Primary central nervous system lymphoma treated with rituximab plus temozolomide in a second line schedule

We report a case of primary CNS lymphoma treated with high-dose methotrexate in the first line. After disease progression the patient received cranial radiotherapy with concomitant temozolomide, followed by rituximab plus temozolomide, with complete remission of the disease maintained for at least two years and without major toxicity.     

Primary central nervous system lymphomas

Opinion statement Primary central nervous system lymphoma (PCNSL) is widely regarded as one of the primary brain tumors most amenable to treatment. Although whole brain radiotherapy was the cornerstone of therapy for decades, recent work clearly indicates that chemotherapy has become the primary focus of treatment for this disease. The initial treatment of PCNSL for all patients, including the elderly, should be chemotherapy using a high-dose methotrexate-based regimen. Although cranial irradiation has often been combined with methotrexate, the unacceptably high incidence of late neurotoxicity, particularly in older patients, has caused many to eliminate radiotherapy, especially in those older than age 60 years. Emerging data support the validity of this approach, and the development of more efficacious chemotherapeutic regimens has been the focus of recent research.     

替莫唑胺联合利妥昔单抗对复发的老年原发中枢神经淋巴瘤的应用

Objective: The aim of our study was to analyze the long-term results of rituximab combined with temozolomide in treatment of elderly patients (> 60 years) with relapsed primary central nervous system lymphoma (PCNSL). Methods: Twelve postoperative elderly patients (> 60 years) were treated between August 2004 and October 2009. Temozolomide 100 mg/m2 to 200 mg/m2 days 1 to 7 and 15 to 21 and rituximab 375 mg/m2 days 1, 5, 8, 22. The maximum number of rituximab cycles was two. After one or two cycles of this ...     

替莫唑胺配合放疗治疗原发性中枢神经系统淋巴瘤的临床观察

目的:探讨替莫唑胺配合放疗对原发性中枢神经系统淋巴瘤(PCNSL)患者的治疗效果.方法:回顾性分析我院2006-06-2010-03应用替莫唑胺配合放疗治疗的33例PCNSL患者的临床资料.结果:随访1～46个月,其中达到完全缓解11例(33.3%),部分缓解3例(9.1%),有效率为42.4%.稳定病灶患者9例(27.3%),进展性病灶患者10例(30.2%),生存时间1～46个月,中位生存期26个月.结论:不良反应主要为恶心、呕吐、脱发、疲倦、肝功损害和骨髓抑制等,程度较轻.替莫唑胺同步化疗配合放疗是治疗原发性中枢神经系统淋巴瘤安全、有效的方法,值得临床推广.     

Successful treatment of systemic and central nervous system lymphomatoid granulomatosis with rituximab

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder with a mortality rate approaching 60% in the first year. The median survival is 14 months from the time of diagnosis. Although a variety of chemotherapeutic regimens have been utilized, there is no standard treatment. Studies have shown that in most cases the malignant cells are B-cells, which induce massive infiltration of reactive T-lymphocytes in the background. The disease is therefore considered as a T-cell rich B-cell lymphoproliferative disorder. We report a case of LYG with pulmonary, hepatic, central and peripheral nervous system involvement that was successfully treated with the anti-CD20 (B-cell) monoclonal antibody, Rituximab.     

Prognostic factors in primary central nervous system lymphomas

Efforts to identify survival predictors in primary central nervous system lymphoma (PCNSL) have produced isolated, unconfirmed observations in small retrospective and prospective series. Age and performance status are two unanimously accepted prognostic factors. These and other independent predictors of survival were used by the International Extranodal Lymphoma Study Group (IELSG) to establish a prognostic scoring system able to distinguish risk groups in PCNSL. The IELSG score will improve further with better knowledge of these malignancies, especially with the inclusion of molecular and pharmacogenetic variables able to identify lymphomas with different chemosensitivities or degrees of aggressiveness. In the years ahead, a well-established prognostic score will allow the separation of patients into risk groups, which could result in the application of risk-tailored therapeutic strategies.     

Effect of temozolomide on central nervous system relapse in patients with advanced melanoma

Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma.     

Primary central nervous system lymphomas—New pathological developments

Summary Primary central nervous system lymphomas (PCNSL) show increased incidence both in immunocompromised high-risk groups and in the general population. They are extranodal diffuse non-Hodgkin's lymphomas with a morphology similar to systemic lymphomas, but differ in their biological and molecular behaviour. The majority are large B-cell variants of high-grade malignancy; low-grade subtypes and T-cell lymphomas are rare; up to 50% remain unclassified according to the New Working Formulation and updated Kiel classification. Monoclonality of immunoglobulin receptor gene rearrangement can be diagnostically useful. The pathogenesis of PCNSL is obscure. Epstein-Barr virus (EBV) genome/proteins expression in two-thirds of HIV-related PCNSL but only in 15% of those in immunocompetent patients suggest different EBV latency stages in both types; human herpesvirus type 6 does not appear to play a pathogenic role. Comparison of expression patterns of integrin chains and adhesion molecules are very similar for PCNSL and nodal lymphomas suggesting that they are not selective mediators of lymphoma cell homing to the brain. In HIV-negative PCNSL they appear not to be influenced by EBV. Studies of protooncogenes (bcl-1 and bcl-2 genes) revealed no rearrangement in PCNSL, suggesting that they are not involved in the pathogenesis of PCNSL that probably do not differ cytogenetically from nodal B-cell lymphomas. Since most of the currently known molecular parameters are probably not the primary pathogenic events, the molecular genetics and pathogenesis of PCNSL are still to be elucidated.     

Characterization of genomic alterations in primary central nervous system lymphomas

Glioblastoma (GBM) is a highly fatal disease with a 5 year survival rate of less than 22%. One of the most effective treatment regimens to date is the use of radiotherapy which induces lethal DNA double-strand breaks to prevent tumour growth. However, recurrence occurs in the majority of patients and is in-part a result of robust radioresistance mechanisms. In this study, we demonstrate that the multifunctional cytokine, interleukin-6 (IL-6), confers a growth advantage in GBM cells but does not have the same effect on normal neural progenitor cells. Further analysis showed IL-6 can promote radioresistance in GBM cells when exposed to ionising radiation. Ablation of the Ataxia-telangiectasia mutated serine/threonine kinase that is recruited and activated by DNA double-strand breaks reverses the effect of radioresistance and re-sensitised GBM to DNA damage thus leading to increase cell death. Our finding suggests targeting the signaling cascade of DNA damage response is a potential therapeutic approach to circumvent IL-6 from promoting radioresistance in GBM.     

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors

Purpose To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors.Methods We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m² per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling.Results The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C_max 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 g/ml·h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C_max (P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies.Conclusions This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.This work was supported in part by USPHS awards CA 23099, Cancer Center CORE grant CA21765, the Schering Plough Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).     

利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果

目的 探讨利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果.方法 按照入院顺序将84例原发性中枢神经系统淋巴瘤患者分为对照组和观察组,每组42例,对照组接受大量甲氨蝶呤治疗,观察组患者接受利妥昔单抗联合大剂量甲氨蝶呤治疗.比较两组患者的临床疗效、不良反应、生存期和生活质量.结果 观察组患者的治疗总...     

High-dose intravenous rituximab for multifocal,monomorphic primary central nervous system posttransplant lymphoproliferative disorder

Primary central nervous system (CNS) posttransplant lymphoproliferative disorder (PTLD) is a well-recognized but rare complication of solid organ transplantation. Most of these disorders are B-cell in origin and generally carry poor prognosis. Rituximab, an anti-CD20 monoclonal antibody, has been used effectively in patients with systemic PTLD. However, its role in primary CNS PTLD is doubtful because it does not cross blood–brain barrier efficiently (<5%). Also, mechanisms, by which rituximab operates are not optimally effective in CNS. Here, we describe a renal transplant patient with monomorphic, multifocal, CD20-positive, primary B-cell CNS PTLD, who was treated with high-dose intravenous rituximab given in dose-escalation protocol, which has been used effectively for the patients with chronic lymphocytic leukemia. At 1-year follow-up, magnetic resonance imaging (MRI) showed complete resolution. High-dose rituximab may have a role in highly selected patients with primary CNS PTLD.     

鞘内注射利妥昔单抗治疗异基因造血干细胞移植后中枢神经系统淋巴细胞增殖性疾病

 目的　评估鞘内注射利妥昔单抗治疗EB病毒（EBV）相关性中枢神经系统（CNS）移植后淋巴细胞增殖性疾病（CNS-PTLD）的疗效及安全性。方法　将2008年8月至2012年5月以静脉注射利妥昔单抗为基础治疗无效的4例CNS-PTLD患者纳入评估,采用剂量递增法鞘内注射利妥昔单抗。结果　对4例在初始静脉注射利妥昔单抗为基础治疗7～11 d后疾病进展的患者加用鞘内注射利妥昔单抗治疗,经3～6次治疗后,4例患者均获得缓解。4例患者共接受21次鞘内注射利妥昔单抗,其中2例患者分别在第3次（30 mg利妥昔单抗）和第4次（40 mg利妥昔单抗）鞘内注射后出现短暂头痛、双下肢麻木,这些表现在24 h内能自行缓解。结论　采用剂量递增方式鞘内注射利妥昔单抗治疗静脉注射利妥昔单抗为基础治疗无效的CNS-PTLD是安全有效的。     

Primary central nervous system lymphomas express Vh genes with intermediate to high somatic mutations

Primary central nervous system lymphoma (PCNSL) is a rare disease, especially among non-AIDS patients. Although almost all PCNSLs belong to the diffuse large B-cell lymphoma (DLBL) category, its clinical course differs from that of other types of DLBL. To elucidate the histogenesis of PCNSL, we analyzed the source of the cells from its variable region (VH) sequences using the polymerase chain reaction (PCR) method to amplify the immunoglobulin heavy chain (IgH) gene of DNA extracted from paraffin sections. Fifteen patients with AIDS-unrelated PCNSL of DLBL type, (7 males and 8 females), were evaluated. Only one case showed positive evidence of EBV infection. The prognosis was very poor with a median survival of 9 months. Analysis of the VH sequences revealed that the VH4 family was used in 4 cases and the VH3 family in 2 cases. The homology with previously published germline sequences was random, ranging from 82.7-93.2%, showing intermediate to high somatic mutations. In 3 of 6 cases, the existence of intraclonal diversity was suspected. These findings suggest that PCNSLs are histogenetically derived from antigen selected B cells in the germinal center (GC) environment.     

Primary central nervous system lymphomas: clinico-pathologic and immunohistochemical analysis of 30 cases

AIMS AND BACKGROUND: Primary Central Nervous System lymphomas are attracting mounting interest because of their increasing incidence in an immunocompetent population and as sporadic tumors. A new lymphoma classification has been proposed, based on new morphologic entities and on advanced immunologic and molecular techniques. METHODS AND RESULTS: The study concerns the clinical and pathologic characterization of 30 cases of primary central nervous system non-Hodgkin's lymphomas in non-HIV patients using a wide monoclonal antibodies panel. Comparative evaluation of effectiveness and reliability between surgery and stereotactic biopsies was made according to Kiel and Real lymphoma classifications. There were 24 high-grade and only 3 low-grade lymphomas. Three stereotactic biopsies were not diagnostic. CONCLUSIONS: Stereotactic procedures were confirmed as the most immediate and least aggressive approach to CNS tumors, but inadequate sampling caused a deadlock to a full lymphoma diagnosis, which requires immunohistochemical and sometimes also molecular studies. However, it should be stressed that morphologic criteria (tumor cell cytology and neoplastic cuffing of the vascular walls) maintain their diagnostic effectiveness.     

Array-based DNA methylation profiling of primary lymphomas of the central nervous system

Background  

Although primary lymphomas of the central nervous system (PCNSL) and extracerebral diffuse large B-cell lymphoma (DLBCL) cannot be distinguished histologically, it is still a matter of debate whether PCNSL differ from systemic DLBCL with respect to their molecular features and pathogenesis. Analysis of the DNA methylation pattern might provide further data distinguishing these entities at a molecular level.     

Immunochemotherapy with rituximab, vincristine and 5-day cyclophosphamide for heavily pretreated follicular lymphoma

PURPOSE: Therapeutic options for relapsed or refractory follicular lymphoma include combination chemotherapy, immunotherapy and, for selected patients, autotransplant. Because of the different mechanisms of action and non-overlapping toxicities, combination of rituximab with chemotherapy is a rational approach. METHODS: 30 patients with follicular non-Hodgkin's lymphoma with advanced-stage disease were treated with four cycles of immunochemotherapy with rituximab 375 mg/m2 on day 1, vincristine 2 mg i.v. on day 2 and cyclophosphamide 400 mg/m2 i.v. from days 2 to 6, repeated at 3-week intervals. All patients had received multiple lines of therapy (median 3); 9 (30%) had relapses (2 after high-dose therapy with autologous transplant), and 21 (70%) were in relapse and refractory to salvage treatment (with an anthracycline-containing regimen in 19). RESULTS: Of 29 patients evaluable for response, 16 (55 %) obtained a complete response (CR) and 3 (10%) a partial response (PR), with an overall response rate of 65% (19/29); 10 patients (35%) achieved less than PR. The median event-free survival was 16.1 months for all patients, being 22.8 months for responders. After a median follow-up of 2 years from the start of therapy (range 6 months to 3.8 years), of 16 patients who achieved CR, 10 remain free of disease. CONCLUSION: The combination of rituximab with vincristine and 5-day cyclophosphamide is able to produce CR in patients with advanced follicular lymphoma, even in patients resistant to third-generation regimens. The regimen designed on the basis of pharmacokinetics of the chimeric antibody seemed important for the clinical efficacy of the combination.