Increased Risk of Venous Thromboembolism in Primary Central Nervous System Lymphoma Patients Undergoing Therapy
Authors: Ravi Gayathri , Cooper Brenda , Campagnaro Erica L , William Basem M. , Creger Richard J. , Gerson Stanton L. , De Lima Marcos , Lazarus Hillard M. , Caimi Paolo 
Published: October 2019

Abstract
Introduction: Primary CNS Lymphoma (PCNSL) is a rare and aggressive NHL associated with poor prognosis. Age, performance status, serum LDH and monocytosis at diagnosis as well as tumor location are reported to be associated with outcomes. We conducted a retrospective review of PCNSL patients to evaluate outcomes and the influence of known prognostic factors.
Methods: Patients diagnosed with PCNSL between 06/2006 and 06/2014 at University Hospitals Seidman Cancer Center (Cleveland, OH) were eligible. Five patients that did not receive treatment because of very poor performance status or significant comorbidities were included. Treatment regimens included high dose methotrexate (HD-MTX) based regimens (DeAngelis LM, et al J Clin Oncol 20: 4643-8, 2002; and Ferreri AJ, et al. Lancet 374(9700):1512-20, 2009) and temozolomide plus rituximab (Wong ET, et al. Cancer 101: 139-45, 2004). In patients younger than 60 years, whole brain radiation therapy (WBRT) was administered based on patient and physician preference. Overall survival (OS) and progression free survival (PFS) were calculated from date of diagnosis to death or progression, respectively. Survival outcomes were analyzed with the Kaplan Meier method and compared between groups using the log-rank test.
Results: Thirty patients were included. Patient characteristics are summarized in table 1. Median age at diagnosis was 64.5 (18-82) years. None of these patients had received a prior solid organ transplant or had prior diagnosis of lymphoma. One patient had HIV infection diagnosed at the time of PCNSL diagnosis. Lymphoma subtype was predominantly diffuse large B cell lymphoma (n=25; 83%). High-dose methotrexate (HD-MTX)-containing regimens (with or without high dose cytarabine) were used in 20 patients (66.6%).
After a median follow-up of 16 months, estimated 2-year overall survival (OS) for all patients was 66.4%. Patients ineligible to receive any treatment had dismal OS (median 1.5 months), significantly inferior than patients who received any type of treatment (p < 0.0001). Two year OS for patients receiving treatment was 77%; there was no difference in OS among patients treated with different treatment regimens. Rituximab was not associated with longer OS. Two year PFS for patients treated with HD-MTX containing regimens was 85.7% vs. 37.5% for patients treated without HD-MTX (p=0.08). Use of WBRT was not associated with prolonged OS or PFS. On univariate analysis, elevated CSF protein was associated with inferior OS (p = 0.03); age, ECOG performance status, serum LDH at diagnosis, tumor location within the CNS, neutrophil and lymphocyte count at diagnosis and monocyte counts did not predict for OS or PFS. Among patients receiving HD-MTX based regimens 6/20 (30%) had a venous thromboembolic (VTE) episode, all occurred during HD-MTX based regimens; median time from diagnosis to VTE was 70 days (range 24 – 154), and occurred after a median of 2 cycles of chemotherapy (range 1 – 5).
Conclusions: Treatment of PCNSL can result in improved outcomes and prolonged survival. Patients treated with lower intensity treatments such as temozolomide and rituximab have better OS than those not capable of tolerating even these therapies. We observed a high incidence of VTE in patients receiving HD-MTX treatment for PCNSL. The risk factors for this complication include frequent hospitalizations, use of central venous catheters and decreased mobility. Close monitoring and surveillance should be done and prophylactic measures to prevent VTE should be considered. A larger case – control study is planned to identify the specific risk factors for VTE compared with other CNS neoplasms and non – PCNSL lymphomas. Table 1.Baseline patient charachteristicsVariablePatient Number (%)Gender (Male / Female)22/8Median Age (Range)64.5 (18-82) yearsLymphoma subtype DLBCL MZL T cell lymphoma Unclassifiable25 (83.3%) 2 (6.6%) 1 (3.3%) 2 (6.6%)PCNSL location in CNS Cortex Deep brain Structures13 (43.3%) 17 (56.6%)CSF involvement9 (30%)Elevated protein in CSF14 (46.6%)Elevated serum LDH8/30 (26.6%)ECOG performance status at diagnosis 0 1 2 3 47 (23.3%) 15 (50%) 5 (16.6%) 1 (3.3%) 2 (6.6%)Age > 60 years21 (70%)Elevated WBC (>10,000/mcl) at diagnosis13 (43.3%)Hemoglobin (<10 g/dl) at diagnosis8 (26.7%)Treatment High dose Methotrexate - based Temozolomide – based No treatment20 (66.6%) 5 (16.6%) 5 (16.6%)Rituximab15 (50%)Whole brain radiation therapy11 (36%)

Disclosures
No relevant conflicts of interest to declare.