. A two-sided P < 0.05 indicated a significant difference.

Patient characteristics

A total of 16 patients were retrospectively analyzed. The clinical characteristics are summarized in Table 1, including 7 males (n = 7, 43.75%) and 9 females (n = 9, 56.25%). The median age was 60 years old (range 28–78). Among them, 11 cases were of non-GCB type (n = 11, 68.75%) and 5 cases of GCB type (n = 5, 31.25%). Deep intracranial lesions were observed in 11 patients (n = 11, 68.75%), and elevated serum LDH was noted in 3 patients (n = 3, 18.75%).

Table 1

Baseline characteristics of patients (n = 16)
Characteristics	Patients number	Percent(%)
Gender
Male	7	43.75
Female	9	56.25
Age(median, range)	60(28–78)
KPS
≤ 70	5	31.25
>70	11	68.75
MSKCC
Low-risk	6	37.5
Median-risk	7	43.75
High-risk	3	18.75
Deep intracranial lesion
Yes	11	68.75
No	5	31.25
Serum LDH
Normal	13	81.25
Elevated	3	18.75
Subtype of DLBCL
GCB	5	31.25
Non-GCB	11	68.75

The most prevalent symptom was limb fatigue (n = 6, 37.5%), followed by headache (n = 3, 18.75%), dysarthria (n = 3, 18.75%), dizziness (n = 2, 12.5%), seizure (n = 2, 12.5%), intelligence disorders (n = 2, 12.5%) and vision disorder (n = 1, 6.25%). All patients underwent the positron emission tomography/computedtomography (PET/CT) examination prior to therapy which revealed common lesion sites in the basal ganglia (n = 8, 50%) and frontal lobe (n = 7, 43.75%), other affected areas included parietal lobe (n = 4, 25%), corpus callosum (n = 3, 18.75%), ventricle (n = 3, 18.75%), cerebellum (n = 2, 12.5%), corona radiata (n = 2, 12.5%) and temporal lobe (n = 1, 6.25%).

16 patients received a total of 96 cycles of RMOT regimen: 2 with 4 cycles (n = 2, 12.5%), 12 with 6 cycles (n = 12, 75%), and 2 with 8 cycles (n = 2, 12.5%). After the end of RMOT treatment, a total of 8 patients (n = 8, 50%) received consolidation therapy, of which 7 patients received WBRT (n = 7, 43.75%), 1 patient received ASCT (n = 1, 6.25%).

Treatment Outcomes

The effectiveness of the treatment was evaluated in all 16 patients, and the summary of effectiveness data is presented in Table 2. An interim evaluation after 4 cycles revealed that 13 patients achieved a complete response (CR), yielding a complete response rate (CRR) of 81.25%. In the post-treatment evaluation, 14 patients achieved CR with a CRR of 87.5%. One patient achieved PR (6.25%) and one patient had PD (6.25%), leading to an overall response rate (ORR) of 93.75%.

Table 2

Effectiveness data
	Interim evaluation after 4 cycles (N = 16)	Evaluation after the last cycle (N = 16)
Best overall response, n (%)
ORR	15 (93.75%; 69.8–99.8)	15 (93.75%; 69.8–99.8)
CR	13 (81.25%; 54.4–96.0)	14(87.5%; 0.2–30.2)
PR	2 (12.5%; 1.6–38.3)	1(6.25%; 0.2–30.2)
SD	0	0
PD	1(6.25%; 0.2–30.2)	1(6.25%; 0.2–30.2)
Median PFS/OS, month (95% CI)		NR (NR - NR)

The follow-up period extended until June 30, 2024 with a median duration of 18.7 months. At the end of the follow-up time, persistent complete remission was observed in 13 out of 14 patients (92.9%). One patient, who had achieved CR, died from a COVID-19 infection after 5.2 months. All 14 patients received oral orelabrutinib maintenance therapy for a maxium duration of 2 years. The median duration of orelabrutinib was 17.4 months and 4 patients completed the full course of maintenance treatment. Notably, another patient with PR remained stable disease after receiving thiotepa, polatuzumab vedotin and pomalidomide treatment. One patient developed PD after 4 cycles, and an MRI scan revealed the presence of a new lesion in the left frontal lobe region. However, this patient is still alive after receiving salvage therapy including tislelizumab, lenalidomide, thiotepa administration followed by WBRT (Fig. 1).

Median PFS and OS were not reached, with a 1-year PFS rate and OS rate of 90% (Figs. 2 and 3). Meanwhile, there were no statistically significant difference in the effect of consolidation therapy on OS (P = 0.23) and PFS (P = 0.27).

Safety

The most common adverse reactions were anemia (n = 5, 31.25%) with other reactions including neutropenia (n = 4, 25%), thrombocytopenia (n = 2, 12.5%), and increased creatinine (n = 1, 6.25%). Adverse reactions reported were all manageable and resolved promptly after supportive care. Only 1 patient (n = 1, 6.25%) experienced a severe adverse reaction - Acute Kidney Injury (AKI) after the fourth cycle of treatment, which showed improvement following nephrology intervention and was permanently discontinued with methotrexate. No treatment-related deaths occurred. All safety data are summarized in Table 3.

Table 3

All adverse reactions at least possibly related to the RMOT regimen
All adverse reactions	Total(%)	G1(%)	G2(%)	G3(%)	G4(%)
Hematologic ADR
Leukopenia	4(25%)	2(12.5%)	2(12.5%)	0	0
Neutropenia	3(18.75%)	1(6.25%)	2(12.5%)	0	0
Anemia	5(31.25%)	5(31.25%)	0	0	0
Thrombocytopenia	2(12.5%)	2(12.5%)	0	0	0
Non hematologic ADR
Elevated creatinine	1(6.25%)	1(6.25%)	0	0	0
Acute kidney injury	1(6.25%)	0	0	1(6.25%)	0

Case example

A 45-year-old male (Patient ID: No.15) presented with headaches, and the positron emission tomography/computedtomography (PET/CT) revealed lesions in the left forehead and bilateral corpus callosum (Fig. 4A) prior to therapy. Intracranial stereotactic biopsy confirmed the diagnosis of PCNSL (non-germinal center B-cell subtype) on June 27, 2022. The patient underwent treatment with RMOT regimen, achieving complete response after 4 cycles (Fig. 4B) and sustained complete remission following 6 cycles (Fig. 4C). Due to the specific lesion locations, consolidation therapy was not administered after induction therapy. Instead, the patient received orelabrutinib as maintenance therapy until now. Throughout the follow-up period, the patient remained in complete remission.

Regarding safety, the patient experienced increased creatinine levels (118.6 µmol/L, medical reference range 57–97 µmol/L) after the second cycle of RMOT, which resolved promptly with supportive care. No other adverse reactions were reported.

Primary central nervous system lymphoma (PCNSL) constitutes 6% of malignant primary central nervous system tumors[19]. PCNSL has a favorable response to treatment compare to other primary malignant CNS tumors. However, the prognosis is inferior to that of other subtypes of NHL, the median survival time for PCNSL is 26 months, with a 5-year OS rate of 35.2%[20]. High-dose methotrexate (HD-MTX) forms the cornerstone of current chemotherapy protocols for PCNSL patients[2]. Despite evolving treatment options, a standardized consensus on optimal therapy is yet to be established. Polychemotherapy regimens including rituximab demonstrated an ORR of 35–74%[5], but nearly half of patients experience relapse shortly thereafter[7].

A retrospective study conducted at our cancer center evaluated the effectiveness and safety of methotrexate (MT) regimens compared to rituximab in combination with MT (RMT) in newly diagnosed PCNSL patients[21]. The ORR of the RMT group was 93.7%, significantly higher than the 69.0% observed in the MT group. The 2-year and 5-year OS were 82.3% and 82.3% in the RMT group and 65.7% and 50.0% in the MT group, respectively. However, the CRR for the RMT regimen was only 53.2%, suggesting that the treatment regimens need further optimization.

BTK is a crucial component in the B-cell antigen receptor (BCR), Toll-like receptor (TLR), and chemokine receptor signaling pathways[9–10]. Activated BTK influences the downstream NF-κB signaling pathway, which plays a key role in the progression of B cell disease. In PCNSL, alterations in B cell receptor signaling pathway-related genes, represented by MYD88 and CD79B, mediate responses to BTK inhibition (BTKi)[22]. Ibrutinib, a first-generation selective BTK inhibitor, has demonstrated significant efficacy in relapsed/refractory PCNSL, though its sustained response rate remains low. Meanwhile, although a phase Ib clinical study of ibrutinib in combination with DA-TEDDi-R (etoposide, cytarabine, and liposomal doxorubicin) reported a high ORR of 86% (12/14), its toxicity was relatively high, and 5 patients died during treatment[10]. Therefore, the high-efficient and low-toxicity regimens need further exploration.

Orelabrutinib is a newly developed BTK inhibitor with high selectivity and a high concentration in the cerebrospinal fluid, a phase 2 clinical study of orelabrutinib in combination with a PD-1 inhibitor in relapsed and refractory PCNSL showed an ORR of 61.5% (8/13) after a median follow-up of 7 months with an estimated one-year PFS rate of 67.7%. Except for one case of interstitial pneumonia, no other grade 3–4 hematologic or non-hematologic AEs were reported, and the toxicity was mild. In addition, multiple clinical trials have reported the efficacy and safety of orelabrutinib in the treatment of PCNSL[16]. Based on the above results, we use a combination regimen of orelabrutinib, rituximab, temozolomide, and HD-MTX (RMOT) in our daily practice in treatment newly diagnosed PCNSL patients for better effectiveness and lower toxicity.

In our study, we found that the sequential use of orelabrutinib with RMT was well tolerated as first-line therapy in PCNSL. All patients were included for the evaluation of effectiveness. The CRR was 87.5% after the post-treatment evaluation, significantly higher than the 53.2% CRR observed with the RMT regimen[21] (P = 0.026) above. At the end of the follow-up time, 13 of the CR patients (13/14, 92.9%) maintained complete remission, with a median PFS and OS not yet reached and a 1-year PFS rate and OS rate of 90%. All reported adverse reactions were generally manageable and resolved with supportive treatment, and no treatment-related deaths occurred. These findings suggest that RMOT regimen offers superior effectiveness and lower toxicity campared to previous research and has the potential to become the standard of care for newly diagnosed PCNSL patients.

Furthermore, the current treatment guidelines for PCNSL recommend WBRT or ASCT as the consolidation therapy after chemotherapy[23–25]. Previous studies have demonstrated superior OS and ORR with consolidation[26]. In our study, 8 patients received consolidation therapy, unlike other stydies, 15 patients received orelabrutinib monotherapy as maintenance after RMOT therapy. Subsequent statistical analysis revealed no statistically significant difference in the effect of consolidation therapy on OS (P = 0.27) and PFS (P = 0.23), suggesting that maintenance therapy with orelabrutinib may provide a viable option for patients intolerant to consolidation.

Interestingly, in diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by BTKi[27–31]. A phase II study of ibrutinib in relapsed/refractory DLBCL showed a 37% response rate in ABC cases compared to 5% in GCB cases[30]. However, in our study, 5 patients of GCB type (n = 5, 31.25%), there was no statistically significant difference in the effect of COO type on CRR (P = 0.308), OS (P = 0.513) and PFS (P = 0.414). This result is inconsistent with the data of previous BTK inhibitors used in DLBCL, and we speculate that in addition to the anti-tumor effect of immunochemotherapy with RMT in these patients, PCNSL may have a unique mutation profile compared with systemic DLBCL, such as higher CD79B and MYD88 mutations, and the specific mechanism needs to be further explored and discussed.

Because our study is a single-center and retrospective study, it has the following limitations. First, the number of sample size is small. Second, the follow-up time is relatively insufficient. Therefore, more prospective studies with larger sample size and longer follow-up time are needed to verify the effectiveness and safety of RMOT regimen.

This retrospective data suggested that RMOT had an encouraging anti-tumor activity in newly diagnosed PCNSL patients, with a toleratable safety profile. This orelabrutinib-containing regimen may provide a potential treatment strategy for patients with PCNSL.

Acknowledgements

Funding

This work is supported by the National Natural Science Foundation of China (82070215), the Natural Science Foundation of Guangdong Province (2024A1515012975), the Natural Science Foundation of Guangdong Province (2024A1515011150), Guangzhou Basic and Applied Basic Research Scheme (2023A04J1765), Beijing Xisike Clinical Oncology Research Foundation (Y-SYBLD2022MS-0142).

Author contributions

All authors contributed to the study conception and design. Qingqing Cai and Yi Xia conceived and designed the study and reviewed the manuscript; Peng Zhang and Man Nie were involved in the study conception, collected, arranged, analyzed the data and wrote the manuscript; Dongyu Zhuang, Tao Chen, Silan Huang, Dexin Lei and Yanlou Wang designed and prepared the figures and tables. All authors read and approved the final manuscript.

Availability of data and materials

All data generated or analyzed during this study is included in this published article.

Competing Interests

The authors have declared that no competing interest exists.

Ethics declarations

Ethics approval

Approval for data collection and publication was obtained from the Ethics Committee of Sun-Yat Sen University Cancer Center (B2024-549-01).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis.

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