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

Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis. Peng Zhang, Man Nie, Dongyu Zhuang, Tao Chen, Silan Huang, Dexin Lei, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5025573/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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/m 2 iv day 1; MTX 3.5 g/m 2 iv day 2; temozolomide 150 mg/m 2 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) Figures Figure 1 Figure 2 Figure 3 Figure 4 Novelty and Impact 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. Background 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,. Materials and Methods 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/m 2 iv day 1; MTX 3.5 g/m 2 iv day 2; temozolomide 150 mg/m 2 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. Result 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. 4 A) 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. 4 B) and sustained complete remission following 6 cycles (Fig. 4 C). 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. Discussion 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. Conclusion 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. Declarations 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. References Batchelor TT, DeAngelis LM (2013) Lymphoma and leukemia of the nervous system, 2nd edn. 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Neuro Oncol 21(Suppl 5):v1–v100. https://doi.org/10.1093/neuonc/noz150 Chen C, Sun P, Cui J, Yan S, Chen H, Xia Y, Bi X, Liu P, Wang Y, Yang H, Nie M, Zhang XW, Jiang W, Li ZM (2019) High-dose Methotrexate plus temozolomide with or without rituximab in patients with untreated primary central nervous system lymphoma: A retrospective study from China. Cancer Med 8(4):1359–1367. https://doi.org/10.1002/cam4.1906 Nakamura T, Tateishi K, Niwa T, Matsushita Y, Tamura K, Kinoshita M, Tanaka K, Fukushima S, Takami H, Arita H, Kubo A, Shuto T, Ohno M, Miyakita Y, Kocialkowski S, Sasayama T, Hashimoto N, Maehara T, Shibui S, Ushijima T, Kawahara N, Narita Y, Ichimura K (2016) Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol 42(3):279–290. https://doi.org/10.1111/nan.12259 Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M (2015) Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology 84(12):1242–1248. https://doi.org/10.1212/WNL.0000000000001395 Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A (2013) Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 31(31):3971–3979. https://doi.org/10.1200/JCO.2013.50.4910 Houillier C, Taillandier L, Dureau S, Lamy T, Laadhari M, Chinot O, Moluçon-Chabrot C, Soubeyran P, Gressin R, Choquet S, Damaj G, Thyss A, Abraham J, Delwail V, Gyan E, Sanhes L, Cornillon J, Garidi R, Delmer A, Tanguy ML, Al Jijakli A, Morel P, Bourquard P, Moles MP, Chauchet A, Gastinne T, Constans JM, Langer A, Martin A, Moisson P, Lacomblez L, Martin-Duverneuil N, Delgadillo D, Turbiez I, Feuvret L, Cassoux N, Touitou V, Ricard D, Hoang-Xuan K, Soussain C (2019) Intergroupe GOELAMS–ANOCEF and the LOC Network for CNS Lymphoma. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study. J Clin Oncol 37(10):823–833. https://doi.org/10.1200/JCO.18.00306 Fleur AD, Groot JK, Doorduijn M, Brink, Ruben AL, De Groen LM, De Haan T, Noordenbos A, Sijs-Szabo KH, Lam H, Böhmer JoséeM, Zijlstra L, Koens M, Durian MA, Oudshoorn H, Veelken, Marjolein WM, Van Der Poel MA, Hamid, Wendy BC, Stevens JLM, van Rooij R, Oostvogels KJ, van den Neelis FJ, Sherida H. Woei-a-Jin, Thomas Tousseyn, Daan Dierickx, Patty M. Jansen, Marie Jose Kersten, Jacoline Bromberg, Marcel Nijland, Joost SP (2022) Vermaat; Consolidation Improves Survival in Primary Central Nervous System Lymphoma without Preference for Type of High-Dose Methotrexate-Based Induction Treatment Regimen. Blood ; 140 (Supplement 1): 369–371. https://doi.org/10.1182/blood-2022-163244 Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, Powell J, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Campo E, Jaffe ES, Delabie J, Smeland EB, Rimsza LM, Fisher RI, Weisenburger DD, Chan WC, Staudt LM (2008) Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A 105(36):13520–13525. https://doi.org/10.1073/pnas.0804295105 Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463(7277):88–92. https://doi.org/10.1038/nature08638 Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, Banham AH, Leppä S (2009) Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol 22(8):1094–1101. https://doi.org/10.1038/modpathol.2009.73 Wilson WH, Wright GW, Huang DW, Hodkinson B, Balasubramanian S, Fan Y, Vermeulen J, Shreeve M, Staudt LM (2021) Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell 39(12):1643–1653e3. https://doi.org/10.1016/j.ccell.2021.10.006 Severson EA, Haberberger J, Hemmerich A, Huang RSP, Edgerly C, Schiavone K, Najafian A, Hiemenz M, Lechpammer M, Vergilio JA, Lesser G, Strowd R, Elvin J, Ross JS, Hegde P, Alexander B, Singer S, Ramkissoon S (2023) Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition. Oncologist 28(1):e26–e35. https://doi.org/10.1093/oncolo/oyac190 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5025573","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":360244814,"identity":"ffc2800c-f8ad-499f-8826-8510a410a1e6","order_by":0,"name":"Peng Zhang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Zhang","suffix":""},{"id":360244815,"identity":"bc953103-5fcf-49f4-96e7-3377c0266302","order_by":1,"name":"Man Nie","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Man","middleName":"","lastName":"Nie","suffix":""},{"id":360244816,"identity":"76333ff2-da7d-45db-b042-a62ee24edfbf","order_by":2,"name":"Dongyu Zhuang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Dongyu","middleName":"","lastName":"Zhuang","suffix":""},{"id":360244817,"identity":"6f001303-21f1-4e1c-8122-c889c8bee1ce","order_by":3,"name":"Tao Chen","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Chen","suffix":""},{"id":360244818,"identity":"9cd4ef62-a8f7-4fb4-b55a-7c6930510945","order_by":4,"name":"Silan Huang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Silan","middleName":"","lastName":"Huang","suffix":""},{"id":360244819,"identity":"009db3f5-802f-4f6d-b01f-53ca389d2701","order_by":5,"name":"Dexin Lei","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Dexin","middleName":"","lastName":"Lei","suffix":""},{"id":360244820,"identity":"fe92b1a2-6f08-4071-97c4-f20477e73b27","order_by":6,"name":"Yanlou Wang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Yanlou","middleName":"","lastName":"Wang","suffix":""},{"id":360244821,"identity":"0277b8f3-b8a3-4b37-bd9c-6009df399bd6","order_by":7,"name":"Qingqing Cai","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Qingqing","middleName":"","lastName":"Cai","suffix":""},{"id":360244822,"identity":"cbbf31aa-4696-4e86-881d-c3eb919174ac","order_by":8,"name":"Yi Xia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYDACZiBOqCBdyxmSbWJsI0W1wXHmZxIP59Ulzp+R/PADQ8U9uwb2swfwapFsZjOTSNx2OHHDjTRjCYYzxckNPHkJeLXwMzOAtBxI3CCRwwZ0YUIygwSPAV4tbMzs3yQS54AcRqwWfmYeoC0NzIkNNyBa7AhqkWzmKbZIOHbYeMOZZ8YSCWcSEth4cvBrMTh/fOPNHzV1svPbgSH2oSLBnp/9DH4tQMAiASQcG0DMBAaGRGLiiPkDkLCH8ezxqBwFo2AUjIIRCgAgTz8dtk4vcgAAAABJRU5ErkJggg==","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Yi","middleName":"","lastName":"Xia","suffix":""}],"badges":[],"createdAt":"2024-09-03 14:00:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5025573/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5025573/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67194637,"identity":"be41ffed-9064-4654-b7d6-9792f0cbd8af","added_by":"auto","created_at":"2024-10-22 09:00:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152609,"visible":true,"origin":"","legend":"\u003cp\u003eSwimming plot of PCNSL response\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5025573/v1/54d4053f6a00abd2869ab549.png"},{"id":67194639,"identity":"0f84afbf-edc2-400d-afab-a5ec5d8a07b3","added_by":"auto","created_at":"2024-10-22 09:00:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11147,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of progression free survival (PFS) in 16 PCNSL patients treated with the first-line RMOT therapy.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5025573/v1/d8b8ef4427f52feae9a76dec.png"},{"id":67194636,"identity":"226952f2-e6bf-4f86-8e5b-07851dfc2e38","added_by":"auto","created_at":"2024-10-22 09:00:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":9925,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of overall survival (OS) in 16 PCNSL patients treated with the first-line RMOT therapy.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5025573/v1/eba9183c1861818e167623c7.png"},{"id":67194638,"identity":"04266d81-b693-4f82-8000-d13711a50bd4","added_by":"auto","created_at":"2024-10-22 09:00:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":587680,"visible":true,"origin":"","legend":"\u003cp\u003eCase example: RMOT therapy in a multiple site involvement primary central nervous system lymphoma patient. Representative imaging of baseline, 3 weeks after 4 cycles and 1 month after the last cycle were shown. (A) PET/CT revealed the left forehead and bilateral corpus callosum lesions before therapy. (B) PET/CT imaging after cycle 4 treatment with RMOT shows considerable reduction in the previous lesions, suggest that the patient received complete response. (C) PET/CT imaging after cycle 6 treatment with RMOT, suggest that the patient remained complete response.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5025573/v1/e0a265fe687c916230985543.png"},{"id":67197108,"identity":"9eead8ff-84d0-473f-8ad9-06ff723d21a5","added_by":"auto","created_at":"2024-10-22 09:16:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1202131,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5025573/v1/6077361d-f637-43c5-8ae9-7480b47b3ff4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis.","fulltext":[{"header":"Novelty and Impact","content":"\u003cp\u003eThis 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.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003ePrimary 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[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. 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[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The incorporation of additional chemo-therapeutic agents has been explored in various trials, demonstrating significant improvements in patient outcomes[\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Despite these advances, approximately half of patients experience relapse or develop refractory disease within a short period of time[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBruton\u0026rsquo;s tyrosine kinase (BTK) plays a crucial role in the B-cell receptor signaling pathway[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], 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[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. 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[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Orelabrutinib is a novel, potent, highly selective second-generation BTK inhibitor with a high CSF concentration[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. 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[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eThis study retrospectively analyzed the clinical characteristics, outcomes and adverse reactions in newly diagnosed PCNSL patients who were treated with RMOT therapy,.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eAll 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003eAll patients received at least 4 cycles of RMOT regimen (rituximab 375 mg/m\u003csup\u003e2\u003c/sup\u003e iv day 1; MTX 3.5 g/m\u003csup\u003e2\u003c/sup\u003e iv day 2; temozolomide 150 mg/m\u003csup\u003e2\u003c/sup\u003e 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 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical assessment and follow-up\u003c/h2\u003e \u003cp\u003eTreatment 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\u0026ndash;5[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. 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.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical 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\u0026rsquo;s exact tests. A two-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated a significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 16 patients were retrospectively analyzed. The clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, including 7 males (n\u0026thinsp;=\u0026thinsp;7, 43.75%) and 9 females (n\u0026thinsp;=\u0026thinsp;9, 56.25%). The median age was 60 years old (range 28\u0026ndash;78). Among them, 11 cases were of non-GCB type (n\u0026thinsp;=\u0026thinsp;11, 68.75%) and 5 cases of GCB type (n\u0026thinsp;=\u0026thinsp;5, 31.25%). Deep intracranial lesions were observed in 11 patients (n\u0026thinsp;=\u0026thinsp;11, 68.75%), and elevated serum LDH was noted in 3 patients (n\u0026thinsp;=\u0026thinsp;3, 18.75%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of patients (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercent(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e60(28\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eKPS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMSKCC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian-risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eDeep intracranial lesion\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSerum LDH\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eSubtype of DLBCL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-GCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe most prevalent symptom was limb fatigue (n\u0026thinsp;=\u0026thinsp;6, 37.5%), followed by headache (n\u0026thinsp;=\u0026thinsp;3, 18.75%), dysarthria (n\u0026thinsp;=\u0026thinsp;3, 18.75%), dizziness (n\u0026thinsp;=\u0026thinsp;2, 12.5%), seizure (n\u0026thinsp;=\u0026thinsp;2, 12.5%), intelligence disorders (n\u0026thinsp;=\u0026thinsp;2, 12.5%) and vision disorder (n\u0026thinsp;=\u0026thinsp;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\u0026thinsp;=\u0026thinsp;8, 50%) and frontal lobe (n\u0026thinsp;=\u0026thinsp;7, 43.75%), other affected areas included parietal lobe (n\u0026thinsp;=\u0026thinsp;4, 25%), corpus callosum (n\u0026thinsp;=\u0026thinsp;3, 18.75%), ventricle (n\u0026thinsp;=\u0026thinsp;3, 18.75%), cerebellum (n\u0026thinsp;=\u0026thinsp;2, 12.5%), corona radiata (n\u0026thinsp;=\u0026thinsp;2, 12.5%) and temporal lobe (n\u0026thinsp;=\u0026thinsp;1, 6.25%).\u003c/p\u003e \u003cp\u003e16 patients received a total of 96 cycles of RMOT regimen: 2 with 4 cycles (n\u0026thinsp;=\u0026thinsp;2, 12.5%), 12 with 6 cycles (n\u0026thinsp;=\u0026thinsp;12, 75%), and 2 with 8 cycles (n\u0026thinsp;=\u0026thinsp;2, 12.5%). After the end of RMOT treatment, a total of 8 patients (n\u0026thinsp;=\u0026thinsp;8, 50%) received consolidation therapy, of which 7 patients received WBRT (n\u0026thinsp;=\u0026thinsp;7, 43.75%), 1 patient received ASCT (n\u0026thinsp;=\u0026thinsp;1, 6.25%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTreatment Outcomes\u003c/h2\u003e \u003cp\u003eThe effectiveness of the treatment was evaluated in all 16 patients, and the summary of effectiveness data is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. 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%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEffectiveness data\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInterim evaluation after 4 cycles\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEvaluation after the last cycle\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBest overall response, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (93.75%; 69.8\u0026ndash;99.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (93.75%; 69.8\u0026ndash;99.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (81.25%; 54.4\u0026ndash;96.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(87.5%; 0.2\u0026ndash;30.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5%; 1.6\u0026ndash;38.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(6.25%; 0.2\u0026ndash;30.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(6.25%; 0.2\u0026ndash;30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(6.25%; 0.2\u0026ndash;30.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian PFS/OS, month (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR (NR - NR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMedian PFS and OS were not reached, with a 1-year PFS rate and OS rate of 90% (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Meanwhile, there were no statistically significant difference in the effect of consolidation therapy on OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.23) and PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.27).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eThe most common adverse reactions were anemia (n\u0026thinsp;=\u0026thinsp;5, 31.25%) with other reactions including neutropenia (n\u0026thinsp;=\u0026thinsp;4, 25%), thrombocytopenia (n\u0026thinsp;=\u0026thinsp;2, 12.5%), and increased creatinine (n\u0026thinsp;=\u0026thinsp;1, 6.25%). Adverse reactions reported were all manageable and resolved promptly after supportive care. Only 1 patient (n\u0026thinsp;=\u0026thinsp;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\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAll adverse reactions at least possibly related to the RMOT regimen\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll adverse reactions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eG1(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eG2(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG3(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eG4(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic ADR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(18.75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(31.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(31.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon hematologic ADR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated creatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute kidney injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCase example\u003c/h2\u003e \u003cp\u003eA 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.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA) 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.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB) and sustained complete remission following 6 cycles (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). 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.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRegarding safety, the patient experienced increased creatinine levels (118.6 \u0026micro;mol/L, medical reference range 57\u0026ndash;97 \u0026micro;mol/L) after the second cycle of RMOT, which resolved promptly with supportive care. No other adverse reactions were reported.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrimary central nervous system lymphoma (PCNSL) constitutes 6% of malignant primary central nervous system tumors[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. 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%[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. High-dose methotrexate (HD-MTX) forms the cornerstone of current chemotherapy protocols for PCNSL patients[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite evolving treatment options, a standardized consensus on optimal therapy is yet to be established. Polychemotherapy regimens including rituximab demonstrated an ORR of 35\u0026ndash;74%[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], but nearly half of patients experience relapse shortly thereafter[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA 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[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eBTK is a crucial component in the B-cell antigen receptor (BCR), Toll-like receptor (TLR), and chemokine receptor signaling pathways[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. 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)[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. 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[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, the high-efficient and low-toxicity regimens need further exploration.\u003c/p\u003e \u003cp\u003eOrelabrutinib 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\u0026ndash;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[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eIn 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[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eFurthermore, the current treatment guidelines for PCNSL recommend WBRT or ASCT as the consolidation therapy after chemotherapy[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Previous studies have demonstrated superior OS and ORR with consolidation[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. 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 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.27) and PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.23), suggesting that maintenance therapy with orelabrutinib may provide a viable option for patients intolerant to consolidation.\u003c/p\u003e \u003cp\u003eInterestingly, 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[\u003cspan additionalcitationids=\"CR28 CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. A phase II study of ibrutinib in relapsed/refractory DLBCL showed a 37% response rate in ABC cases compared to 5% in GCB cases[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. However, in our study, 5 patients of GCB type (n\u0026thinsp;=\u0026thinsp;5, 31.25%), there was no statistically significant difference in the effect of COO type on CRR (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.308), OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.513) and PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eBecause 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.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis 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).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study is included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared that no competing interest exists.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval for data collection and publication was obtained from the Ethics Committee of Sun-Yat Sen University Cancer Center (B2024-549-01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBatchelor TT, DeAngelis LM (2013) Lymphoma and leukemia of the nervous system, 2nd edn. Springer, New York\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReni M, Ferreri AJ, Guha-Thakurta N, Blay JY, Dell'Oro S, Biron P, Hochberg FH (2001) Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Int J Radiat Oncol Biol Phys 51(2):419\u0026ndash;425. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0360-3016(01)01639-x\u003c/span\u003e\u003cspan address=\"10.1016/s0360-3016(01)01639-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F (2009) High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374(9700):1512\u0026ndash;1520. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(09)61416-1\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(09)61416-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. International Extranodal Lymphoma Study Group (IELSG)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMocikova H, Pytlik R, Sykorova A, Janikova A, Prochazka V, Vokurka S, Berkova A, Belada D, Campr V, Buresova L, Trneny M, Czech Lymphoma Study Group (2016) Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry. 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Cancer Cell 39(12):1643\u0026ndash;1653e3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ccell.2021.10.006\u003c/span\u003e\u003cspan address=\"10.1016/j.ccell.2021.10.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeverson EA, Haberberger J, Hemmerich A, Huang RSP, Edgerly C, Schiavone K, Najafian A, Hiemenz M, Lechpammer M, Vergilio JA, Lesser G, Strowd R, Elvin J, Ross JS, Hegde P, Alexander B, Singer S, Ramkissoon S (2023) Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition. Oncologist 28(1):e26\u0026ndash;e35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/oncolo/oyac190\u003c/span\u003e\u003cspan address=\"10.1093/oncolo/oyac190\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"primary central nervous system lymphoma (PCNSL), bruton tyrosine kinase, orelabrutinib, rituximab, temozolomide (TMZ)","lastPublishedDoi":"10.21203/rs.3.rs-5025573/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5025573/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003ePrimary 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.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003ePatients diagnosed with PCNSL were included in this retrospective study. All patients received at least 4 cycles of RMOT regimen (rituximab 375 mg/m\u003csup\u003e2\u003c/sup\u003e iv day 1; MTX 3.5 g/m\u003csup\u003e2\u003c/sup\u003e iv day 2; temozolomide 150 mg/m\u003csup\u003e2\u003c/sup\u003e 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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e16 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\u0026ndash;2, and only 1 patient (6.25%) occurred grade 3 adverse reactions.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis 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.\u003c/p\u003e","manuscriptTitle":"Orelabrutinib, Rituximab, Temozolomide and High-Dose Methotrexate (RMOT) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Single-center Retrospective Analysis.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-22 09:00:03","doi":"10.21203/rs.3.rs-5025573/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6746922b-1454-45cc-b8d5-c2ddef832471","owner":[],"postedDate":"October 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-14T02:38:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-22 09:00:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5025573","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5025573","identity":"rs-5025573","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}