Ibrutinib-based combination therapy exhibited therapeutic benefit in newly diagnosed primary central nervous system lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Feili Chen ◽  
Diwen Pang ◽  
Hanguo Guo ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Combination Therapy ◽  
De Novo ◽  
Single Agent ◽  
Objective Response ◽  
Central Nervous System Lymphoma ◽  
High Dose ◽  
Induction Phase ◽  
Newly Diagnosed

2556 Background: Ibrutinib has shown single-agent activity in relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL), and the high dose methotrexate (HD-MTX) has been the backbone of treatment of de-novo PCNSLs. Combination therapy of HD-MTX and ibrutinib has recently shown activity in R/R PCNSLs. Methods: Eleven newly diagnosed PCNSL patients who underwent combination therapy of HD-MTX and ibrutinib were analyzed for treatment response and safety profile. HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses. Ibrutinib was held on days of HD-MTX infusion until HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. Patients’ clinicopathologic characteristics were retrospectively reviewed and genomic traits were further analyzed. Results: Nine out of 11 patients have completed the induction phase of ibrutinib-based combination therapy and received ibrutinib maintenance in addition to two patients whose disease progressed during the therapy. An objective response rate (ORR) of 82% (9/11) was observed, including 7 patients with complete response (CR, 64%) and 2 patients with partial response (PR, 18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The combination therapy of HD-MTX and ibrutinib was well tolerated and has acceptable safety. In addition, the presence of ctDNA in cerebrospinal fluid (CSF) samples closely correlated with tumor response. Sustained tumor responses were associated with the clearance of ctDNA from the CSF. Conclusions: Combination of ibrutinib and HD-MTX has acceptable safety and has demonstrated anti-tumor activity in newly diagnosed de-novo PCNSL patients. The detection of ctDNA in CSF is feasible for monitoring tumor burden in PCNSL patients.

scholarly journals Lenalidomide, Rituximab and Methotrexate（R2-MTX）in Newly Diagnosed Primary Central Nervous System Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2491-2491
Author(s):  
Xianggui Yuan ◽  
Yun Liang ◽  
Hui Liu ◽  
Yang Xu ◽  
Aiqi Zhao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Conflict Of Interest ◽  
Response Rate ◽  
Objective Response ◽  
Central Nervous System Lymphoma ◽  
High Dose ◽  
Newly Diagnosed ◽  
Common Grade

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin's lymphoma with poor prognosis. High-dose methotrexate (HD-MTX) is the cornerstone for treatment. However, there is no consensus on the best combination chemotherapy regimen. This study aimed to explore the efficacy and safety study of R2-MTX (Lenalidomide, Rituximab and Methotrexate) as a first-line induction regimen in the treatment of newly diagnosed PCNSLs. Methods This is a single-arm, prospective phase II study. Immunocompetent patients (18 to 75 years of age) with newly diagnosed PCNSLs were treated with 6 cycles of R2-MTX induction chemotherapy. Lenalidomide was dosed at 25mg daily (day 1-10); rituximab was dosed at 375mg/m2 (d0), MTX was dosed at 3.5g/m2 (d1). Every 21 days were as a course of treatment. Patients who did not reach CR after 6 courses of treatment were given salvage whole-brain radiotherapy (WBRT) to 30-36 Gy followed by a limited field to gross disease to 45 Gy. Then the patients received R2 maintenance (Rituximab 375mg/m 2 d1, lenalidomide 25mg d1-14, 29-42, 56 days per cycle) for 4 cycles. The primary endpoint is the objective response rate. Results 14 patients were enrolled from Feb 2020 to June 2021. Six (42.9%) patients were male and the median age was 59 (range 44-73). Ten (83.3%) patients were mediate or high-risk group (2-5 points) according to IELSG score. The last follow-up was July 15th 2021. Twelve patients were evaluable for response (one patient withdrew the consent; another patient was found with chronic lymphocytic leukemia). The overall response rate (ORR) was 91.7% (11/12). Nine patients achieved complete remission, and two patients achieved partial remission at the last follow-up. The median follow-up time was 11.3 (1.3-16.9) months. Only one patient did not respond and died for disease progression (Figure 1). The most common grade ≥3 adverse events (AEs) included elevated alanine transaminase (ALT) (16.7%), neutropenia (16.7%), thrombocytopenia (8.3%), infection (8.3%), and acute kidney injury (8.3%) (One patient with MTX overdose suffered from all these ≥3AEs). The most common grade 1-2 AEs were neutropenia (66.7%), anemia (58.3%), thrombocytopenia (16.7%) elevated ALT (41.7%). Conclusion R2-MTX regimen is an effective and well-tolerated combination treatment for newly diagnosed PCNSLs. More clinical data will be updated. Keyword(s): Primary Central Nervous System Lymphoma, Lymphoma therapy, Methotrexate, Rituximab, Methotrexate, Lenalidomide Trial registration: ClinicalTrials.gov NCT04934579. Conflict of Interest: The authors declare that they have no conflict of interest. Figure 1 Swimmer plots of all PCNSL patients evaluable for response. Each bar represents one patient; the length of the bars shows the time between the initiation of treatment and the last follow-up. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma

2020 ◽  
Vol 18 (11) ◽  
pp. 1571-1578
Author(s):  
Matthias Holdhoff ◽  
Maciej M. Mrugala ◽  
Christian Grommes ◽  
Thomas J. Kaley ◽  
Lode J. Swinnen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Phase Ii Trials ◽  
Whole Brain Radiation ◽  
The Central Nervous System

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3–8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX–based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX–based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

scholarly journals Efficacy and Toxicity of Treatments for Primary Central System Lymphoma: Review of the Recent Literature

2019 ◽  
Vol 9 (1) ◽  
pp. 61-67
Author(s):  
Mohammad Jay ◽  
David. A. MacDonald
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Survival Benefit ◽  
Radiation Treatment ◽  
Single Agent ◽  
Central Nervous System Lymphoma ◽  
Chemotherapeutic Agents ◽  
High Dose ◽  
Cell Transplant ◽  
Wide Range

Primary Central Nervous system lymphoma (PCNSL) is an uncommon type of central nervous system lymphoma, most commonly presenting as hemiparesis and headache. Currently, there is a wide range of treatments for PCNSL, consisting of various permutations between chemotherapy, radiation and autologous stem cell transplant (ASCT). Although the backbone of PCNSL treatment consists of High-dose Methotrexate (HD-MTX), the role of combination versus single agent chemotherapy, combined modality (chemotherapy + radiation) versus chemotherapy or radiation alone, and the use of consolidative ASCT are contested. Surgery does not have a role in the treatment of PCNSL although stereotactic biopsies tend to help with symptomatic relief. Radiation monotherapy is generally reserved for patients with contraindications to chemotherapy or as a palliative measure. Combined chemotherapy and radiation treatment has been shown to have a great efficacy, although its increased neurotoxicity compared to chemotherapy alone is a major drawback. A growing body of research is focused on comparing the efficacy of various chemotherapeutic regimens. Currently, the MATRix regimen comprising of HD-MTX(3.5g/m2)-cytarabine/rituximab/thiotepa is widely used. The additional survival benefit of ASCT is contested although its role in the treatment of refractory or relapsed PCNSL is generally agreed upon. Finally, intrathecal HD-MTX has been shown to have added survival benefit when added to the standard therapies. Further retrospective and prospective studies are required to compare the efficacy and toxicity of various treatment options, with a focus on different chemotherapeutic agents and ASCT.

What Is The Optimal Dose Of Methotrexate In Primary Central Nervous System Lymphoma Treatment Regimens?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3040-3040
Author(s):  
Samir Dalia ◽  
Samantha L Price ◽  
Peter Forsyth ◽  
Celeste M. Bello ◽  
Bijal D. Shah ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Total Dose ◽  
Single Agent ◽  
Central Nervous System Lymphoma ◽  
Chemotherapeutic Agents ◽  
High Dose ◽  
Significant Difference ◽  
Treatment Data ◽  
Dose Reductions

Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a rare disorder with a poor prognosis. The mainstay of treatment is single agent or combination high dose (≥3.5g/m2) methotrexate (HDMTX) based regimens. There is no consensus as to which dose of HDMTX improves outcomes in patients with PCNSL but doses of MTX greater than 3 g/m2 intravenously achieve therapeutic cerebrospinal fluid (CSF) concentrations. Purpose To determine if there is an optimal or total dose of HDMTX in PCNSL therapies that results in improved progression free (PFS) or overall survival (OS). Methods Patients at Moffitt Cancer Center with PCNSL were identified using our institutional database between January 1, 2000 and September 30, 2011. Patients with complete treatment data who were treated with HDMTX were included in this study. HDMTX was defined as MTX at a dose ≥ 3.5g/m2. Patient demographics, clinical, and treatment data were collected and analyzed. Treatment information collected included the starting dose of HDMTX, IV rituximab use, MTX toxicity and clearance, cycles of MTX, and total amount of MTX administered (g/m2). Data were analyzed using descriptive statistics and the Kaplan-Meier (KM) method was used to estimate median PFS and OS using the log rank test. P value of <0.05 was considered significant. All data was analyzed using SPSS statistical software version 21.0. Results A total of 51 patients were identified (Table 1). Median PFS was 13months (0-33) and median OS 43months (29-57). The addition of IV rituximab or other chemotherapy failed to improve PFS or OS. HDMTX dose reductions or the total dose of HDMTX administered did not significantly impact PFS or OS. Similarly, when comparing dosing of HDMTX there was no significant difference in 8g/m2 versus 3.5g/m2 (PFS p=0.56, OS p=0.68), or between patients receiving 8g/m2 versus <8g/m2 (PFS p=0.77, OS p=0.6) (Figure 1). Patients receiving 8g/m2 versus those receiving <8g/m2 of HDMTX had similar baseline characteristics except for more liver function abnormalities in the 8g/m2 group. Conclusions Differences in initial dosing of HDMTX or total dose of HDMTX therapy did not influence outcomes in our patients with PCNSL. Dose reductions in HDMTX, addition of other chemotherapeutic agents, or rituximab were not associated with improved PFS or OS. An intriguing plateau was observed in OS in the 8gm/m2 arm despite similar PFS, suggesting that the receipt of novel therapies in the relapsed setting may contribute to OS. Multicenter collaborative clinical trials are needed to further assess the optimal initial dose of HDMTX to administer in PCNSL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals LINC-33. MULTIMODALITY MANAGEMENT OF PAEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA- UPDATED EXPERIENCE FROM A REGIONAL CANCER CENTRE IN NORTH INDIA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii385-iii385
Author(s):  
Ahitagni Biswas ◽  
Swarnaditya Roy ◽  
Yousra KN ◽  
Sameer Bakhshi ◽  
Vaishali Suri ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Single Agent ◽  
Central Nervous System Lymphoma ◽  
North India ◽  
High Dose ◽  
Ocular Involvement ◽  
Csf Cytology ◽  
Whole Brain ◽  
Female Ratio

Abstract Paediatric primary central nervous system lymphoma(PCNSL) constitutes 1% of all PCNSLs. Data pertaining to paediatric PCNSL (2016–19) was abstracted by retrospective chart review. We identified 7 paediatric patients with PCNSL. None had congenital or acquired immunodeficiency. The median age at presentation was 13 years. The male to female ratio was 4:3. The median ECOG performance status was 2. On neuro-imaging, 3 patients had solitary and 4 patients had multiple lesions. CSF cytology showed atypical cells in 1 patient. None had ocular involvement. Systemic lymphoma work-up was negative in all. Biopsy and resection of tumour were done in 4 patients each. Histopathology revealed DLBCL in 6 and B-cell NHL in 1 patient. All patients underwent induction chemotherapy (median-5 cycles)- modified DeAngelis protocol (IV Methotrexate-2.5g/m2,IT Methotrexate-12 mg,Vincristine,Procarbazine and Rituximab-375mg/m2 every 2 weeks) in 6 and single agent Methotrexate -3.5g/m2 every 3 weeks in 1 patient. Severe haematological toxicities included grade 3 neutropenia, leucopenia and febrile neutropenia in 2,1 and 1 patient respectively. Radiotherapy(RT) was administered in all-whole brain RT(36-45Gy/20-25fractions/4-5weeks) in 6 patients and craniospinal RT(36Gy/18fractions/3.5weeks) followed by whole brain RT(9Gy/5fractions/1week) in 1 patient(with positive CSF cytology). Subsequently consolidation chemotherapy with 2 cycles of Cytarabine(3g/m2 IV D1-2 every 3 weeks) was administered in 5 patients. After a median follow-up of 14 months(mean-18.2 months), all patients are in complete radiological remission. Paediatric PCNSL is a rare tumour entity and multimodality management with high dose Methotrexate and Rituximab based chemo-immunotherapy and cranial radiotherapy leads to excellent early clinical outcome.

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