Methotrexate-based Chemotherapy Regimens Research Articles

Clinical and diagnostic observation of primary lymphoma of the central nervous system

Background. Lymphoma of the central nervous system (CNS), both primary and secondary, is a rare but very aggressive type of non-Hodgkin’s lymphoma. Primary CNS lymphoma (PCNSL) refers to cases confined to the CNS parenchyma, dura mater, leptomeninges, cranial nerves, and spinal cord or intraocular region. The prognosis of PCNSL has been very dismal with an overall survival of 1.5 months without treatment and a 5-year survival rate of 30%. Due to the introduction of high-dose methotrexatebased chemotherapy regimens, there has been substantial progress in treating patients with lymphomas of the CNS, leading to improved survival. Diagnosis and differential diagnosis of PCNSL can often cause complications because it may have similar clinical and radiological signs with some other tumors, primarily with high-grade gliomas and metastatic lesion of the CNS. Stereotactic biopsy remains the main diagnostic method.
 Purpose – to investigate the complexity of the diagnostic and therapeutic process in PCNSL on the example of a clinical case.
 Materials and methods. Clinical observation of patient K., 59 years old, who underwent examination and inpatient treatment at the Department of Radiation Pathology and Palliative Care of the State Organization «Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine» regarding multifocal lesions of the brain (volumetric formations of the white matter of the left hemisphere of the brain).
 Results and discussion. In this clinical case, the presence of multiple volumetric white matter formations of the left hemisphere of the brain in the frontal and temporal lobes of the brain with pronounced perifocal edema, mass effect and signal amplification from the described formations after the administration of a contrast agent in the patient in magnetic resonance imaging allowed us to assume metastatic lesion of the central nervous system. However, a comprehensive examination made it possible to exclude the presence of primary cancer, as well as an infectious lesion of the brain. The diagnosis of primary non-Hodgkin’s diffuse large B-cell lymphoma with damage to the central nervous system was established only after the neurosurgical removal of one of the neoplasms with the conduction of pathohistological and immunohistochemical studies.
 Conclusion. Multifocal brain injury often causes difficulties in diagnosis. Magnetic resonance imaging using T1, T2 and Flair imaging, although very important for the diagnosis of PCNSL, is not always specific. Timely cerebral biopsy with immunohistochemical examination remains the method of choice for verification of the pathological process, which is necessary for the correct treatment.

Impact of Double Expression of MYC and BCL-2 on Outcomes in Primary CNS Lymphoma: A UK Multicentre Analysis

Introduction Primary central nervous system lymphoma (PCNSL) is a rare B cell lymphoma with an aggressive course. Relapses remain common even with intensive immuno-chemotherapy treatment options such as MATRix and consolidation with autologous stem cell transplant (ASCT), and prognostic tools are limited. Although, double expressor status (co-expression of both MYC and BCL-2) is well established in systemic de novo DLBCL, its prognostic impact in PCNSL has been understudied. Here we evaluated the prognostic value of BCL-2, BCL-6, and MYC expression in a retrospective cohort of treated PCNSL patients diagnosed at 7 academic centres in the UK. Methods We performed this retrospective analysis on histologically-confirmed PCNSL patients diagnosed consecutively between 1st May 2015 and 31st May 2020. Treatment with a high-dose methotrexate-based chemotherapy regimen was a mandatory inclusion criterion. BCL-2 and MYC immunohistochemistry (IHC) protein expression data were collated from local diagnostic histology reports and double expressor (DE) status was defined as per WHO criteria (MYC: surface expression > 40% of cells and BCL-2: >50% of cells). Outcomes included response rates, progression-free survival (PFS) and overall survival (OS). Where available, diagnostic fluorescence in situ hybridisation (FISH) data was collected for BCL-2, BCL-6 and MYC loci translocations. Cox-regression for PFS and OS were used to determine baseline predictors of response and survival and to construct multivariable models for factors associated with outcome. Results In total, 242 patients were analysed. Key baseline patient characteristics and IHC data are summarised in Table 1. Median age was 65 years (IQR 56-71), 60% were male and 64% of patients had an ECOG performance status (PS) of 0-1. One hundred and seventy-four (72%) patients received treatment with MATRix chemotherapy; these patients were younger (median age 62 vs. 73 years, p< 0.01), had better baseline PS (PS ≤ 1: 75% vs. 37%, p< 0.01) and higher rates of consolidation with BCNU-thiotepa ASCT (58% vs. 7%, p< 0.01). Double expressor (DE) status was assessable in 169/242 (69%) patients. Reasons for absent DE status were missing IHC expression data (BCL-2: n=28; MYC: n=44) or IHC expression data not reported in line with WHO recommended criteria (BCL-2: n=45; MYC: n=7). In the DE-assessable cohort (n = 169 patients), 40% of patients had DE PCNSL, higher than estimates of DE prevalence in systemic DLBCL (reported rates between 20 and 30%). As only 40 cases (17%) underwent FISH assessment for concurrent MYC and BCL-2 loci translocation (double hit status), correlation between double hit and DE status was not possible. DE status was not associated with patient age at diagnosis, baseline PS or treatment received. With a median follow up of 1.7 years, 34% of patients relapsed and 45% died. Although single MYC or BCL-2 expression alone had no significant association with OS or PFS in the entire cohort, DE status was associated with significantly poorer PFS, and earlier relapse (median 0.86 years vs. 2.77 years; HR 1.61 (1.07 - 2.41); p=0.021) (Fig. 1). In a subgroup analysis restricted to patients treated with MATRix chemotherapy (n = 116 patients), there was a trend towards inferior PFS and OS, although this did not reach significance in a univariable analysis. However, the adverse prognostic impact of DE status on PFS was maintained in a multivariable analysis modelling age, baseline PS, treatment received, ASCT consolidation status and DE status both for the entire cohort (HR 1.75 (1.15 - 2.66); p<0.01) and the MATRix treated subgroup (HR 1.91 (1.08 - 3.36); p=0.03). A trend towards an association between DE status and OS was noted but did not reach significance in either a univariable or multivariable analysis. We observed no significant difference in PFS or OS between DE-PCNSL and non-DE-PCNSL patients who received MATRix and consolidation with ASCT, perhaps indicating that the adverse impact of DE status is modified by this treatment strategy, although the sample size was small (n=66). Conclusions In a large, retrospective cohort of PCNSL patients treated at 7 UK academic treatment centres, double expression of MYC and BCL-2 by IHC was associated with inferior PFS even in patients treated with MATRix chemotherapy. Validation of this finding in independent cohorts is warranted. ___ JO, CPF and KC share senior authorship Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thiotepa, Busulfan, and Cyclophosphamide and Busulfan, Cyclophosphamide, Etoposide As Autologous Stem Cell Transplantation Conditioning Regimen in Primary Central Nervous System Lymphoma

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma and standard treatment is yet to be established. Induction therapy with methotrexate-based chemotherapy regimen and consolidation with high-dose chemotherapy followed-by autologous stem cell transplantation (ASCT) is a good treatment option with promising outcomes, but only few studies are available. Asan Medical Center had previously used busulfan, cyclophosphamide, and etoposide regimen (BuCyE) as standard high-dose chemotherapy in consolidation therapy until thiotepa, busulfan, and cyclophosphamide regimen (TBC) was introduced in December, 2012. The purpose of this study is to compare outcomes and toxicity profile of BuCyE and TBC as conditioning regimens for ASCT in consolidation therapy of PCNSL patients.MethodsThe registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients who had BuCyE or TBC as conditioning regimens were enrolled in analyses. BuCyE group had busulfan with dose of 3.2 mg/kg IV in day-7 to day-5, etoposide 200 mg/ IV in day-5 to day-4 and cyclophosphamide 50 mg/kg IV in day-3 to day-2. TBC group had thiotepa with dose of 250 mg/ IV in day-9 to day-7, busulfan 3.2 mg/kg IV in day-6 to day-4 and cyclophosphamide 60 mg/kg IV in day-3 to day-2. OS was defined as from beginning of high-dose chemotherapy conditioning to any cause of death, and PFS as from beginning of ASCT to disease progression or any cause of death. Analyses with chi-square test or Fisher's exact test were done to compare variables between two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analyses were done with known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.ResultsTotal 241 patients with diagnosis of PCNSL were identified and 73 patients who had ASCT as frontline or salvage setting with conditioning regimens of either TBC (45 patients) or BuCyE (28 patients) were enrolled in analyses. Median follow-up duration was 3.7 years [IQR 0.01-10.3], median OS was 6.1 years [95% CI 3.7-8.5], and median PFS was 6.5 [95% CI 1.4-11.7]. Median age was 54 years (range, 17-65), 27.4% of patients were 60 years or older and 54.8% of patients was male. Fifty three patients (72.6%) had upfront ASCT after induction therapy and 27.4% of patients had relapsed or refractory disease. ECOG performance status and infused dose of CD34 positive cells showed no statistical difference between two groups. Proportion of patient with refractory or relapsed disease was significantly higher in TBC group [TBC 37.8%, BuCyE 10.7%, p = 0.012]. Median OS of TBC group was not reached and median OS of BuCyE group was 4.5 years [95% CI 1.8-7.2] and TBC group showed better OS with log-rank test (p = 0.048). Median PFS of TBC group was not reached and median PFS of BuCyE group was 1.3 years [95% CI 0.00-2.7] and TBC group showed better PFS with log-rank test (p = 0.007). In multivariate analyses with age, ECOG performance status, CSF protein level, serum LD level, TBC group showed significantly better OS with HR of 0.20 [95% CI 0.04-0.97, p = 0.046] and better PFS with HR of 0.24 [95% CI 0.09-0.66, p = 0.006] compared to BuCyE group. Severe oral mucositis, nausea, vomiting (NCI CTC grade 3 or 4) was higher in TBC group. Median days to engraftment were 8 days (range, 3-19) in TBC group, and 9 days (range, 3-15) in BuCyE group. Median admission duration was 17 days (range, 4-42) in TBC group, and 18.5 days (range, 14-36) in BuCyE group. One case of treatment-related mortality was reported in TBC group due to septic shock.ConclusionTBC regimen showed better outcomes in both OS, PFS compared to BuCyE. Although TBC group showed more oral mucositis, nausea, vomiting, and diarrhea, it maybe tolerable regimen compared with BuCyE considering the fact that admission duration and days to engraftment was not inferior. Further long-term follow-up results with TBC regimen are warranted. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Intensive Etoposide Aracytine Consolidation Following Rituximab Methotrexate Temozolomide Induction in Newly Diagnosed Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is reported as having a dismal prognosis, due to the limited blood-brain barrier crossing capacity of lymphoma chemotherapies. Long-term remission and even cure could be achieved for a significant proportion of PCNSL patients using methotrexate-based chemotherapy regimens and intensive consolidation strategies. We report our single center experience of 27 consecutive patients with newly diagnosed PCNSL treated with Rituximab Methotrexate Temozolomide (RMT) regimen, and high-dose Etoposide Aracytine (EA) consolidation, with particular consideration for safety data.Methods: All patients consecutively diagnosed with PCNSL from November 2013 to December 2016 at Cochin hospital (Paris, France) were retrospectively included. Primary vitro-retinal lymphoma without cerebral involvement (n=1) and immunodeficient patients (n=1) were excluded. Contrast-enhanced magnetic resonance imaging (MRI) was performed at diagnosis for all patients. Slit lamp evaluation and cerebrospinal fluid examination were performed at the diagnosis or during therapy. Induction therapy consisted of four cycles of 375mg/m² Rituximab and 8g/m² Methotrexate (with folinic acid rescue) at day 1 and 14, and Temozolomide 150mg/m² days 7 through 11, repeated every four weeks (the RMT regimen). Patients under 75 year-old without significant comorbidities and achieving a complete response (CR) or a partial response (PR) were treated with intravenous Etoposide 40mg/kg on a continuous 96h infusion days 1 through 4 and Aracytine 2g/m² twice a day days 1 through 4 (the EA regimen). MRI was performed after the second and fourth cycle of RMT and after treatment completion. Response was evaluated according to international PCNSL cooperative group (IPCG) criteria.Results: Median age was 68 and 26% of the patients were under 60. Median Karnofsky performans status was 60 (range, 40-100). After induction, we observed 16 (59.3%) CR/CRu, 6 (22.2%) progressive disease (PD), 2 (7.4%) unrelated lymphoma death and 3 (11.1%) were not evaluated but were in PR after 2 cycles. Nineteen patients achieved CR/PR and were eligible for subsequent consolidation therapy. Four patients received whole brain radiotherapy (30.6 Gy n=1, 23.4 Gy n=3), and two patients had a watchful waiting strategy. Thirteen (48.1%) patients received EA. Median age of EA cohort was 60. After 29 months (range, 8-43 months) of follow-up, 19 (70.4%) patients were alive in CR. Eight patients deceased, 4 (14.8%) from progressive disease and 4 (14.8%) from lymphoma-unrelated cause. Median of progression free survival (PFS) and overall survival (OS) were not reached. The two-year PFS and OS were 57% (CI 95%, 36-74%) and 67% (CI 95%, 44-82%), respectively when considering the whole cohort; and 82% (CI 95%, 44-95%) and 92% (CI 95%, 54-99%), respectively when focusing on patients who received EA consolidation (Figures 1a and 1b). Main toxic side-effects of RMT regimen, evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events V4.0 were infections (30% of grade 3-4) and liver enzymes modifications (37% of grade 3-4). We observed a single-case of fully-resolved grade 3 renal dysfunction. Regarding EA consolidation, median hospital stay and neutrophil recovery (neutrophil count over 0.5x109/l) was 22 (range, 20-183 days) and 11 days (range, 9-14 days), respectively. All patients developed grade 4 neutropenia and thrombocytopenia. Sixty one percent of patients experienced grade 3 anemia. Neutropenic fever was observed in 92.3% of patients. Grade 3-4 mucositis developed in 22.2% of patients. Sixty one percent of EA-treated patients experienced grade 3-4 infections, including documented bacterial infection in 6 patients (central venous catheter infection, n=3; septicemia, n=2 and Clostridium difficile colitis, n=1) and fungal infection in two patients (probable aspergillosis, n=1 and documented mucormycosis, n=1). We observed one case of vancomycine-induced grade 4 renal failure during febrile aplasia that fully recovered.Conclusion : The RMT regimen allowed a near 60% complete response rate with limited toxicity. Intensive Etoposide Aracytine consolidation is feasible but more toxic than previously reported. The high survival rate observed in patients receiving RMT induction and then EA consolidation support further comparative evaluation of this strategy in prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Central Nervous System Lymphomas.

Primary central nervous system (CNS) lymphoma is a rare, aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, CSF, or spinal cord without systemic, non-CNS involvement. This article reviews the clinical presentation, imaging characteristics, diagnostic workup, novel pathophysiologic insights, and treatment of immunocompetent patients with primary CNS lymphoma. The prognosis of primary CNS lymphoma has significantly improved over the past few decades because of the introduction of and widespread use of high-dose methotrexate, which is now the backbone of all first-line combination chemotherapy treatments. Despite this progress, durable remission is still observed in only approximately 50% of patients. Novel insights into the pathophysiology of primary CNS lymphoma have identified the B-cell receptor pathway as well as the suppressed tumor immune microenvironment and immune evasion as key mechanisms in the pathogenesis of primary CNS lymphoma. Novel, small molecules and agents targeting these aberrant pathways have been introduced into clinical trials of recurrent/refractory primary CNS lymphomas. Agents such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs such as lenalidomide and pomalidomide have shown promising response rates in the relapsed setting. Diagnosis of primary CNS lymphoma requires a high level of suspicion because clinical signs and deficits can vary and depend on the involved CNS compartments. Rapid initiation of therapy is essential for recovery and prognosis. The optimal treatment regimen has not been defined, but methotrexate-based chemotherapy regimens are considered the standard treatment approach for induction treatment. Novel, targeted agents have recently been introduced into the therapeutic arsenal.

Updates on Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive malignancy confined to the brain, spinal cord, leptomeninges, and eyes. Due to its rarity, there is a paucity of randomized trials and a varied approach to its management in the oncologic community. This review summarizes recent literature guiding current clinical practice. The presentation, work up, and management of PCNSL are discussed. Induction therapy incorporates a methotrexate-based chemotherapy regimen and is generally followed by a consolidation regimen including high dose chemotherapy (with or without autologous stem cell rescue). Whole brain radiation therapy (WBRT) is a potential additional consolidation strategy. Management of relapsed and refractory disease poses a special challenge due to poor outcomes. Immunotherapy and targeted treatments are promising novel strategies for recurrent/refractory patients. Currently, there is little consensus in the management of PCNSL. Treatment recommendations should be tailored to the individual patient, with consideration for risk of neurotoxicity. New, exciting strategies are in development and when feasible, enrollment in a clinical trial should be considered.

Intravenous vs. intra-arterial methotrexate-based chemotherapy regimens for newly diagnosed primary central nervous system lymphoma.

e13505Background: High-dose (HD) methotrexate (MTX) is currently the most beneficial drug for newly diagnosed primary central nervous system lymphoma, however approximately 50% of patients relapse ...

Advances in Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that is limited to the CNS. Although novel imaging techniques aid in discriminating lymphoma from other brain tumors, definitive diagnosis requires brain biopsy, vitreoretinal biopsy, or cerebrospinal fluid analysis. Survival rates in clinical studies have improved over the past 20years due to the addition of high-dose methotrexate-based chemotherapy regimens to whole-brain radiotherapy. Long-term survival, however, is complicated by clinically devastating delayed neurotoxicity. Newer regimens are attempting to reduce or eliminate radiotherapy from first-line treatment with chemotherapy dose intensification. Significant advances have also been made in the fields of pathobiology and treatment, with more targeted treatments on the horizon. The rarity of the disease makes conducting of prospective clinical trials challenging, requiring collaborative efforts between institutions. This review highlights recent advances in the biology, detection, and treatment of PCNSL in immunocompetent patients.

Lymphome primitif du système nerveux central : quel rôle pour la radiothérapie ?

Primary central nervous system lymphoma is a rare extranodal form of non-Hodgkin lymphoma with an aggressive course and unsatisfactory outcome. Historically, whole-brain radiotherapy was the sole treatment for patients with primary central nervous system lymphoma, with high response rates but typically, this did not result in long-lasting remissions. The addition of high-dose methotrexate-based chemotherapy regimens to whole-brain radiotherapy has significantly improved patients’ outcome, but has resulted in a higher incidence of late neurotoxicity, particularly in elderly patients. To date, the role of consolidation radiotherapy is controversial, and some investigators have developed alternative strategies aiming at avoiding immediate irradiation or using a reduced radiotherapy dose to the whole-brain with promising results.

Prophylactic intrathecal chemotherapy in primary CNS lymphoma

The role of prophylactic intrathecal chemotherapy in the treatment of primary central nervous system lymphoma remains controversial. We report a retrospective single center study of a cohort of 69 patients with primary central nervous system lymphoma who had been treated with a regimen that combined high intravenous doses of Methotrexate, CCNU, procarbazine and methylprednisolone. Before 2000, patients systematically received intrathecal prophylaxis including Methotrexate, cytarabine, and hydrocortisone delivered either by intraventricular or lumbar injection along with the systemic chemotherapy (group A, n = 39). After this date, the procedure was changed and intrathecal chemotherapy was withdrawn from the protocol (group B, n = 30). The median age and Karnofsky index were comparable in both groups. At the time of analysis, we found no significant difference between patients with and without intrathecal prophylaxis in terms of objective response rate, patterns of relapse, progression-free survival or overall survival. In our study, intrathecal prophylaxis withdrawal from a high dose intravenous Methotrexate-based chemotherapy regimen did not influence disease control and outcome of primary central nervous system lymphoma. Further studies prospectively investigating the role of intrathecal chemoprophylaxis are warranted for this disease.

Chemotherapy in newly diagnosed primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) accounts for only 3% of brain tumors. It can involve the brain parenchyma, leptomeninges, eyes and the spinal cord. Unlike systemic lymphoma, durable remissions remain uncommon. Although phase III trials in this rare disease are difficult to perform, many phase II trials have attempted to define standards of care. Treatment modalities for patients with newly diagnosed PCNSL include radiation and/or chemotherapy. While the role of radiation therapy for initial management of PCNSL is controversial, clinical trials will attempt to improve the therapeutic index of this modality. Routes of chemotherapy administration include intravenous, intraocular, intraventricular or intra-arterial. Multiple trials have outlined different methotrexate-based chemotherapy regimens and have used local techniques to improve drug delivery. A major challenge in the management of patients with PCNSL remains the delivery of aggressive treatment with preservation of neurocognitive function. Because PCNSL is rare, it is important to perform multicenter clinical trials and to incorporate detailed measurements of long-term toxicities. In this review we focus on different chemotherapeutic approaches for immunocompetent patients with newly diagnosed PCNSL and discuss the role of local drug delivery in addition to systemic therapy. We also address the neurocognitive toxicity of treatment.

Higher Incidence of Venous Thromboembolism Is Associated with Initial Cycles of Chemotherapy in Lymphoma Patients: Creatinine and Hemoglobin as Key Risk Factors.

Background: While Lymphoma patients are at increased risk of venous thromboembolism (VTE), the timing of VTE occurrence in reference to chemotherapy (CT) and risk factors are not well defined.Methods: Medical records of all newly referred lymphoma patients (1046) to MD Anderson Cancer Center (MDACC) in 2003 were retrospectively reviewed over a follow-up period of two years for demographics, tumor histology, laboratory values, CT regimens, incidence of VTE, risk factors and management of VTE.Results: Four hundred and twenty-two (422) out of 1046 patients received at least one cycle of CT at MDACC (total CT cycles 2126). The median age of the patients was 57 years (range, 17 to 87). Fifty eight % of pts were male and 62% were newly diagnosed. Seventy-three patients (17.3%) out of 422 had 80 new episodes of VTE; 58 deep vein thromboses (DVT) only, 17 pulmonary embolisms (PE) only, and 5 were combined DVT and PE. Only less than 5% (20/422) of pts received thromboprophylaxis during treatment for lymphoma. Interestingly, 68% (54/80) of episodes occurred by cycle 3 of CT suggesting that VTE episodes occurred primarily in patients with highest disease burden or during initiation of CT. Since the incidence was highest during the initial cycles of CT, we analyzed risk factors for the first regimen of CT. By multivariate logistic regression analysis, gender (female vs. male, OR=3.6, 95%CI 1.707 to 7.61, p=0.0008), high hemoglobin (OR=1.29, 95%CI 1.059 to 1.561, p =0.011), high serum creatinine (OR=3.36, 95%CI 1.372 to 8.228, p=0.0080), doxorubicin (DOX) and/or methotrexate (MTX)-based CT regimen (OR=2.948, 95%CI 1.352 to 6.429, p=0.0066) were found to be important risk factors for new VTE. Specifically, the estimated risk for lymphoma patients with baseline hemoglobin 12 gm/dL receiving DOX and/or MTX based CT with renal insufficiency (creatinine 2.0mg/dL) is 50% in females and 21% in males.Conclusions: Lymphoma patients are at higher risk for VTE in the initial cycles of CT (cycles 1–3). Patients with high hemoglobin, elevated creatinine, female gender, and those receiving DOX and/or MTX based CT regimens are at higher risk for VTE than others. These clinically relevant findings suggest that a thromboprophylaxis strategy is needed in the patients presenting with these risk factors, particularly, in the initial cycles of chemotherapy.

High Incidence of Venous Thromboembolism in Patients with Lymphoma Receiving Chemotherapy: Assessment of Risk Factors.

Background: Venous thromboembolism (VTE) is a significant cause of cancer morbidity and mortality. Lymphoma patients (pts) are at increased risk of VTE, however, the exact incidence and risk factors are unknown.Methods: Of the 1050 newly referred Lymphoma pts to MDACC in 2003 identified, medical records (MR) of 538 consecutive pts were reviewed for demographics, tumor histology, staging, laboratory values, type of chemotherapy (CT) regimens, risk factors for VTE, incidence of VTE and management over a follow up of 2 years.Results: 207 out of 538 pts received at least one cycle of CT at MDACC (total CT cycles 1125). The median age was 56 years (range 17–82); there were 81 females and 126 males. Majority of pts (61.8%) were newly diagnosed and the most common histologies were Large Cell Lymphoma (31.88%), followed by Hodgkin's Disease (16.9%) and Follicular Lymphoma (14.98%). Thirteen out of 207 (6.28%) pts had history of VTE prior to CT and 37 (17.9 %) pts out of 207 had 41 new episodes of VTE; 29 Deep Vein Thrombosis (DVT) (12 upper and 12 lower extremity) and 12 Pulmonary Embolism (PE); 2 pts had both DVT and PE. All VTE episodes were confirmed by imaging except in 3 pts. The mean baseline hemoglobin (Hb) in VTE pts was 12.8 g/dL. The median cycle number for VTE occurrence was cycle 3 with 24/37 (64.86%) pts experiencing VTE by cycle 3 and 6/37 (16.2%) pts had VTE in cycle 1. Two out of the 37 (5.4%) pts had recurrent VTE. Among those with new VTE, 31/37 (83.78%) pts were of age greater than 40, 25/37 (67.56%) pts had BMI > 25, 32/37 (86.4%) pts had aggressive or highly aggressive histology and 29/37 (78.37%) pts had stage 3 or 4 disease. Twenty-three out of 31 (74.2%) pts had received erythropoietin before or during the cycle of VTE. Fourteen of 207 (6.79%) pts were on thromboprophylaxis before the chemotherapy. Only 1 of these 14 pts experienced VTE, approximately 2 months after the discontinuation of prophylaxis. Central venous catheter (CVC) thrombosis occurred in 6/174 (3.44%) patients with CVC. The most common systemic treatment for VTE was Enoxaparin (12/33). By multivariate logistic regression analysis of many of the previously described risk factors and other variables, Doxorubicin and/or Methotrexate based CT regimen was found to be a significant independent risk factor for VTE (OR 5.58, 95%CI 1.62 to 19.13. p = 0.0062).Conclusion: VTE is a frequent and underestimated complication in Lymphoma pts. These findings underscore the importance of prospective clinical trials of anticoagulation prophylaxis in the high risk patients receiving CT.

Implications of the blood–brain barrier in primary central nervous system lymphoma

The optimal treatment of primary central nervous system lymphoma (PCNSL), a rare form of extranodal non-Hodgkin lymphoma, has yet to be defined. Whole-brain radiation therapy (WBRT) has limited efficacy as a single therapeutic modality and is associated with a high risk of delayed neurotoxicity. Methotrexate-based chemotherapy regimens yield poor drug penetration across the blood-brain barrier (BBB), thus necessitating administration of high doses with the concomitant risk of increased systemic and neurological toxicity. Combined-modality therapy (WBRT plus chemotherapy) can improve response and survival rates, yet it is associated with a high risk of neurotoxicity. The aim of chemotherapy in conjunction with BBB disruption is to maximize drug delivery to the brain and improve the agent's efficacy, while preserving neurocognitive function and minimizing systemic toxicity. Methotrexate-based chemotherapy regimens administered in conjunction with BBB disruption have shown promising results in PCNSL. Animal models of central nervous system lymphoma and drug neurotoxicity offer new possibilities to study the effects of various treatments on PCNSL and normal brain and can also help understand biological and pathophysiological aspects of this disease. Because the intact BBB is even less permeable to antibodies than it is to drugs, preclinical and clinical studies of monoclonal antibody delivery (for example, rituximab and 90Y ibritumomab tiuxetan) to the brain in conjunction with BBB disruption offer a new possibility to make these novel treatments more efficient against PCNSL. Regarding the evaluation of more sensitive and specific diagnostic imaging tools, iron oxide-based contrast agents for magnetic resonance imaging have shown promise for better differentiation of PCNSL from other white matter diseases.

An Update on Therapy of Primary Central Nervous System Lymphoma

The most important advance in primary central nervous system (CNS) lymphoma treatment has been the convincing data that high-dose methotrexate-based chemotherapy regimens improve survival compared to historical controls treated with radiotherapy alone. However, the optimal treatment approach is still unclear and therapy can be associated with long-term neurotoxicity. Current research focuses on maximizing survival while minimizing neurologic sequelae.

Treatment of primary central nervous system lymphoma in the elderly

Although the incidence of primary central nervous system lymphoma has recently declined among people with acquired immunodeficiency syndrome, the incidence of primary central nervous system lymphoma remains high among the immunocompetent population ≥60 years of age. Elderly patients represent an important subgroup that accounts for approximately half of primary central nervous system lymphoma cases. Radiotherapy (RT) alone has produced disappointing results in the elderly. Improved clinical outcomes have been achieved with high-dose methotrexate-based chemotherapy regimens in combination with whole-brain RT. Unfortunately, combination therapy exposes elderly patients to a high risk of severe delayed neurotoxicity in up to 80%. Chemotherapy alone may be the best approach for treating elderly patients and appears to be more effective than RT, while considerably reducing the risk of neurotoxicity. Clinical studies are needed to define the optimal chemotherapy regimen for the elderly in an effort to delay or completely avoid the need for RT.