CNS prophylaxis in aggressive non-hodgkin s lymphoma

Transcription

1 232 CNS prophylaxis in aggressive non-hodgkin s lymphoma C. Meert, MD, D. Dierickx, MD, PhD, V. Vergote, MD, G. Verhoef, MD, PhD, A. Janssens, MD, PhD SUMMARY Although it doesn t occur frequently, central nervous system relapse in aggressive non-hodgkin lymphoma carries a very dismal prognosis. Indications for the use of prophylactic strategies are clear-cut in Burkitt and lymphoblastic lymphoma. However, this remains subject to much debate in other types of aggressive non-hodgkin lymphoma, like diffuse large B-cell lymphoma. Available strategies consist of intrathecal administration of chemotherapy, the systemic use of high-dose central nervous system-penetrating cytotoxic agents or a combination of both. Nevertheless, all known methods entail a certain risk for toxicity in patients. Hence, great effort has been put in the search for risk factors and scores to identify high-risk patients who have benefit from central nervous system-prophylaxis and to exclude those who do not. This article aims to provide an overview of existing strategies, pharmacological properties and side effects of available cytotoxic agents, as well as an update on the current guidelines for the implementation of central nervous system prophylaxis in different types of non-hodgkin lymphoma. However, due to lack of qualitative prospective data, a golden standard in this field is still lacking. (BELG J HEMATOL 2017;8(6):232-8) INTRODUCTION The incidence of central nervous system (CNS) relapse in aggressive non-hodgkin lymphoma (NHL) varies greatly between entities, ranging from 5% in diffuse large B-cell lymphoma (DLBCL) to over 30% in Burkitt (BL) and lymphoblastic lymphoma (LBL). 1-4 Nonetheless, the appearance of CNS relapse severely complicates the clinical outcome of patients and is associated with high mortality rates, regardless of the underlying lymphoma type. CNS involvement can manifest itself in two ways, either by forming masses in the brain parenchyma or by dissemination of lymphoma cells in the leptomeningeal compartment. It mostly occurs early (6-12 months after start of treatment) suggesting the presence of subclinical disease at the time of diagnosis. This finding implies a need for a more accurate diagnostic approach from the very beginning, by incorporating magnetic resonance imaging (MRI) and flow cytometry on cerebrospinal fluid (CSF) in the initial work-up of highrisk patients. Flow cytometry has been reported to be double as sensitive in detecting leptomeningeal involvement compared to morphology alone. 5 MRI is found to be superior to computed tomography (CT) in detecting CNS lymphoma, although the differentiation with other brain tumours like glioblastoma, inflammatory diseases like neurosarcoidosis and infectious diseases like toxoplasmosis remains challenging in immunocompromised patients. 6 The pattern of CNS involvement seems to be specific for each type of lymphoma. In BL, malignant cells typically spread in the meninges, while for DLBCL the predominant site for CNS dissemination in the post rituximab era is the brain parenchyma. 7 This might explain why intrathecal (IT) chemotherapy is less effective in preventing CNS relapse in DLBCL. We will review commonly used strategies for CNS prophylaxis including IT and high-dose CNS penetrating chemotherapy, followed by an update of the current literature on the implementation of CNS prophylaxis in different types of NHL. INTRATHECAL CHEMOTHERAPY The ideal strategy for CNS prophylaxis would be a method that has a good distribution in the leptomeningeal compartment as well as the brain parenchyma, has a long half-life Department of Clinical Haematology, Catholic University of Leuven, Leuven, Belgium. Please send all correspondence to: C. Meert, MD, Department of Clinical Haematology, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium, tel: , caressa.meert@uzleuven.be. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: aggressive non-hodgkin lymphoma, central nervous system, intrathecal, prophylaxis, relapse, risk factors.

2 PHARMACOTHERAPY 233 and is associated with limited toxicity. To achieve these goals, and given the fact most cytotoxic agents are known to have poor penetrance across the blood-brain barrier, a method was developed intuitively to administer chemotherapy directly in the CSF via lumbar puncture. Traditionally, CNS prophylaxis consists of IT administration of methotrexate (MTX), cytarabine or dexamethasone/hydrocortisone or a combination of these agents. Regimens are based on positive experiences in the treatment of BL and LBL. In accordance with the early occurrence of relapse in the CNS, a minimum of 4 IT injections are given with or in between the first systemic treatment courses. Comparative studies on timing, frequency, dose and type of cytotoxic agents are not readily available. As the CSF consists of an almost fixed volume ( ml), the dose does not have to be adjusted to body weight or body surface area. To achieve an even better distribution throughout the CNS, an intraventricular catheter system can be implanted operatively (a.k.a. Ommaya reservoir). This system reduces the burden on patients by removing the need for repeated lumbar punctures, but carries risks of infectious (up to 27%) and noninfectious complications (up to 30%). The incidence of these complications is highly dependent on the surgeon s experience and the use of strict aseptic techniques. 8 The system is mostly used in patients with primary CNS disease who require long-term CNS-directed treatment. METHOTREXATE MTX is the most commonly employed IT drug for CNS prophylaxis at a dose of 12 to 15 mg, either as a single agent or in combination with cytarabine and steroids. It is eliminated from the CSF biphasically through capillary resorption in the brain parenchyma as well as the choroid plexus with half-lives of 4.5 to 14 hours. Systemic toxicity is limited, although mucositis and cytopenia can appear after multiple administrations. To reduce the risk of systemic complications, leucovorin (reduced folate or N5-formyl-tetrahydrofolate) can be considered in patients with an impaired renal function. Neurotoxicity can occur acutely, sub-acutely or even several months or years after treatment. Chemical arachnoiditis presents itself the first hours to days after administration and is characterized by vomiting, headache, fever and neck stiffness. Severe neurotoxicity is rare and can appear days to weeks after administration under the form of irreversible paraplegia or encephalopathy. On a more long-term basis (months to years) a syndrome with cognitive decay and gait disturbances resulting in dementia has been described. It is identified by the presence of leukoencephalopathy on imaging and more frequently occurs in patients who underwent concomitant radiotherapy. 9 CYTARABINE Next in line is cytarabine. This agent is more frequently administered in combination with MTX than as a single agent. Systemically, it is eliminated quickly from the plasma by the hepatic enzyme deoxycytidine kinase. Considering this enzyme is not present in the CNS, cytotoxic levels can be maintained up to 24 hours. Its elimination from the CSF is biphasic with a half-life of 1 and 3.4 hours. As serum levels are not detectable, systemic toxicities are infrequent to non-existing. Neurotoxicity has been reported in the form of chemical arachnoiditis or, less frequently as transient paraplegia, seizures, peripheral neuropathy, myelopathy or encephalopathy. Many different doses have been used in trials (25 to 100 mg). Due to a lack of comparative studies, it is unknown which is the best dose to use. In the end, it is important not to exceed a dose of 100 mg of IT cytarabine per week because of the increased risk for neurotoxicity. Because cytarabine is an S-phase specific drug, prolonged exposure could be beneficial. Keeping this in mind, a slowrelease formula was developed by encapsulating cytarabine in vesicular micro particles (liposomal cytarabine). The exposure time of liposomal cytarabine is up to 40 times higher than with regular cytarabine, reducing the administration frequency to once every two weeks at a dose of 50 mg. In treatment of lymphomatous meningitis, liposomal cytarabine has proven its worth by inducing better outcomes and securing the quality of life of patients. In the setting of CNS prophylaxis for DLBCL there are some data suggesting a benefit of reducing the rate of CNS relapse, although the level of evidence for this is poor. 10 An increased incidence of chemical meningitis has been reported with the use of liposomal cytarabine. Hence, steroids should be administered concomitantly. It is advised to administer 8 mg of dexamethasone per day orally 2 days prior until 2 days after IT liposomal cytarabine is administered. RITUXIMAB It is well known that rituximab had a revolutionary impact on the treatment of both aggressive and indolent B-cell NHL, improving patient s outcomes in a very significant manner. Studies assessing the role of rituximab in preventing CNS relapse provided contradicting results. When given systemically, only about 0.1% of this large monoclonal antibody crosses the blood-brain barrier and we suspect subclinical disease to be present already at diagnosis. On the other hand, better systemic control could be able to reduce the risk of CNS relapse to some extent. IT rituximab has proven to be effective in treating primary CNS lymphoma at a dose of 10 to 40 mg in case reports, but its role in CNS prophylaxis remains unclear. Given its excellent safety and 6

3 234 tolerability profile, rituximab would be an interesting subject to explore in future studies. Side effects like nausea, chills and hypotension can occur immediately after IT administration, but are fully reversible and only appear when doses of 30 mg or higher are used. 11 SYSTEMIC CHEMOTHERAPY High-dose (HD) CNS penetrating agents have been successfully implemented in regimens for BL and LBL in the prevention of CNS dissemination. 2-4 In other high risk NHL (including DLBCL) treated with R-CHOP or equivalent immunochemotherapy, there is no golden standard regarding the timing of HD CNS-penetrating agents. One study showed that the implementation of HD-MTX after the completion of R-CHOP results in an increased risk of early relapse in DLBCL. 12 In another study by Abramson HD-MTX was added to R-CHOP on day 15 of alternating cycles (i.e. cycles 2, 4 and 6) in 65 patients with high-risk DLBCL. An incidence of 3.3% of CNS relapse was found in this group which was considered low in comparison to historical data. However, renal insufficiency was a major concern in this study and led to delay or even discontinuation of CNS prophylaxis in some cases. 13 In the end, the use of HD CNS penetrating agents should not be allowed to interfere with standard immunochemotherapy, as its role in the treatment of DLBCL as a whole is not proven. Again, most experience was gained with MTX as CNS penetrating agent in the treatment of lymphoma. Overall, 3-10% of plasma levels are obtained in the CSF, which is equal or even higher than what is achieved with IT administration. A dose of 1 g/m2 is sufficient to treat lesions in the brain parenchyma in primary CNS lymphoma. For leptomeningeal disease however, a higher dose of g/m 2 is required. Since an adequate CNS prophylaxis deems to target both compartments, we recommend infusions of g/m 2 over 4-6 hours. Lower-dose longer-lasting infusions (e.g. 1 g/m 2 over 12h) are associated with a greater risk of severe neurotoxicity. 14 The half-life of MTX following infusion is variable (between 8 and 12 hours). Almost 90% of MTX is excreted unchanged in the urine, the remaining 10% is metabolized to 7-hydroxy methotrexate by the hepatic enzyme aldehyde oxidase. Due to its lower water solubility, this metabolite may significantly contribute to renal toxicity. 15 The most relevant systemic complications of HD-MTX are renal insufficiency, myelosuppression and mucositis. To shield patients from these toxicities, rescue therapy with leucovorin should be initiated at least 24 to 36 hours after the HD-MTX infusion has started. We recommend a leucovorin dose of 10 to 15 mg/m 2 IV or 20 to 30 mg/m 2 orally every 6 hours until MTX plasma levels are lower than 0.05 microm. MTX plasma levels should be measured every 12 hours starting from 24 hours after start of administration of the MTXinfusion until the targeted MTX level is reached. Leucovorin can bypass the metabolic block on purine and thymidine synthesis that is induced by MTX by competing for the binding site on the enzyme dihydrofolate reductase. Furthermore, the effect of leucovorin is much more potent in normal cells than in malignant cells. The reason for this selectivity is unclear but could be related to the lack of a folate carrier protein in malignant cells or a cellular difference in polyglutamation of MTX between tumor cells, gut epithelium and bone marrow In addition, HD IV Cytarabine also has proven efficacy in the treatment of primary CNS lymphoma, improving the outcome in patients when added to HD-MTX. 19 Its use has also been investigated in the prophylactic setting by the Nordic Lymphoma Group. They reported a lower than estimated incidence of CNS relapse in a group of 156 patients with DLBCL or grade III follicular lymphoma. 20 In this study, a dose of 3 g/m 2 was given twice a day for 2 consecutive days after the end of standard immunochemotherapy (6 cycles of R-CHOEP-14), followed by HD-MTX 3 weeks later. Since all 7 relapses occurred within 6 months after registration, the authors suggested that earlier initiation of prophylaxis may be indicated to further reduce CNS relapse rate. Grade III-IV toxicities reported in trials mainly consisted of myelosuppression, mucositis and sepsis. Etoposide and ifosfamide possess considerable CNS penetration as well and have been successfully implemented in the treatment of BL. Although it is hard to judge their individual usefulness, as other CNS penetrating agents like HD-MTX are also incorporated in these regimens. In a large retrospective analysis of the DSHNHL that used R-CHOEP as standard chemotherapy, etoposide had no proven benefit in preventing CNS relapse in DLCBL. 21 INDICATIONS AND EFFICACY Indications for CNS prophylaxis are clearly defined in some types of lymphoma, yet still controversial in others. In LBL, the incidence of primary CNS involvement is approximately 7%. 3,22-24 In older studies performed before CNS prophylaxis was implemented, relapses were observed in 32%-50% of patients, suggesting a definite need for prophylactic measures. 23 With IT chemotherapy only, the CNS relapse rate in LBL could be reduced to 0-36%. 8,23 In BL extraordinary high CNS relapse rates of 43-55% are seen and leptomeningeal involvement is detected in 11-40% patients at the time of diagnosis. In early studies implementing CNS prophylaxis in the form of IT and systemic MTX, a significant decrease in CNS relapse rate to 6-11% was seen. 25,26 Adequate CNS

4 PHARMACOTHERAPY 235 prophylaxis should therefore be a mandatory feature in the treatment of LBL and BL and should consist of high dose systemic chemotherapy, IT chemotherapy or preferably a combination of both. Prophylactic cranial irradiation has shown efficacy in preventing CNS relapse in LBL as well as BL, but has been more and more abandoned in more modern regimens, and especially in young patients, because of serious adverse events (neuropsychological sequelae, growth restriction in children and increased risk for secondary malignancies). 2,27 CNS relapse in DLBCL is not that common with an incidence of 5%. As DLBCL is a very heterogeneous group of lymphomas, much effort has been put in trying to identify patients who are at an increased risk for dissemination and might benefit from CNS prophylaxis. In 2009, the DSHNHL developed a risk model the CNS-IPI, composed of the International Prognostic Index (IPI) factors (stage III-IV, >1 extranodal site, LDH>ULN, age >65y, ECOG >1) in addition to involvement of the kidney s and/or adrenal glands. Using this tool, patients can be divided into three risk groups: low-risk (0-1 factors, 2-year relapse risk 0.6%, CI ), intermediate-risk (2-3 factors, 2-year relapse risk 3.4%, CI ) and high-risk (4-6 factors, 2-year relapse risk 10.2%, CI ) (Table 1). 28 This model has been independently validated in several large patient groups, leading to a recommendation for the use of CNS prophylaxis in high-risk patients. 29,30 Several extranodal localisations are also associated with an increased risk for CNS relapse. These include intraocular sites, intravascular lymphoma, kidney s, adrenal glands, testis, cranial vault, skull and spine lesions and specific subtypes like DLBCL of leg type. 31 These patients should definitely be taken into account for CNS-directed prophylaxis, regardless of their CNS-IPI status. Stage I-II DLBCL of the nasal cavity and paranasal sinuses used to be considered high-risk. After the introduction of rituximab however this finding is no longer apparent. 30 Data about CNS recurrence in lymphoma with bone marrow involvement is inconsistent and cannot prove there is an increased risk for developing CNS dissemination. 32,33 Over last decade, more and more effort has been put in correlating genetics to prognosis in lymphoma. Recent genomic and proteomic studies have been able to identify a prognostic role for MYC, BCL2 and BCL6, either in the setting of gene rearrangement (the so-called double hit and triple hit lymphomas) or in the setting of dual expressing lymphoma by immunohistochemistry. Double and triple lymphomas were found to have inferior complete response rates, a shorter progression free survival and overall survival, as well as an increased risk for CNS relapse. In one study a two-year risk TABLE 1A. Risk factors associated with significantly increased risk of CNS relapse in DLBCL. Age >65 years ECOG >1 LDH > ULN Stage III-IV >1 site of extranodal involvement Specific sites of extranodal involvement: intraocular sites, intravascular lymphoma, kidney s, adrenal glands, testis, cranial vault, skull and spine lesions, DLBCL of leg type Double-hot, triple-hit and dual expresser lymphoma Abbreviations: CNS - central nervous system; DLBCL - diffuse large B-cell lymphoma; ECOG - Eastern cooperative oncology group performance status; LDH - lactate dehydrogenase; ULN - upper limit of normal. TABLE 1B. Risk stratification according to the CNS-IPI. Risk CNS-IPI factors Percentage of CNS relapse (2y) Low %, CI Intermediate %, CI High %, CI Abbreviations: CNS - central nervous system; IPI - international prognostic index. of CNS relapse of 13% was reported in patients with double and triple hit lymphomas. 34 In another study that evaluated dual expressers, a two-year risk for CNS relapse of 9.7% was found as compared to 2.2% in non-dual expressers. 35 These biomarkers are awaiting further validation, but may help in the identification of a high-risk patients that should undergo CNS-directed workup and could be considered for CNS prophylaxis in the future. Currently, strong evidence supporting the efficacy of IT chemotherapy in preventing CNS relapse in DLBCL is lacking. Arkenau conducted a retrospective analysis of a group of 259 high-risk patients, primarily defined by extranodal involvement of certain sites. These patients received IT chemotherapy consisting of either MTX or a combination of 6

5 236 TABLE 2. Studies evaluating the benefit of intrathecal chemoprophylaxis in DLBCL. Study Total number of patients Indications for CNS prophylaxis Standard chemotherapy Type of IT prophylaxis % of CNS relapse Statistical significance regarding difference in CNS relapse rate Boehme BM, testes, head, sinuses, orbits, oral cavity, tongue and salivary glands (R-)CHOP IT MTX 2.5 (no prophylaxis) 4.4 (with prophylaxis) NS Schmitz Testes, BM, upper cervical nodes, sinuses or other sites in the cranial regions (R-)CHO(E)P or (R-) Mega- CHOEP IT MTX 2.3 (total) NS Tai >1 extranodal site, orbit, sinus/posterior nasal space, breast, testes, BM (R-)CHOP IT MTX 5.1 (CHOP) 6 (R-CHOP) NS Schmitz BM, testes, head, sinuses, orbits, oral cavity, tongue and salivary glands (R-)CHOEP IT MTX 2.6 (total) NS (P 0.386) Kumar BM, orbit, testes, peripheral blood, bone/vertebrae, nasal/paranasal sinuses, high intermediate or high IPI-score R-CHOP IT MTX ± IT Ara-C IV MTX (28%) 2.0 (total) NS Abbreviations: BM - bone marrow; R rituximab; CHOP - cyclophosphamide, vincristine, doxorubicin, prednisolone; E - Etoposide; Mega - high dose; IT - intrathecal; MTX - methotrexate; S - significant; NS - not significant. MTX and cytarabine. An incidence of CNS relapse of 1.1% was reported, which was considered low in this high-risk group of patients. 36 A study by the Groupe d Etude de Lymphome d Adulte (GELA) including 974 patients with histologically aggressive lymphoma (mostly DLBCL) was performed in All these patients were treated with 15 mg IT MTX per cycle of ACVBP (doxorubicine, cyclophosphamide, vindesine, bleomycin, prednisone) regardless of their risk scores often followed by consolidation chemotherapy with 2 administrations of systemic HD MTX. A relatively low incidence of CNS relapse of 2.2% was found in comparison to the expected incidence (estimated at 5% by the authors based on historical data without the use of prophylaxis. 37 Most of the available comparative data comes from retrospective analyses of large trials of which a smaller group was deemed to be high-risk and treated with IT chemotherapy upon the physician s preference. Within these groups no significant risk reduction was found between those who were treated with IT chemotherapy and those who were not (Table 2) Unfortunately, there is a great deal of heterogeneity between these studies regarding the definition of high-risk patients, the diagnostic methods and the type of prophylaxis that was used. The use of high-dose MTX has been investigated for DLBCL with positive results. A relatively recent retrospective study by Ferreri showed a significant reduction in the CNS relapse rate in a group of patients that received HD-MTX (3-4 courses of 3 g/m 2 MTX every 2-3 weeks +/- IT liposomal cytarabine) in comparison with those who received no CNS-prophylaxis (2.5% vs. 12%). 44 Although evidence is weak (grade IVC), the European Society of Medical Oncology (ESMO) guidelines now recommend HD-MTX as the preferred choice for CNS prophylaxis in DLBCL, but also recognize that prospective analyses are needed to further verify the benefit of this approach. 45 Generally, mantle cell lymphoma (MCL) has a poorer outcome than lymphoma of indolent histology. The incidence of secondary CNS involvement has been reported to be 4-23%. A major risk factor is blastoid transformation, raising the CNS relapse rate to 20-50% Well-defined guidelines for CNS prophylaxis in MCL are not available. CNS relapse almost always occurs in the context of systemic relapse or resistance with a median time of months from diagnosis, which might suggest that better control of systemic disease should be the primary objective CNS prophylaxis should be considered in patients with blastoid

6 PHARMACOTHERAPY 237 KEY MESSAGES FOR CLINICAL PRACTICE 1 Burkitt and lymphoblastic lymphoma carry extraordinarily high risk for CNS relapse. Therefor CNS prophylaxis is crucial in primary treatment and would preferably consist of HD MTX and cytarabine and a minimum of 4 intrathecal injections of MTX-cytarabine-steroids combined. 2 Indications for CNS prophylaxis in DLBCL are less clear. A validated prognostic model the CNS-IPI is a user-friendly tool for identifying a high-risk group of patients that will benefit from CNS prophylaxis. In addition, patients with certain types of extranodal involvement, double/triple hit lymphomas and dual expressers should be considered for CNS prophylaxis. 3 ESMO guidelines now recommend the use of high dose CNS penetrating agents like MTX to be the first choice for CNS prophylaxis in DLBCL. A proposed regimen would be to add a minimum of 3 administrations of HD-MTX to R-CHOP on day 15 of alternating cycles (i.e. cycles 2, 4 and 6). 4 CNS prophylaxis in mantle cell lymphoma should be considered in patients with blastoid transformation that will be treated with curative intent. Well-defined guidelines for CNS prophylaxis in MCL are not available. 5 Currently there is no evidence that the use of CNS prophylaxis is of any benefit in inhl. transformation of MCL and an intention to treat with curative intent. In peripheral T-cell lymphoma (PTCL) CNS involvement is present in 4% of cases at diagnosis. 49 Unfortunately, CNS relapse is not studied in PTCL, hence sensible conclusions about the use of CNS prophylaxis cannot be made. It has been suggested in literature that the same risk stratification method as for DLBCL should be used as for now. Indolent NHL (inhl) has a risk of CNS relapse of about 0-4.9%. More than half of relapses occur in the setting of transformation to DLBCL Currently, there is no evidence that the use of CNS prophylaxis is of any benefit in inhl. CONCLUSION Despite many innovations in the treatment of aggressive lymphoma and the subsequent improvements in quality of life and survival, the use of CNS prophylaxis remains a controversial topic. IT chemotherapy has proven worth as a prophylactic strategy in BL and LBL, but its role in other types of aggressive NHL remains unclear. Over the last decade, progress has been made in identifying high-risk groups in DLBCL by the development and validation of the CNS-IPI prognostic model. Much uncertainty still exists on how to implement an adequate CNS-directed prophylactic strategy in these patients. In the end, prospective randomised controlled trials are needed to further clarify this issue. REFERENCES 1. Ghose A, Influence of Rituximab on central nervous system relapse in diffuse large B-cell lymphoma and role of prophylaxis a systematic review of prospective studies. Clin Lymphoma Myeloma Leuk. 2015;15: Perkins AS, Burkitt lymphoma in adults. Hematol. 2008;1: Bernasconi C, Lymphoblastic lymphoma in adult patients: Clinicopathological features and response to intensive multiagent chemotherapy analogous to that used in acute lymphoblastic leukemia. Ann Oncol. 1990;1: Thomas DA, Lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2001;15: Roma AA, Lymphoid and myeloid neoplasms involving the cerebrospinal fluid: comparison of morphologic examination and immunophenotyping by flowcytometry. Diagn Cytopathol. 2002;27: Baraniskin A, Current strategies in the diagnosis of diffuse large B-cell lymphoma of the central nervous system. Br J Haematol. 2012;156: Kansara R, Evaluation of the site of central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma by the CNS Risk Model. Br J Haematol [Epub ahead of print]. 8. JL Cohen-Pfeffer, Introcerebroventricular delivery as a safe, long-term route of drug administration. Pediatr Neurol. 2017;67: Kwong YL, Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities. Ann Hematol. 2009;88: Barca-Gonzales E, Central nervous system pro-phylaxis with intrathecal liposomal cytarabine in a subset of high-risk patients with diffuse large B-cell lymphoma receiving first line systemic therapy in a prospective trail. Ann Hematol. 2016;95: Antonini G, Intrathecal anti-cd20: an effective and safe treatment for leptomeningeal lymphoma. J Neurooncol. 2007;81: Boehme V, Incidence and risk factors of central nervous system recurrence in agressive lymphoma - a survey of 1693 patients treated in protocols of German High-Grade Non-Hodhkin s Lymphoma Group (DSHNHL). Ann Oncol. 2007;18: Abramson JS, Intravenous methotrexate as central nervous system 6

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