Search

Secondary CNS non-Hodgkin lymphoma (SCNSL) is estimated to occur in ∼5% of patients with non-Hodgkin lymphoma, and it carries a poor prognosis. Early CNS relapse (i.e. during treatment or within the first 6 months following chemotherapy) may represent subclinical CNS lymphoma present at the time of diagnosis. DLBCL is the most common histology seen in SCNSL and primary CNS (PCNSL) lymphoma. PCNSL DLBCL is usually characterized by an activated B-cell like (ABC) phenotype; it is unknown whether SCNSL follows the same pattern or if it includes germinal center B-cell (GCB) and non-ABC/non-GCB phenotypes.We queried our IRB approved clinicopathologic database of hematologic malignancies for patients with lymphoma diagnosed between 1999 and July 2011 who had brain or spine MRI, head CT, lumbar puncture or intrathecal chemotherapy. Clinical data and patient characteristics were extracted. We also obtained pathologic features of tumors including immunohistochemistry and cytogenetics, when available. Descriptive statistics were used to characterize patients at baseline. Overall survival (OS) is defined as the time from time from systemic lymphoma diagnosis (i.e. disease outside of the CNS) to death (event), or censored at last known date of survival. Overall survival curves were obtained using the Kaplan-Meier method with 95% confidence intervals calculated using Greenwood's formula. We did an analysis of CNS lymphoma diagnosis within the first 6 months from systemic lymphoma diagnosis (Early CNS involvement) versus greater than 6 months from systemic lymphoma diagnosis (Late CNS relapse), based on Multivariable logistic regression. The associations between potential risk factors and OS after CNS relapse have been explored using the stepwise Cox regression models.One-hundred and twelve patients met the criteria of systemic lymphoma with CNS relapse/involvement with 68% DLBCL and the remainder including Mantle Cell lymphoma (5%), BL (5%), CLL/SLL (4%) and others. Of the DLBCL patients, 25/76 (33%) were GCB type, 20/76 (26%) were non-GCB, and the remaining unclassifiable with the data available. The median OS for all patients was 23 mo (95% CI=11–41), and 6.7 mo (95% CI=4.6–9.9) after CNS lymphoma diagnosis. Sixty-one of 112 patients (54%) were found to have CNS lymphoma within 6 mo of systemic lymphoma diagnosis including 40 patients (36%) where CNS involvement was present at the time of, or within the first month of, systemic diagnosis, suggesting that these are concurrent presentations. Median OS for patients with early (i.e. concurrent systemic and CNS lymphoma and early CNS relapse patients) v. late CNS relapse was 8.5 mo (95% CI=5.5–10.4) compared to 57.8 mo (95% CI=33.2–94.7), (p < 0.003). The OS after CNS diagnosis was similar between the two groups at 5.5 mo (95% CI=2.85–11) and 8.2 mo (95% CI=3.9–9.7), respectively (p=0.5). Regression analysis of clinical and pathological features (e.g. age, sex, stage, IPI score, LDH, histology, cytogenetics, immunohistochemistry, initial treatment and others) was performed to determine if there were factors associated with early versus late CNS lymphoma involvement and none were significant or clinically relevant. Hazard ratios (HR) for OS after CNS relapse favored patients who obtained a CNS complete response (CR1, HR=0.18, p=<0.01, 95% CI=0.08–0.40) or partial response (PR1, HR=0.31, p=0.004, 95% CI=0.14–0.68). Fifteen patients underwent autologous stem cell transplantation (ASCT) for CNS lymphoma therapy; the median OS after CNS relapse was over 1000 days (HR=0.19, p=0.002, 95% CI=0.07–0.56), suggesting a benefit for intensive therapy in selected patients. HR's for OS after CNS relapse were worse for DLBCL patients with non-GCB phenotype (HR=5.61, 95% CI=2.85–11) and those with an elevated LDH and >1 site of EN disease (HR=2.50, p=0.004, 95% CI=1.34–4.68) at the time of systemic diagnosis, perhaps reflecting more aggressive disease at initial presentation.The prognosis of secondary CNS lymphoma remains poor, though selected patients who undergo high-dose chemotherapy with ASCT may enjoy prolonged remissions. In contrast to PCNSL, both GCB and non-GCB DLBCL relapse in the CNS, with the non-GCB subtype associated with an inferior prognosis. For patients at high-risk of CNS involvement, efforts must be directed at prophylactic strategies and novel therapeutic approaches.No relevant conflicts of interest to declare.

Abstract 5181

PCNSL is a rare form of non-Hodgkin lymphoma. High-dose methotrexate (HD-MTX) is the backbone of therapy but uncertainty remains about what additional chemotherapies should be added to HD-MTX to improve response rates.After receiving IRB consent, we retrospectively evaluated patients with PCNSL treated at our hospital with combination M/R/T at initial diagnosis or at relapse. Patients were treated in 28-day induction cycles as follows: HD-MTX (8g/m2- dose adjusted based on creatinine clearance) on days 1 and 15; rituximab (375 mg/m2) on days 3, 10, 17, and 24; and temozolomide (150-200 mg/m2) on days 7-11. HD-MTX was given every 2 weeks until complete response (CR) and for 2 additional treatments followed by monthly maintenance treatments for 11 months. Rituximab was given weekly for a total of 8 weeks. Temozolomide was continued for 6 months after CR. Brain MRI was done after every other methotrexate treatment to assess response.Sixteen patients were treated between February 2006 and August 2009. Ten patients received MRT as first-line therapy at the time of initial diagnosis and 6 received MRT as salvage therapy at first or second recurrence. The median age of newly diagnosed patients was 58 (range 47-76) and of relapsed patients was 60 (range 46-76). CSF cytology was atypical in 5/15 patients who underwent lumbar puncture (4 first-line, 1 relapse). After first-line therapy, there were 9 CRs (median cycles to CR = 3) and 1 PR (patient still receiving induction treatment). After salvage therapy, there were 4 CRs (median cycles to CR = 4) and 2 PRs (both patients died while receiving treatment- 1 from an unrelated myocardial infarction). With a median follow-up of 10.3 months in the first-line group and 7.2 months in the relapse group, only 3 patients have progressed; one of whom had clinical progression after a PR and a second who relapsed in the skin. Treatment was well tolerated with reversible grade 4 transammonitis in 1 patient and grade 3 hematological toxicities in 8 patients. One patient experienced grade 4 thrombocytopenia related to temozolomide requiring dose reduction for subsequent cycles.Combination MRT is well tolerated and resulted in a promising early response rate. The median number of cycles needed to achieve a CR for patients with newly diagnosed PCNSL was less than the 6 cycles we have previously reported for HD-MTX monotherapy suggesting that adding rituximab and temozolomide is beneficial to patients. This combination warrants further evaluation in larger scale, prospective studies.Off Label Use: temozolomide and rituximab for PCNSL..

HMG-CoA reductase inhibitors (statins) have been used to treat hypercholesterolemia and hyperlipidemia for over 20 years. Statins competitively inhibit HMG-CoA reductase thereby blocking the synthesis of mevalonate. They directly inhibit synthesis of steroid hormones and cholesterol but also indirectly inhibit prenylation and ubiqitination. As all currently marketed statins are lipophillic, with the exception of Pravachol (pravastatin), several therapeutic trials have attempted to exploit these indirect actions to treat both neoplastic (glioblastoma, anaplastic astrocytoma) and degenerative (Alzheimer's, Parkinson's) neurologic disease. We studied the impact of incidentally prescribed statins on high-risk patients with primary central nervous system diffuse large B cell lymphoma (PCNSL).We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, to identify all patients diagnosed with primary central nervous system lymphoma (PCNSL) between 1991 and 2007 (n=118). We excluded pediatric patients, patients who did not receive curative treatment and patients who failed to achieve a CR with initial therapy. Automated analysis of billing and medication administration records was used to identify the administration of statins to these patients. We compared the outcome of patients who were receiving statins to controls with PCNSL who did not receive statins. We excluded patients who did not receive statins within the time interval from 6 months prior to 2 years after their PCNSL diagnosis. As only a single statin pt was less than 50 we excluded all pts below this age from the cases and controls. All patients received high dose MTX based therapy. Overall survival (OS) was calculated from the date of first methotrexate.Median age of statin patients was 66 yrs (range 52 – 76); median age of controls was 66 years (range 50 - 86). Nine patients were on atorvastatin, 9 were on simvastatin, 1 each were on pravastatin, rosuvastatin and fluvastatin. At a median follow-up of 47.5 months, concurrent statin therapy was associated with improved OS (62% vs. 37%)(p=0.04 Log-rank test). The median OS for all statin patients > 50 years old (n=21) was 60 months versus 37 months for all other patients > 50 years old (n=67) (p=<0.005 t-test two tailed).Concurrent prescription of HMG-CoA reductase inhibitors is associated with improved outcome in patients with high risk PCNSL compared to controls. Prospective controlled trials will be required to validate this observation.Hochberg: Amgen: Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Enzon: Speakers Bureau.

Abstract 1672

Abstract 2496

Introduction:Chronic Lymphocytic Leukemia (CLL) is a low-grade B-cell lymphoma that manifests as high white blood cell counts and lymphadenopathy. Current clinical paradigms for the care of CLL do not include evaluation or prophylaxis of the central nervous system. Four percent of our patients with CLL developed neurologic manifestations which approximates the 3–7% risk of CNS involvement in large series of diffuse large B cell lymphoma (DLBCL). We found that the majority of these cases had no evidence of histologic Richter's transformation. Our experience confirms prior anecdotal reports of involvement of the central nervous system by CLL which have described: abnormal lymphocytes in the CSF or vitreous, MRI dural enhancement, enhancement within the spinal cord or cranial/peripheral nerves, orbital mass, PML-like diffuse white matter abnormalities of brain (without the presence of JC virus DNA) and/or Richter's transformation in the nervous system.

Introduction: Chronic Lymphocytic Leukemia (CLL) is a low-grade B-cell lymphoma that manifests as high white blood cell counts and lymphadenopathy. Current clinical paradigms for the care of CLL do not include evaluation or prophylaxis of the central nervous system. Four percent of our patients with CLL developed neurologic manifestations which approximates the 3–7% risk of CNS involvement in large series of diffuse large B cell lymphoma (DLBCL). We found that the majority of these cases had no evidence of histologic Richter’s transformation. Our experience confirms prior anecdotal reports of involvement of the central nervous system by CLL which have described: abnormal lymphocytes in the CSF or vitreous, MRI dural enhancement, enhancement within the spinal cord or cranial/peripheral nerves, orbital mass, PML-like diffuse white matter abnormalities of brain (without the presence of JC virus DNA) and/or Richter’s transformation in the nervous system. Methods: A CLL medical records review protocol was approved by the Dana Farber Harvard Cancer Center Institutional Review Board. Using our clinical lymphoma database we collected records of 755 patients at Massachusetts General Hospital (MGH) Cancer Center who carried a diagnosis of CLL from January 1988 to August 2008. We will present the neurologic involvement identified by restricting cases to those with the following diagnostic studies: patients who had received brain, head or spine MRIs, patients who had received lumbar punctures or post-mortem examinations. We also included any patient with brain, nerve (peripheral or otherwise) and/or orbital biopsies. Within this cohort, 30 patients were found with the following sites of predominant neurological involvement of CLL: dural infiltration (2), CSF infiltration by cytology or flow cytometry (6), infiltration of peripheral nerve, optic nerve or spinal nerve roots (6), ocular involvement of the vitreous or conus (7), Richter’s transformation into primary CNS DLBCL (6), and diffuse non-enhancing white matter abnormalities without the presence of JC virus (3). Many patients presented with multiple neurological sites of disease. Discussion: Recognition of the risk of central nervous involvement in DLBCL has led to a new paradigm of CNS prophylaxis in high risk patients. Our estimate of 3.97% involvement of the nervous system with CLL likely underestimates the true risk of this fatal complication for the following reasons. We did not directly examine patient records for neurologic symptoms. We did not re-evaluate the cytology of CLL patients whose neurologic symptoms prompted a negative lumbar puncture nor neuro-pathology specimens of autopsied CLL patients with negative gross involvement. Patients who were diagnosed with CLL at MGH but who had their neurologic studies performed outside of our electronic medical record (EMR) system are clearly not included in our numerator. Current CLL therapies have limited CNS penetration. Our risk estimate, if confirmed, will stimulate the inclusion of neur-axis penetrating agents into CLL therapy in high-risk patients.