Treatment Of Primary Central Nervous System Lymphoma Research Articles

Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma limited to the brain, spinal cord, leptomeninges, and eyes. The majority of patients are immunocompetent, with a median age of 65 years at diagnosis. Historically, whole-brain radiation therapy (WBRT) was the first and sole treatment for PCNSL. Today, due to the recognized neurotoxicity of WBRT, this modality is usually avoided in the treatment. Most chemotherapy regimens are based on high-dose methotrexate plus the anti-CD20 monoclonal antibody rituximab, leading to high response rates, but 5-year survival is still poor at approximately 30% compared with other extranodal lymphomas. New treatment strategies including high-dose chemotherapy/autologous stem cell transplantation, targeted therapies focusing on, for example, genetic alterations in B cells or mammalian target of rapamycin signaling, and immunotherapy with inhibitors of the programmed cell death 1 receptor are only a few options to improve the armamentarium against PCNSL.

The role of surgery in intracranial PCNSL.

This aimed to evaluate the effect of surgery for overall survival (OS) and progression-free survival (PFS) in intracranial primary CNS lymphoma (PCNSL) of all patients diagnosed at a single center. A prospective database at Oslo University Hospital of PCNSL was reviewed over a 12-year period (2003-2014). Seventy-nine patients with intracranial PCNSL were identified. Deep brain involvement was shown in 63 patients. Thirty-two patients underwent craniotomy with resection, while all other patients had a biopsy. Fifty-seven patients were given chemotherapy: 18 were treated with the MSKCC (Memorial Sloan-Kettering Cancer Center) with rituximab, 21 with the MSKCC without rituximab, and 14 within a Nordic prospective phase II protocol. Forty-four patients achieved complete response (CR) and had OS of 46.3months. Patients who underwent resection had a median OS of 28.6 versus 11.7months for those who had a biopsy performed. Resection showed an insignificant prolongation of OS. Multivariate analysis confirmed statistical significance of deep brain involvement only (p < 0.005). Neither chemotherapy regimen, Karnofsky Performance Status (KPS), type of surgery, nor patient age was significant factors for OS or PFS. Resective surgery played no role in significantly improving either OS or PFS and therefore it is not recommended as treatment for PCNSL.

Primary CNS Lymphoma Treatment : Current Status and Future Directions

中枢神経原発リンパ腫 (PCNSL) は, 近年高齢者を中心に発生が増加している. 現在, 大量methotrexate (MTX) 療法が治療の中心となっているが, 治療成績の向上を目指してさまざまな薬剤との併用レジメンが開発されている. しかし寛解導入率には差があるものの, 生存期間中央値は3～4年で頭打ちの状態である. 一方放射線治療は, 特に高齢者において神経毒性の問題が生じている. そこで, 生命予後と機能的予後を同時に改善する治療法の開発が求められており, 大量MTX療法後の造血幹細胞移植併用大量化学療法による地固めと, 全脳照射の廃止が候補として挙げられる. また, PCNSLの発生機序は解明されておらず, 分子生物学的解析に基づく病因・病態解明が, 新たな治療法の開発に結びつくことが期待される.

Primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined, however HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials address the role of rituximab, and of consolidative treatment using ASCT or reduced-dose WBRT. Despite high tumor response rates to initial treatment, many patients have relapsing disease with very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on age, previous treatment and response, performance status and comorbidities at the time of relapse. Novel therapeutics targeting underlying tumor biology include small molecule inhibitors of B-cell receptor, cereblon, and mammalian target of rapamycin signaling, and immunotherapy programmed cell death 1 receptor inhibitors and chimeric antigen receptor T cells.

Primary central nervous system lymphoma: Retrospective analysis of 34 cases in a single centre.

ObjectiveTo retrospectively analyse outcomes in patients with primary central nervous system lymphoma (PCNSL), which is a malignant CNS non-Hodgkin’s lymphoma with a poor prognosis.MethodsThis study retrospectively analysed the treatment and outcomes of patients with PCNSL, which were divided into two groups: surgery (S) group and surgery/biopsy+chemotherapy (SC) group. The latter group was further subdivided into four cohorts based on the treatment regimen: cyclophosphamide, epidoxorubicin, vincristine and prednisone (CHOP), high-dose methotrexate (HDM)+dexamethasone+rituximab (HDM+D+R), HDM+D+temozolomide (HDM+D+T), and HDM+D+R+T.ResultsThe study enrolled 34 patients; 10 of which received surgery only. Between the S and SC groups, the median progression-free survival (PFS) and overall survival (OS) of intracranial PCNSLs (n = 32) were 8.5 months versus 29 months, respectively; and 8.5 months versus 54 months, respectively (5-year OS: 10.0% versus 48.7%, respectively; 2-year PFS: 0.0% versus 52.6%, respectively). Comparing the CHOP and HDM-based chemotherapy cohorts, the median PFS and OS were 15 months versus not achieved, respectively, and 25 months versus not achieved, respectively (5-year OS: 20.0% versus 60.8%, respectively; 2-year PFS: 20.0% versus 62.7%, respectively).ConclusionChemotherapy appears to provide a better OS and PFS for patients with PCNSLs compared with surgery alone. HDM+D+T and HDM+D+R+T may be effective choices for PCNSL treatment.

Diagnosis and management of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314-24. © 2017 American Cancer Society.

Role of radiation therapy in primary central nervous system lymphoma : KROG 14-20 Collaborative Study of Brain and Lymphoma Committee.

We analyzed patterns of care and outcomes for patients with primary central nervous system lymphoma (PCNSL) in this multi-institutional retrospective study. Between January 2000 and December 2011, 220 patients with PCNSL received radiotherapy (RT). Among these patients, 26 patients received RT alone; 179 patients were treated with chemotherapy and radiotherapy; the rest of the patients (N = 15) initially underwent chemotherapy alone, then received RT as a salvage treatment. Most of the patients (N = 188) received methotrexate-based chemotherapy. The median follow up duration was 38months (range 3-179months). The median RT dose and whole brain RT (WBRT) dose were 45.0Gy (range 20.0-59.4) and 30.6Gy (range 18.0-45.0), respectively. Seventy-seven (35%) patients received WBRT alone, and 143 patients (65%) underwent WBRT plus boost RT. Total RT dose and WBRT dose decreased during the study period. The median survival was 64months and actuarial 5-year overall survival was 51.4%. In multivariate analysis, age (P < 0.001), ECOG performance status (P = 0.036), deep structure involvement (P = 0.011) and treatment response (P = 0.001) were significant prognosticators. RT combined with chemotherapy is effective modality for treatment of PCNSL. The survival outcome improved in spite of total radiation dose and whole brain RT (WBRT) dose having been decreased over the study period, indicating that low-dose WBRT could be effective.

333PD - Meta-analysis of the effect of rituximab in the treatment of primary central nervous system lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is a rare subtype of agressive non-hodgkin lymphoma (NHL), and is most commonly of B cell phenotype. The standard treatment is not well established but high dose methotraxate is the most commonly used regimen. Intravenous rituximab (iv Rtx) treatment is integrated into the protocols for systemic B cell lymphomas. However there are mixed results with the use of Rtx. The aim of this meta-analysis is to investigate the role of iv Rtx in the treatment of PCNSL. Methods: PubMed and EBSCOhost databases are searched for rituximab, primary central nervous lymphoma, rituximab, survival. Browsing databases was done in English. Results: 580 patients were included to meta-analysis. Pooled hazard ratio showed that overall survival is correlated with iv Rtx (HR, 0,498; 95% CI, 0,366 - 0,678; p:<0,001). Pooled hazard ratio was calculated by using fixed effect model. The quality determinations of 7 studies were done by using Newcastle-Ottowa Scale. The studies were counted low quality with the score 1-3, average quality with the score 4-6, high quality with the score7-9. Median score of the studies was calculated as 5. Conclusions: In this meta-analysis, we showed that the addition of iv Rtx as part of a treatment protocol for PCNSL has a positive impact on survival. Legal entity responsible for the study: Mustafa Yıldırım Funding: None Disclosure: All authors have declared no conflicts of interest.

A rare type primary central nervous system lymphoma with primarily psychiatric diagnosis- a case report

Primary central nervous system lymphoma (PCNSL) is a high-grade malignant B-cell non-Hodgkin neoplasm that is an infrequent variant of all intracranial neoplasms (1%) and all lymphomas (&lt; 1%)PCNSL is documented mainly in immunocompromised patient groups, although it may also be diagnosed in immunocompetent patients. It affects mainly the eyes, supratentorial areas, or the spinal cord. The lesions are typically localized in frontal lobes, corpus callosum and basal ganglia. Additionally, lesions might rarely be detected at infratentorial areas and in medulla spinalis. Even though a wide spectrum of treatment options are available, such as chemotherapy, radiotherapy, or surgery; response rates are low and prognosis is poor in spite of appropriate treatment.The case we reported here is 57-year-old male presented with symptoms of aggresivity, impulsivity, depressive mood and personality changes. Histopathological diagnosis was CD5 positive diffuse large B cell lymphoma, which is very rare in high-grade lymphomas. There were no neurological signs related to CNS tumor and the clinical manifestations responded very well to chemotherapy consisting of high dose methotrexate, vincristine and procarbazine. The significance of such neuropsychiatric symptoms in the course of treatment for PCNSL has been previously documented as well. These behavioral and emotional symptoms might manifest themselves based on where the neoplasm is localized. Therefore, psychiatrists should be more aware of the uncommon manifestation of the disorder as reported in this case. Consultation for differential diagnosis might also be necessary in such cases.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Abstract A21: Chimeric antigen receptor T cells targeting primary CNS lymphoma: Visualizing the anti-tumor response in vivo

Abstract Introduction: Advances in the treatment of primary CNS lymphoma (PCNSL) have led to prolonged survival. However, long-term remission is achieved infrequently. Chimeric antigen receptor T cells (CAR T cells) have proven to be a promising therapeutic approach for systemic B cell malignancies. Even in patients with advanced chemotherapy-refractory disease, syngeneic or allograft-derived CAR T cells can achieve durable remission. The most successful CAR targets CD19, a pan-B cell antigen also expressed in PCNSL. Whether CAR T cells are able to control PCNSL growth, and if so, if allogeneic or syngeneic CAR T cells are equally effective is not known. Additionally, information on the exact cellular interactions leading to tumor regression remains scarce. Methods: To analyze the therapeutic effect of CAR T cells on orthotopic PCNSL at single-cell resolution in vivo, we established a novel mouse model. After microsurgical preparation of a cranial window, human red fluorescent B-cell lymphoma cells were stereotactically implanted into the cortex of nude mice. After the tumour reached a threshold diameter, we injected green fluorescent CAR T cells adjacent to the tumour. To unravel the ensuing CAR T cell - tumor interactions, we performed in vivo imaging using dual photon microscopy over several weeks. Results: After implantation, allogeneic as well as syngeneic CAR T cells migrate throughout both hemispheres and preferentially accumulate in the subarachnoid compartment. Over time, CAR T cells infiltrate the tumor in high numbers. Upon encountering their cognate antigen, CAR T cells proliferate, their migration velocity decreases and they arrest in close contact with tumour cells. Cell-cell interactions can be observed in real time and are accompanied by tumor regression. Control CAR T cells, lacking the extracellular domain of the CAR, infiltrate the tumor in lower numbers and barely arrest, proliferate or kill tumor cells. After several weeks, allogeneic CAR T cells disappear and persisting lymphoma cells lead to tumor regrowth. However, repeated therapy with CAR T cells remains successful. Syngeneic CAR T cells show longer persistence and improved efficacy compared to allogeneic CAR T cells. Conclusions: For the first time, CAR T cell interactions with tumor cells have been visualized repeatedly over several weeks. In vivo microscopy reveals important aspects of CAR T cell biology. Long-term analysis indicates that CAR T cells are generally able to control PCNSL growth. Allogeneic CAR T cells show lower persistence than syngeneic T cells. These findings corroborate preclinical data suggesting that CAR expression does not protect against allogeneic T cell deletion. However, syngeneic CAR T cell therapy as well as repeated therapy with allogeneic CAR T cells reduces tumor growth, indicating persistence as a key factor limiting efficacy of CAR T cell therapy in PCNSL. These results emphasize the need for new strategies to enhance CAR T cell persistence. Citation Format: Matthias Mulazzani, Simon Fräßle, Veit Buchholz, Andreas Straube, Dirk Busch, Louisa von Baumgarten. Chimeric antigen receptor T cells targeting primary CNS lymphoma: Visualizing the anti-tumor response in vivo. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A21.

Advances in the treatment of newly diagnosed primary central nervous system lymphomas.

Primary central nervous system lymphoma (PCNSL) is a type of highly invasive non-Hodgkin lymphoma. With a growing number of organ transplantation and immunosuppressant therapy, the incidence of PCNSL has been growing rapidly in recent years, which is attributed to the increased incidence of HIV/AIDS, a prominent risk factor for developing PCNSL. The rising rate of PCNSL incidence is the highest among the intracranial tumors. In the past 20 years, dozens of clinical trials related to PCNSL have been registered, but adequate therapeutics are still challenging. Currently, the chemotherapy regimens based on high-dose methotrexate and whole-brain radiotherapy are the two main therapeutic options; however, the toxicity associated with those is the main problem that challenges medical researchers. Novel agents and therapeutic strategies have been developed in recent years. In the current review, we describe advances in the treatment of PCNSL and discuss novel therapeutic approaches currently in development, such as the use of rituximab, disruption of the blood-brain barrier, and state-of-the-art radiotherapy.

Primary diffuse large B-cell lymphoma of the central nervous system (case report and literature review)

The central nervous system (CNS) involvement in patients with non-Hodgkin’s lymphomas is not uncommon, especially in children with mature B-cells lymphomas, unlike the primary CNS lymphoma (PCNSL). PCNSL is a rare extranodal form of NHL that occurs only in the CNS – in the brain, spinal cord, meninges, in the eyes, and not extending beyond CNS. Its frequency in adults is 1–2 % of lymphomas and 5 % of all CNS tumors. Data on prevalence in childhood are not available, limited to some case reports. This article presents a literature review about PCNSL diagnosis and treatment and case report of such lymphoma with intraspinal lesion in 11 years old child.

Autologous Stem Cell Transplantation with Thiotepa, Busulfan, and Cyclophosphamide Conditioning in Patients with Primary Central Nervous System Lymphoma: A Remarkable Outcome Form Single-Center Experience

IntroductionHigh dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) has been adopted as an effective treatment in patients with relapsed or refractory primary central nervous system lymphoma (PCNSL) and also has been proposed as a consolidative treatment option for newly diagnosed PCNSL. HDC-ASCT may overcome chemoresistance mediated by blood-brain barrier by affording higher drug concentrations in the central nervous system. We investigated the feasibility of thiotepa, busulfan, and cyclophosphamide (TBC) conditioning followed by ASCT in patients with PCNSL.MethodBetween December 2012 and July 2015, a total of 27 patients with PCNSL underwent TBC conditioning followed by ASCT. Those with a complete or partial response after induction chemotherapy or salvage chemotherapy proceeded with TBC conditioning followed by ASCT. TBC conditioning consists of thiotepa 250 mg/m2 on days -9 to day -7, busulfan 3.2 mg/kg on days -6 to day -4 and cyclophosphamide 60 mg/kg on days -3 to day -2. The event free survival (EFS) was defined from the date of transplant to the date of relapse, progression or any cause of death, while overall survival (OS) was calculated from the date of transplant to death.ResultBaseline characteristics were summarized in table 1. Twenty patients received TBC conditioning followed by ASCT as a consolidative therapy after high-dose methotrexate-based induction chemotherapy and the other 7 patients received TBC conditioning followed by ASCT after salvage chemotherapy due to relapsed or refractory disease. The median time to neutrophil recovery (absolute neutrophil count >500/uL) and platelet recovery (>20000 x103/uL) were 8 (range, 7-9) and 8 (range, 4-15) days, respectively. All 27 patients experienced febrile neutropenia and 33.3% of patients (9/27) and 7.4% of patients (2/27) had documented bacterial and viral infection, respectively. Commonly observed nonhematologic grade 3 or 4 toxicities were mucositis (63%), diarrhea (59.3%) and nausea (25.9%). The 100-day transplant-related mortality rate was 0%. With median follow-up duration of 27.8 months (range 6.7-42.6), median EFS and OS were not reached. The 2-year EFS and OS estimates were 76.8% (95% CI: 68.4-85.2) and 88.9% (95% CI: 82.9-94.9), respectively (Figure 1).ConclusionASCT with TBC conditioning appears to be feasible in patients with PCNSL. Although survival outcomes are encouraging, longer follow-up is required. Further studies are warranted to investigate the role of ASCT with TBC conditioning in both clinical settings of consolidative treatment of newly diagnosed PCNSL and salvage treatment of relapsed or refractory PCNSL. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation (ASCT) As Upfront Treatment in Primary Central Nervous System Lymphoma (PCNSL): A Systematic Review and Comparative Analysis in Clinical Trials Setting

Purpose PCNSL standard treatment encompass 2 phases: induction and consolidation. Induction consists of high-dose methotrexate-based polychemotherapy for most patients and consolidation is still to be defined. ASCT is an effective treatment and despite the advancements in this technique for other disease sites, its role in PCNSL remains unclear. This systematic review aims to evaluate toxicity and outcomes of ASCT as upfront treatment in PNCSL.Material and Methods In accordance to PRISMA guidelines, a systematic review of the literature was conducted on studies reporting ASCT in PCNSL. EMBASE, MEDLINE and Cochrane databases were systematically searched for relevant studies until May 2016. All clinical trials (CT) evaluating the role of ASCT as up front treatment for PCNSL (excluding recurrence or salvage) were included. Studies were classified into 2 groups for statistical analysis: (1) Regimens containing thiotepa (either on induction or intensification regimen or conditioning regimen; (2) Regimens without thiotepa. Dichotomous outcomes were summarized as risk ratios (RRs). The size effect of the intervention for time-to-event outcomes was calculated by the pooled hazard ratio (HR), followed by the confidence interval (CI) of 95%. For determining derivative of expected events, the Z-Score for two-tailed p-value was calculated based on relative risk of each study.Results From 1803 references, 7 articles (6 phase 2; 1 pilot trial) from 2006 to 2016 were selected, comprising a total of 181 patients. For up front treatment of PCNSL with ASCT regimens containing thiotepa plus or minus WBRT: total of 128 patients were identified in 5 studies. Patient's median age was 54,5 (range, 54 to 57), KPS ranged from 70 to 90, WBRT was allowed in 3 studies and a median of 81% of the patients completes the ASCT protocol. Median complete response rate (CRR) was 69% (range, 54 to 81%), 2-years progression free survival (2PFS) 69% (range, 54 to 81%) and 2-years overall survival (2OS) 84% ranging from 83 to 91% in a median follow-up time of 15 to 63 months. Median neurotoxicity rates (NR) and treatment related mortality (TRM) were 3% (0 to 33%) and 3% (0 to 13%), respectively. (2) Up front ASCT regimens without thiotepa plus or minus WBRT: total of 53 patients were identified in 2 studies. Patient's median age was 52,5 (range, 52 to 53), KPS ranged from 70 to 80, WBRT was allowed in 1 study and a median of 59% of the patients completes the ASCT protocol. Median CRR was 31% (range, 18 to 44%), 2PFS 44% (range, 25 to 62%), 2OS of 65% ranging from 60 to 70% in a median follow-up time of 28 to 34 months. Median NR and TRM were 4% (0 to 8%) and 4%, respectively. Regimens containing thiotepa were associated with better 2OS (RR 0.46; IC95 0.27 to 0.80; P=0.006; Z=2.76) and increased 2PFS (RR 0.52; IC95 0.37 to 0.74; P=0.0002; Z=3.69). The addition of WBRT wasn't associated with better 2OS (RR 0.94; IC95 0.53 to 1.67; P=0.082; Z=0.22)Conclusions Up front ASCT in the management of PCNSL is associated with high CRR and excellent 2OS and 2PFS when thiotepa is added to the regimen. Close to 200 patients treated in CT settings with up front ASCT for PCNSL were found in the literature and at least 4 different treatment scenarios were described. An important rate (>10%) of TRM was seen in two studies however ASCT was seem to be safe in most of the publications. DisclosuresNo relevant conflicts of interest to declare.

Primary Central Nervous System Lymphoma and the Blood-Brain Barrier

Recent reports propose high-dose (HD) methotrexate (MTX)-based cytoreduction followed by consolidation with HD chemotherapy (HDC) with or without autologous stem-cell transplantation (ASCT) as first-line treatment for primary central nervous system lymphoma (PCNSL). The main rationale is that HDC-ASCT may improve disease control by achieving higher therapeutic concentrations of cytotoxic chemotherapy in the CNS, thus circumventing the blood-brain barrier (BBB). We have employed an alternative approach to treat PCNSL patients effectively. This first-line treatment enhances delivery of standard dose (SD) MTX-based chemotherapy administered intra-arterially (i.a.) with osmotic BBB opening plus the anti-CD20 monoclonal antibody (mAb) rituximab, followed in complete responders by anti-CD20 mAb maintenance immunotherapy. The main features that distinguish our approach from HDC-ASCT consolidation are to utilize BBB properties to maximize delivery of SD chemotherapy to the CNS sanctuary, and maintenance immunotherapy to delay recurrence. A multi-center study of 149 PCNSL patients (2,079 i.a. BBB treatments) resulted in one death within 48 hrs after treatment, from pulmonary embolism. Prior to routine use of granulocyte colony stimulating factor, granulocytopenic fever occurred in 3% of BBB treatments (Angelov, J Clin Oncol 2009). This contrasts with HDC-ASCT consolidation which carries substantial morbidity and treatment-related mortality (6% to 9%) (Ferrari, Lancet Hemat 2016; Omuro, Blood 2015). Further, HDC-ASCT is used primarily in younger PCNSL patients (< 60-65 yrs) with good performance status and is not feasible in many PCNSL patients given the median age at diagnosis is 60-65 yrs.First-line enhanced BBB delivery of SD MTX-based chemotherapy in 149 patients provided an overall response rate (ORR) of 82% (58% CR rate) and median overall survival (OS) of 37 mo. In low risk patients (age < 60 yrs and KPS ≥ 70) median OS was approximately 14 yrs. Survivors in CR a minimum of 2 yrs after diagnosis (n = 24) were evaluated with standard neuropsychological tests. Median follow-up was 12 yrs (range 2 to 26 yrs) and results indicated long-term preserved or improved cognitive function (Doolittle, J Clin Oncol 2013). Recently we compared efficacy from two first-line MTX-based regimens: HD MTX (intravenous, 4gr/m2) (Thiel, Lancet Oncol 2010), and enhanced BBB delivery of MTX (i.a., 3.5gr/m2). After adjusting for patient characteristics, CR rate and progression free survival were higher in patients < 65 yrs treated with enhanced delivery of MTX (p < 0.001). When first-line rituximab was added to the i.a. enhanced delivery regimen in 24 patients (median age 64 yrs; median KPS 65), the ORR improved to 92% (75% CR) and OS to 61 mo.To prevent recurrence, Ney (Leuk Lymphoma 2009) treated a small group of patients in CR after standard PCNSL treatment, with maintenance rituximab. The addition of maintenance immunotherapy resulted in average disease control of 22 mo or longer. Consistent with the Ney report, we noted prolonged median CR duration of 38 mo (range: 10 to 85 mo) in a small subset treated with maintenance rituximab (n = 9). Increased survival was also seen in translational laboratory studies of a rodent model of intracerebrally implanted MC116 human B-cell lymphoma cells, using single agent rituximab, whether or not delivered with BBB disruption and whether or not MTX was included (Muldoon, Clin Cancer Res 2011). These results suggest that rituximab slowly leaked into main CNS tumor mass even in absence of BBB opening; and given the long half-life, was trapped by binding to CD20+ on tumor cells, attaining sufficient concentration for antitumor efficacy.Our goal is to maximize first-line enhanced BBB delivery of SD chemotherapy to enable less treatment-related morbidity and mortality than is associated with HDC-ASCT in PCNSL, and increase CR duration. Neurocognitive safety has been demonstrated in long-term survivors treated with BBB delivery. Based on the encouraging results from Ney et al, our pilot data using maintenance rituximab, and translational lab studies of mAb delivery to brain, a new randomized multi-center trial is underway to study the effect of maintenance obinutuzumab on CR duration, neurocognition and quality of life in PCNSL patients who achieve CR following first-line MTX-based chemotherapy (NCT02498951). A trial update will be presented during the ASH 2016 meeting. DisclosuresNo relevant conflicts of interest to declare.

Whole Brain Radiotherapy (WBRT) Versus Intensive Chemotherapy with Haematopoietic Stem Cell Rescue (IC + HCR) for Primary Central Nervous System Lymphoma (PCNSL) in Young Patients: An Intergroup Anocef-Goelams Randomized Phase II Trial (PRECIS)

BackgroundDespite a significant improvement of therapeutic results with the current immuno-chemotherapies, a consolidation treatment is still required for decreasing the risk of relapse.WBRT has been the historical standard consolidation in PCNSL patients, but IC + HCR has shown encouraging results in non-controlled studies. However, each procedure exposes patients to specific side effects, such as cognitive dysfunctions and treatment-related mortality, respectively. In this trial, we addressed the efficacy and toxicity of a standard chemo-immunotherapy followed by either WBRT or IC+HCR in first-line treatment of PCNSL patients.MethodsImmuno-competent patients (aged 18-60) with newly diagnosed PCNSL and measurable disease were enrolled from 23 French centers. All the patients received 2 cycles of R-MBVP (Rituximab 375 mg/m2 D1, Methotrexate 3 g/m2 D1 and D15, VP16 100 mg/m2 D2, BCNU 100 mg/m2 D3, Prednisone 60 mg/kg/D D1-D5) followed by 2 cycles of R-AraC (Rituximab 375 mg/m2 D1, Cytarabine 3g/m2 D1-D2) as induction chemotherapy. Participants were stratified upfront according to performance status (0-1 vs 2-4) and treating institution and randomly assigned (1:1)to receive either WBRT (Arm A) or IC + HCR (Arm B) as a consolidation treatment. IC consisted in thiotepa (250 mg/mg/m2/d days-9 through-7, busulfan 10 mg/kg (total dose) days-6 through -4, and cyclophosphamide 60 mg/kg/d days -3 and -2). Prospective neuro-cognitive evaluations were planned in both arms. Responses were assessed according to the IPCG criteria. A central review of MRIs was scheduled. The primary end-point was the 2-year progression free survival (PFS). Thirty-eight assessable patients who received the complete study treatment for each treatment were needed. Either of the two arms would be deemed effective if > 24/38 patients are free of disease at 2 year with no major side effects. Analysis was intent to treat, in a non-comparative phase 2 trial design.This study is registered with ClinicalTrials.gov, number NCT00863460.ResultsBetween Oct 2008 and Feb 2014, 140 patients (male: 101; female: 39) were recruited (median age = 55 years, range 22-60) and randomized in Arm A (n=70) or Arm B (n = 70). Sixty-seven patients were assessable in each arm. Two patients withdrew their consent during the induction cycles (Arm A: n = 1; Arm B: n = 1). After two cycles of R-MBVP, overall response rates were 82% (CR + uCR = 24 %) and 77 % (CR + uCR = 23 %) in arm A and arm B respectively. At the end of the induction chemotherapy, ORR was 74 % (CR+ uCR = 44 %) and 67 % (CR+ uCR = 42 %) in arm A and B respectively. WBRT was given to 53 patients in arm A and IC+HCR was given to 44 patients in arm B. After consolidation treatment, ORR was 71 % (56 % CR+ Cru) and 67 % (60 % CR+ Cru) in arm A and B respectively. Five treatment-related deaths were reported, during induction chemotherapy in arm A (n = 2) and after IC+ HCT (n = 3). Median follow-up was 27.2 and 28.6 months in arm A and arm B respectively. Relapses occurred in 21 patients after the end of treatment (arm A: n = 16; Arm B: n = 5) with a median time to relapse of 15.1 and 8.5 months in arm A and B respectively. 2-y PFS in the experimental arm was 86.8% (95 CI, 76.6 to 98.3%). 2-y PFS in arm A will be given after the completion of the ongoing MRI review in this arm. The analysis of the prospective neuropsychological evaluations is pending.Conclusion:This study shows a favorable outcome of patients who received the IC+HCR arm. Improvement of the ORR after induction chemotherapy is still needed. The results of the 2-y PFS in arm A and of the neuropsychological evaluations are awaited to define the further standard of treatment in young patients with PCNSL.Fundings: French Government, Roche, Pierre Fabre [Display omitted] DisclosuresChoquet:Janssen: Consultancy; Celgene: Consultancy. Thyss:Takeda: Research Funding; Millennium: Research Funding. Soussain:Pharmacyclics: Research Funding; Roche: Research Funding; Celgene: Research Funding.

Enlargement of deep medullary veins during the early clinical course of Sturge-Weber syndrome

Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-κB pathway is well-established in non-GC DLBCL.2 Mutations of MYD88 , CD79B , and TBL1XR1 , genes involved in the NF-κB pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib. Acknowledgment: The authors thank Cathie Germain, MA, and Cynthia Burnett, BA, for assistance with patient scheduling; Jane Cornett, RN, and Anne Deboard, RN, for performing sedation for imaging; Yang Xuan, BS, for MRI acquisition and preprocessing; and Michael Behen, PhD, for cognitive assessment of the patients .

Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: A retrospective case series.

Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-κB pathway is well-established in non-GC DLBCL.2 Mutations of MYD88 , CD79B , and TBL1XR1 , genes involved in the NF-κB pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib.

5-Aminolaevulinic Acid–Induced Fluorescence in Primary Central Nervous System Lymphoma

Diagnosis of primary central nervous system lymphoma (PCNSL) is usually confirmed by brain biopsy and subsequent neuropathologic workup. 5-Aminolevulinic acid (5-ALA)-induced fluorescence has been established for diagnostic and therapeutic purposes in glioma treatment during the last few years and is discussed for use in other cranial tumors. Its role in diagnosis and treatment of PCNSL is still elusive. This retrospective study includes clinical, magnetic resonance imaging, pathologic and surgical data of selected 11 patients with PCNSL at two university hospitals within the last 4 years undergoing surgical treatment for resection because of imminent mass effect or suspected cerebral glioma. Patients received 5-ALA for fluorescence-guided resection preoperatively. The 11 subjects age ranged from 59 to 81 years. Postsurgical pathologic workup revealed malignant B cell lymphoma with morphologic features of diffuse large B cell lymphoma. Eight of these 11 patients with PCNSL showed a clear fluorescence induced by 5-ALA. After surgical resection, patients were treated with combination chemotherapy regimens. In patients with glioma, the use of 5-ALA is known to be associated with increased extent of resection and survival benefit. Our data and retrospective analysis of a larger patient cohort suggest that the use of 5-ALA in PCNSL should be included in a surgical approach, if this is reconsidered for select patients within a clinical study. In addition, even photodynamic therapy in combination with 5-ALA might be studied.

PC3 - 130 A Meta-Analysis on the use of High-Dose Methotrexate Only Versus Combination Chemotherapy for the Treatment of Newly-Diagnosed Patients with Primary CNS Lymphoma

Primary CNS Lymphoma (PCNSL) is an unusual extranodal form of Non-Hodgkin’s Lymphoma with a locally aggressive course but a rare tendency to disseminate systemically. There are various modalities available for the treatment of PCNSL which include chemotherapy, radiotherapy, surgery and immunotherapy. The effectiveness of adding another anti-neoplastic agent to HD-MTX have been optimized in small scale studies yet the “ perfect combination” has yet to be elucidated Objectives: This study aims to 1) compare the response to treatment of monotherapy with high-dose Methotrexate (HD-MTX) versus HD-MTX and an additional anti-neoplastic agent by evaluating complete response, partial response, stable disease and disease progression and 2) to compare the hematologic and non-hematologic side effects among patients subjected to monotherapy vs combination chemotherapy. Methodology: Journals from Medline, EMBASE, Cochrane Central Register of Control Trials (CENTRAL) and other relevant websites (www.clinicaltrials.org) without any restrictions in the year, language and status of publication were searched. Literatures cited by eligible studies and systemic reviews were also checked to identify useful articles. The following Medical Subject Headings (MeSH) were used: ‘primary CNS lymphoma’, ‘treatment’, ‘chemotherapy’ and ‘randomized control trial’. Statistical analysis was performed using the RevMan software version 5.1. Odds ratio (OR) and 95 % confidence interval (95% CI) were used as summary statistics. Results and Conclusion: The use of high-dose methotrexate and another anti-neoplastic agent showed benefit in terms of achieving complete response and delaying disease progression among patients diagnosed with PCNSL. However, the risks of hematologic toxicities such as anemia, neutropenia, thrombocytopenia and infection was higher in patients treated with the combination chemotherapy. Significant non-hematologic side effects such as mucositis was also observed in patients receiving an add-on to high dose methotrexate.