Abbreviations: CNS, central nervous system; DLBCL, diffuse large B cell lympituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; GELA, Groupe
homa; NHL, non-Hodgkin lymphoma; CSF, cerebrospinal fluid; R-CHOP, d’Etude des Lymphomes de l’Adulte; HIV, human immunodeficiency virus;y Group; NCCN, National Comprehensive Cancer Network; R-CHOEP, rit-P, doxorubicin, cyclophosphamide, vindesine, bleomycine, and prednisone;, and bleomycin; ProMACE-CytaBOM, prednisone,methotrexate, doxoru-ate; M-BACOD, methotrexate, bleomycin, cyclophosphamide, etoposide;tion; IT, intrathecal.venue, ML 0562, Cincinnati, OH 45267, United States.
A. Ghose et al. / Critical Reviews in Oncology/Hematology xxx (2014) xxx–xxx
bstract
Overall survival in diffuse large B-cell lymphoma (DLBCL) has significantly improved in the last decade, especially after the incorporationf rituximab. Involvement of the central nervous system (CNS) at presentation or at recurrence is an uncommon event, but carries a dismalrognosis with median survival of less than 6 months. Although prophylactic CNS directed therapy is a widely used approach to prevent thisomplication, randomized clinical trials have been very limited. CNS prophylaxis has inherent toxicities; therefore, identifying the populationf patients who would receive most benefit is of utmost importance. From an extensive review of current literature, we report the incidence ofNS relapse in DLBCL and describe the role of CNS prophylaxis in the post-rituximab compared to the pre-rituximab era. We also review
he current modalities of CNS prophylaxis and attempt to identify the high-risk patients who would benefit. Lastly, we present a treatmentlgorithm that defines the role of CNS prophylaxis in the management of patients with DLBCL.
2014 Elsevier Ireland Ltd. All rights reserved.
eywords: CNS; Prophylaxis; Diffuse large B cell; Lymphoma
oirolrpt[
2
eis(p([11dtPe6ric6hl6wimab on the risk of CNS recurrence [10]. Although large
. Introduction
Diffuse large B-cell lymphoma (DLBCL) is the mostommon non-Hodgkin lymphoma (NHL), accounting for5–58% of NHL [1]. There will be an estimated 69,740ew cases of NHL and 19,020 deaths from NHL duringhe year 2013 [2]. Incorporation of immunotherapy with rit-ximab in combination with chemotherapy during the lastecade has significantly improved the prognosis of theseatients. According to American Cancer Society estimates,
significant annual decline (3.0%) in the death rate fromHL was noted over the past 10 years (2000–2009) [2].epending upon the international prognostic index (IPI), 4ear event free survival rates have been reported at 47–80%n the post-rituximab era compared to 20–67% in the pre-ituximab era [3]. Involvement of cerebrospinal fluid (CSF),eninges or solid brain parenchyma is one of the most
erious complications for patients with diffuse large B-cellymphoma. Although rare patients can have central nervousystem (CNS) involvement at initial presentation, isolatedNS relapse after successful treatment of their systemicisease is more common and carries an extremely dismalrognosis with median survival of less than 6 months [4–9].reventing this devastating complication with CNS directed
herapy is an important component of the treatment strat-gy for a few patients, but exposing all patients to CNSirected therapy may expose many of them to additionaloxicities without significant benefits. In this article we willeview the currently available evidence and present a treat-ent algorithm for incorporating CNS directed therapy in theanagement of DLBCL.
. Incidence
.1. Pre-rituximab era
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
CNS involvement at the time of initial diagnosis ofLBCL is reported to be only 1% [10–12]. Most episodes
pos
f CNS involvement occur in relapsed disease [13]. Thencidence of isolated CNS relapse without any systemicecurrence varies from 1.1 to 10.4% [14,15]. The wide rangef reported rates of CNS involvement (5–25%) is due toarge variation among study populations, risk factors, accu-acy of diagnostic testing and the type of CNS directedrophylaxis [16,17]. However, major randomized prospec-ive trials have documented an incidence of around 3–5%6,10,18].
.2. Post-rituximab era
Some recent studies have suggested a protectiveffect of rituximab against CNS relapse, although theres contradictory data as well. A recent prospectivetudy on 989 DLBCL patients who received R-CHOPrituximab-cyclophosphamide, doxorubicin, vincristine, andrednisone) documented an incidence of CNS relapse of 2%95% CI 1.1–2.9) after a median follow up of 2.5 years19]. The randomized prospective RICOVER-60 trial on222 patients with aggressive B-cell lymphomas on CHOP-4 with or without rituximab also suggested that rituximabecreased the risk of CNS recurrence [15]. R-CHOP reducedhe relative risk for CNS disease to 0.58 (95% CI 0.3–1.0;
= 0.046). The estimated 2-year incidence of CNS dis-ase was 4.1% (CI 2.3–5.9) after R-CHOP-14 compared to.9% (CI 4.5–9.3) after CHOP-14 [15]. Conversely, a largeetrospective study by Tomita et al. showed no decreasen the incidence of CNS relapse in patients with DLBCLompared to the pre-rituximab era [20,21]. In that study,.7% of 1221 patients who received R-CHOP were noted toave CNS events. The Groupe d’Etude des Lymphomes de’Adulte (GELA) analyzed 399 DLBCL patients greater than0 years of age who were treated with 8 cycles of CHOP,ith or without rituximab. There was no effect of ritux-
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
rospective trials suggest a protective effect of rituximabn CNS involvement, evidence is not uniformly conclu-ive.
roc61mthan 1 year [33,50]. The occurrence of CNS relapse during
A. Ghose et al. / Critical Reviews in
. Risk factors for CNS relapse
.1. Conventional risk factors
Because the incidence of CNS relapse is relatively low,here have been a number of studies that have attempted toefine predictive risk factors in order to identify patients,ho would benefit from CNS directed therapy [11,22–26].ost of these studies have been retrospective and have often
eported conflicting data.Testicular involvement by DLBCL is consistently corre-
ated with high-risk for CNS involvement. For example, in study of 373 patients with testicular lymphoma (exclud-ng acute lymphocytic leukemia/lymphoblastic leukemia andurkitts lymphoma), 56 (15%) had CNS recurrence [27].reast, adrenal glands, and bone have also been defined asigh-risk sites, with breast being more consistently associ-ted with CNS recurrence. Other sites identified as predictingigher risk of CNS involvement in some retrospective stud-es include paranasal sinuses, parameningeal sites/epiduralpace, kidneys and liver. Some studies have also shownigher risk in patients with human immunodeficiency virusHIV) [28–30]. Elevated LDH and >1 extra-nodal site havelso been identified as risk factors [18,31]. Unfortunately,hese findings are not consistent, and other studies havehown no significant increase in CNS relapse risk withhese factors [10,32,33]. Hegde et al. found flow-cytometryo be a more sensitive method of detecting occult CNSnvolvement than conventional cytology, and showed that1 extra-nodal site was the only parameter that corre-
ated with CNS involvement identified by flow-cytometry17].
Combinations of the above factors have been moreonsistently associated with risk for CNS relapse. In theICOVER-60 trial, increased LDH, >1 extra-nodal site of
nvolvement, and presence of B symptoms (fever, nightweats, weight loss) had a cumulative risk of 23.8% forNS relapse at 2 years [34]. The IPI or age-adjusted (aa)-
PI has been inconsistently associated with increased risk14,18,32,33]. A large study on 1220 patients with highrade NHL (excluding lymphoblastic or Burkitt’s/Burkitt’s-ike lymphoma) that was designed to determine risk factorsor CNS relapse identified 5 primary independent risk fac-ors by multivariate analysis: increased LDH (relative riskRR] = 2.1, CI: 2.1–4.4), serum albumin <35 g/l (RR = 2.5,I: 1.3–4.6), age > 60 years (RR = 2.8, CI 1.5–5.4), retroperi-
oneal lymph node involvement (RR = 1.9, CI: 1–3.5), andnvolvement of >1 extra-nodal site (RR = 3,CI 1.7–5.4). Bone
arrow involvement was associated with a significantlyncreased risk of CNS recurrence in univariate analysis, butot in multivariate analysis [18]. The risk of CNS recurrenceas ≤6.2% for patients with < 4 risk factors, but was ≥25%
or those with 4 or 5 risk factors; therefore, the authors rec-
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
mmended CNS prophylaxis for the high-risk group (4–5isk factors) [18]. Data for risk of CNS recurrence afterone marrow involvement has been very inconsistent and
osc
gy/Hematology xxx (2014) xxx–xxx 3
ontroversial, with some studies showing increased risk6,35–39], and others showing decreased risk [40,41].
.2. Biological risk factors
Patients harboring myc oncogene rearrangements (5–10%f DLBCL), including the double hit variant of DLBCL (hav-ng both bcl2 and myc translocations) have a significantlyigher risk of CNS recurrence, ranging from 9 to 50% [42,43].he addition of rituximab to CHOP chemotherapy does notecrease this risk. A myc rearrangement also carries poorerrognosis in terms of overall and progression free survival43,44]. A large retrospective study on 214 DLBCL patientsound that tumor proliferation index, BCL2, BCL6, and CD10ositivity carry no risk of CNS recurrence in the rituximabra [45]. Gene expression profiling analysis enables classifi-ation of DLBCL into two molecular subtypes based on theell of origin phenotype: germinal center B-cell type (GCB)nd activated B-cell type (ABC) [46,47]. Although ABC typeas been associated with poorer prognosis in general, it didot correlate with increased risk of CNS recurrence comparedo GCB type [48,49].
. Pattern of CNS involvement and staging
CNS lymphoma can involve brain parenchyma, theura, leptomeningeal compartment or any combination [14].ccording to a previous review of CNS prophylaxis in NHL,
pproximately 50% of all relapse cases are isolated to theNS and in those patients leptomeningeal disease is moreommon than brain parenchymal disease [21]. Studies in there-rituximab era, such as SWOG 8516, showed a greaterncidence of leptomeningeal disease than parenchymal dis-ase [50]. However, according to some recent trials in theost-rituximab era, brain parenchymal involvement was moreommon (approximately 65–76%) [14,31]. These studiesre in accordance with the poor CNS penetration of ritux-mab. However, the RICOVER-60 trial, a large prospectivetudy as mentioned above, showed a greater proportion ofatients receiving R-CHOP had leptomeningeal recurrencesompared to parenchymal recurrences [15]. Parenchymalnvolvement also seems to be more frequent with lymphomasriginating in certain extranodal sites such as the testes51,52].
van Besien et al. showed 4.5% probability of CNSelapse at 1 year in 605 patients with intermediate grader immunoblastic lymphoma (537/605 had diffuse large-ell lymphoma). The median time to CNS recurrence was
months, with only 1 patient having a recurrence more than3 months after initial diagnosis [40]. In most studies, theedian time from diagnosis to CNS involvement was less
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
r shortly after completion of first cycle of chemotherapyuggests that the patients with CNS involvement have sub-linical CNS disease at diagnosis; therefore, development of
sensitive marker to diagnose subclinical CNS disease andimiting CNS directed therapy to these patients can ovoiddditional toxicities without significant benefits for a largeumber of patients.
CNS staging can help identify occult CNS involvementn high-risk patients. CNS staging includes a comprehensiveistory and neurologic physical exam focusing on signs andymptoms of CNS disease, neuroimaging including MRI ofhe brain and total spine as indicated by symptomatologynd CSF evaluation by both conventional cytology and flowytometry. Conventional cytology has low sensitivity andpecificity with false negative rates of 20–60% [53]. Multipletudies have shown that flow cytometry is significantly bettern identifying occult CNS disease compared to conventionalytology but it still requires a substantial population of intactells [54–57]. The sensitivity increases to approximately 50%hen flow cytometry is combined with cytology [17,55,58].emonstrating monoclonality by immunoglobulin H gene
earrangement analysis is an additional tool that can be usedo complement conventional cytology and flow cytometry59,60]. The technique is still experimental and data onhether it is more sensitive than flow cytometry is limited
lthough one retrospective study suggests that with all 3 tests,ytology, flow cytometry and IgH gene rearrangement, theensitivity increases to 67% [59]. Low cell count can be anssue here too but the advantage of this procedure is thatt does not require intact cells. The specificity of IgH geneearrangement analysis has been studied to be 85–97% withensitivity of 54–58% [59,61]. Detection of CSF microR-As as potential diagnostic tools to diagnose Primary CNS
ymphoma is another actively pursued research area. MicroR-As are short RNA molecules that inhibit gene expressiont a posttranscriptional level by binding the 3′-untranslatedegions of mRNA transcripts [62]. Baraniskin et al. usedicroRNA quantification via RT-PCR in CSF samples of 23
rimary CNS lymphoma patients and demonstrated a sensi-ivity and specificity of 95.7% and 96.7%, respectively, usinghis technique [63]. Additional studies are needed to validatehese results and to determine if these specific microRNAseliably detect secondary CNS involvement too. Once occultNS disease is identified, the patient is generally treated withigh doses of systemic chemotherapy such as methotrexatend cytarabine due to good CNS penetration, and/or intrathe-al therapy with methotrexate, or free/liposomal cytarabine64,65].
. CNS directed therapy
.1. Methotrexate
Methotrexate is an inhibitor of dihydrofolate reductase
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
nd thereby DNA synthesis. It is used either intrathecally orntravenously, and considered standard CNS directed therapy.ixed adult intrathecal dosing is used because CNS growth
s not proportional to body surface area. 12 mg of intrathecal
5
c
gy/Hematology xxx (2014) xxx–xxx
ethotrexate (commonly use dose) achieves therapeutic CSFevels (>1 �mol/l) for 24–48 h, and is given with each cyclef chemotherapy for prophylaxis [29,66]. Some studies alsosed 12.5 mg or 15 mg of intrathecal methotrexate with eachycle of systemic chemotherapy [41,67]. National Compre-ensive Cancer Network (NCCN) guideline recommends 4–8oses of intrathecal methotrexate and/or cytarabine. Appro-riate intravenous dosing to achieve consistent therapeuticevels in the CNS is a little more controversial. Vassal et al.tudied plasma and CSF methotrexate concentrations during1 courses given as a 3-h IV infusion of 3 g/m2 methotrex-te in 29 children with NHL [68]. They found no correlationetween plasma and CSF methotrexate levels and cytotoxicethotrexate levels were detected in all courses at 4 h and half
f the courses at 12 h. Another study evaluated CSF concen-ration at different times during 24 h intravenous infusion of
g/m2 methotrexate during 76 infusions in 25 children withymphoid malignancies [69]. Authors concluded that plasmaoncentration of methotrexate cannot predict CSF concentra-ion as no correlation was found and at least 8 h of infusions needed to achieve steady state concentration in CSF. Inddition a minimum dose of 3 g/m2 is required to reachhe minimum therapeutic concentration of 5 × 10−7 mol/Ln CSF. In another study Lin et al. analyzed CSF concen-ration at 0 h after 6-h or 24-h continuous venous infusionf 1–3 g/m2 methotrexate in 34 NHL patients [70]. Theyound significantly higher levels of methotrexate in 6-h grouphan in 24-h group (0.70 �mol/L vs.0.49 �mol/L, P = 0.044).hey also noted lower rates of grade II–IV mucositis (15.4 vs.7.8%) and grade III–IV myelosuppression (46.2 vs. 67.6%)n the 6-h group.
Many studies employed intravenous methotrexate dosesf 3–5 g/m2 with either R-CHOP or other cytotoxic regi-ens to treat CNS involvement, even though they resulted
n shorter or less consistent therapeutic levels than intrathe-al methotrexate [68,71]. Abramson et al. reported goodutcomes in 65 patients with DLBCL considered at highisk for CNS recurrence who received at least one infusionf Methotrexate at a dose of 3.5 g/m2 intravenously mostommonly administered on Day 15 of alternating cycles of-CHOP (i.e. with Cycles 2, 4, and 6), as an inpatient with
eucovorin rescue [65]. Another recent prospective studyreated 156 high risk NHL patients (age-adjusted IPI 2–3)ith six courses of R-CHOEP-14 followed by a course ofigh-dose cytarabine 3 g/m2 IV twice daily for 2 days and aourse of high-dose methotrexate 3 g/m2 as a 24 h infusion
weeks after high dose cytarabine [72]. Potential adverseffects of methotrexate include mucositis, myelosuppression,eurotoxicity and nephrotoxicity. Pretreatment alkalizationf urine and post treatment leucovorin rescue is consideredtandard approach to reduce many of these toxicities.
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
.2. Cytarabine, cytosine arabinoside or Ara-C
Pyrimidine analogs that inhibit DNA polymerase are alsoommonly used for CNS directed therapy either alone or
n combination with methotrexate. A single 30 mg intra-entricular dose of cytarabine maintains a cytotoxic drugoncentration between 0.4 and 1 �mol/L for at least 24 h73]. Sustained release liposomal Ara-C, when administeredhrough lumbar puncture, results in cytotoxic CSF levelshroughout the neuroaxis for ≥14 days, and may have a role inrophylaxis [74]. High dose systemic cytarabine can be usedo obtain comparable concentrations in the CSF, at a dose of
g/m2 twice daily, but is associated with significantly highereurotoxicity and systemic toxicity [75].
.3. Rituximab
Intravenous administration of rituximab results in CSFevels approximately 0.1% of serum levels due to its poorNS penetration. Animal studies have shown that intra-entricular rituximab may have a role in the treatment ofeptomeningeal disease in patients with CNS lymphoma76]. Several case reports describing intrathecal rituximabse in CNS lymphoma in doses ranging from 10 mg to0 mg have been published with most patients showing cyto-ogic response and improvement in symptoms [77–79]. Ahase 1 study evaluated 10 patients in three rituximab doseohorts: 10 mg, 25 mg or 50 mg. Of the eight patients whoeceived 10- or 25-mg doses, none demonstrated signs orymptoms of major toxicity. The two patients who received0-mg doses both experienced infusion related major toxic-ty, including grade 3 hypertension, chest pain, tachypnea,iplopia and nausea/vomiting. Six patients had cytologicalesponses, with four of those achieving a complete response.
ean CSF concentrations 1 h after dosing were 214 mcg/mLnd 472 mcg/mL for 10-mg and 25-mg doses, respectively,imilar to concentrations achieved after systemic rituximab80]. Rituximab in combination with methotrexate has alsoeen evaluated in another phase 1 trial that included 14atients, and showed complete cytologic response in 75%f the patients without serious toxicity [81].
.4. Prophylactic cranial irradiation
This modality has fallen out of favor for prophylaxis ofNS lymphomas due to concern over its toxicity, includingeuropsychological complications, cognitive impairment,ncreased rate of secondary malignancies and hamperedrowth in children [82–84].
.5. Intrathecal administration
Although lumbar puncture is the most commonlymployed method to deliver CNS directed therapy, repeatedrocedures are associated with discomfort and inconvenienceor patients, headaches, CSF leak, bleeding and thrombosis,
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
nd it may be associated with uneven drug distribution inSF. Use of a non-traumatic needle (as opposed to large cut-
ing needles) can reduce some of these complications, andody positioning (i.e., lying prone after the procedure) can
pwns
gy/Hematology xxx (2014) xxx–xxx 5
mprove drug concentration [85,86]. For example, a primateodel study showed that a >10-fold decrease in ventricularean area under the concentration-versus-time curves (AUC)
an occur if patients do not remain prone for 1 h after dosing87]. Intraventricular administration through an implantableevice like an ommaya reservoir instead of lumbar punctureot only allows painless administration and improved distri-ution, but also has been shown to result in improved clinicalutcomes. Risks include intracranial hemorrhage, catheternfection, malpositioning and localized necrotizing leukoen-ephalopathy [66].
. Effectiveness of CNS prophylaxis: a criticalnalysis of evidence
Evidence regarding the effectiveness of CNS prophylaxisn DLBCL is not as straightforward as in highly aggressiveymphomas such as Burkitts/Burkitts-like and lymphoblas-ic lymphomas. Studies have been widely inconsistent on theenefit of CNS prophylaxis in high-risk groups other thanesticular lymphoma [15,19,25,88,89], and prospective ran-omized clinical trials have yielded inconsistent results withNS prophylaxis [25,50] (Table 1). In addition, for mostatients, isolated CNS relapse is followed within monthsy systemic disease, which mainly determines their prog-osis, raising further questions regarding the utility of CNSrophylaxis [11,40,90].
There has been no convincing data to support theffectiveness of CNS prophylaxis in high-risk DLBCLatients, even in the pre-rituximab era. The Southwestncology Group (SWOG) conducted a prospective study
SWOG 8516) in which 899 patients were followed for0 years. The purpose of the study was to evaluate thencidence, natural history and risk factors predictive ofNS relapse in aggressive B-cell lymphoma [50]. Theatients were randomly assigned to the following regimens:HOP; methotrexate, doxorubicin, cyclophosphamide,incristine, prednisone, and bleomycin (MACOP-B);rednisone, methotrexate, doxorubicin, cyclophosphamide,toposide-cytarabine, bleomycin, vincristine, methotrex-te (ProMACE-CytaBOM); or methotrexate, bleomycin,yclophosphamide, etoposide (m-BACOD). Patients withone marrow involvement at diagnosis receiving ProMACE-ytaBOM received 24 Gy of whole-brain irradiation if theychieve bone marrow remission after 4 cycles of chemother-py. Similarly Patients with bone marrow involvement atiagnosis receiving m-BACOD who achieved Bone Mar-ow remission received intrathecal methotrexate (12 mg) andytarabine (30 mg) twice weekly for six doses. Patientseceiving either CHOP or MACOP-B received no CNS pro-
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
hylaxis. The CNS relapse rates were 2.8% for the patientsho received prophylaxis and 3.6% for those who did not, aon-significant difference (P = 0.74). Although the compari-on was biased in favor of prophylaxis, as CNS prophylaxis
Table 1Prospective studies with CNS prophylaxis in DLBCL lymphoma.
Author (ref) Number ofpatients/no(%)of patientswith DLBCL
Systemic therapy CNS prophylaxis Criteria for CNSprophylaxis
CNS relapse number(%)
Median time to CNSrelapse (months)
Overallsurvival/PFS
Isolated CNSprogression orrelapse (%)
Kumar [19] 989 R-CHOP21 ≥2 doses of IT MTX and/orcytarabine or ≥1 doses ofsystemic MTX
All conventionalrisk factors/if nofactor or 1 riskfactor presentweightage given on4 main factors: >1extra-nodal site,elevated LDH, BMinvolvement, orother high risk siteinvolvement
20 (2%; 95% CI1.1–2.9%)5.4% for those withprophylaxis vs. 1.4%for without (P = .08)
a None with CHOP and MACOP-B; 24 Gy whole-brain irradiation (if there was bone-marrow involvement) with PROMACE-CytaBOM; and six intrathecal methotrexate and cytarabine injections (if therewas bone-marrow involvement) with m-BACOD.
b None for DLBCL (but 4.2% of trial population received intrathecal prophylaxis by choice of investigator).c None with CHOP; four intrathecal methotrexate injections during induction followed by consolidation including two courses of high-dose intravenous methotrexate with ACVBP.d Included lymphoblastic and burkitt/burkitt like lymphoma.e Included follicular grade 3 lymphoma.
as administered only in bone marrow remission cases, theates were not statistically different [50].
Another large retrospective study by the German Highrade Non-Hodgkin Lymphoma study group (DSHNHL)n 2999 patients with aggressive lymphoma (including196 DLBCL lymphoma patients), showed that intrathecalethotrexate, high dose etoposide or standard etoposide did
ot reduce CNS recurrence in patients less than 60 yearsld [91]. Even in patients with anaplastic large cell lym-homa, intrathecal methotrexate has been determined to haveo role in prevention of CNS relapse in addition to currentherapy. In a study of 352 children with anaplastic large-ell lymphoma treated with intravenous methotrexate withr without intrathecal methotrexate, only 2 patients experi-nced an isolated CNS recurrence (both in the intrathecalethotrexate group). However, toxicities including grade 3
nd 4 leukopenia (OR 1.6; CI 1.7–3.2; P = 0.012) and grade and 4 mucositis (OR 2.8; CI 1.8–8.1; P = 0.001) were sig-ificantly higher in the intrathecal methotrexate group [92].n another small retrospective study, 26 high risk patientsith intermediate grade NHL receiving CNS prophylaxisith an average of 5 doses of IT MTX ± cytarabine, 6 (23%)NS recurrence were noted, showing inadequacy of IT pro-hylaxis. However, authors also noted that this cohort hadigher than expected CNS relapse rates even if these patientseceived no prophylaxis based on published estimates [23].
A large prospective study on 989 patients studied theole of CNS prophylaxis in DLBCL in the rituximab era, inigh-risk patients identified by involvement of bone marrow,estes and other high risk sites, >1 extranodal sites, higher IPIcore, elevated LDH and stages III/IV [19]. Of the patientsho received CNS prophylaxis, 71.8% received intrathecalethotrexate and/or cytarabine, and 28.2% received systemicethotrexate. After median follow up of 2.5 years, only 2%
95% CI 1.1–2.9%) of patients experienced CNS recurrences;5% were parenchymal only, and 70% were isolated events.nterestingly, among all patients who had high-intermediater high IPI scores, which were associated with increasedisk of CNS events (3.7%; P = 0.02), there was a signif-cantly higher incidence of relapse in those who receivedrophylaxis (10.9%) compared to those who did not (2.1%;
= 0.007) suggesting better predictor of disease biology iseeded. Among patients with ≥2 high risk factors, the ratef relapse was 2.5% and there was no statistical differenceetween those who received prophylaxis (5.4%) comparedith those who did not (1.4%; P = 0.08). There was no differ-
nce in overall survival or progression free survival betweenhe two groups [19].
The RICOVER-60 is a large prospective randomized clin-cal trial in which 1222 patients aged 61–80 years withggressive B-cell lymphomas were studied to assess theffectiveness of rituximab by comparing 6–8 cycles of R-
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
HOP14 versus CHOP14. Although the protocol requiredNS prophylaxis with 4 cycles of intrathecal methotrexate for
estes, bone marrow involvement or head/neck lymphomas,3% of patients with these features did not receive it due
opcb
gy/Hematology xxx (2014) xxx–xxx 7
o physician preference. 2.5% of patients who received CNSrophylaxis had a CNS event compared with 4.4% of patientsithout prophylaxis (a non-significant difference). Thereas no difference in the incidence of CNS relapse betweenatients treated with or without intrathecal methotrexaten the R-CHOP group. There was a trend toward protec-ive effect of intrathecal methotrexate in the CHOP group15].
The evidence in favor of effectiveness of CNS prophy-axis comes from several other studies however most ofhese studies are retrospective or small single institutionrospective studies. The question of most effective and leastoxic method of delivering CNS prophylaxis, i.e. intravenouss. intrathecal or combination is also largely unanswerednd large scale randomized clinical trials are needed com-aring systemic to intrathecal chemoprophylaxis. In oneeport from the GELA group, 974 patients with aggres-ive lymphoma in complete remission who received CNSrophylaxis consisting of intrathecal methotrexate (15 mger injection) performed between day 1 and day 5 of eachycle of ACVBP (doxorubicin, cyclophosphamide, vinde-ine, bleomycine, and prednisone) as well as two coursesf intravenous methotrexate at a dosage of 3 g/m2, were ana-yzed for rate of CNS relapse and compared to historic control5% risk of CNS relapse). The incidence of isolated CNSelapse in this study was 1.6%. Multivariate analysis showedhat higher IPI was significantly associated with a higherisk of CNS relapse (low-low intermediate: 0.6% versusigh–high intermediate: 4.1%, P = 0.002; RR = 7) [41].
In a retrospective study from Royal Marsden Hospital Sut-on, 51 out of 259 consecutive DLBCL patients receivedntrathecal methotrexate prophylaxis based on lymphomanvolvement at the following sites: bone marrow, testes,asal/paranasal sinuses, orbits, bone/vertebrae and periph-ral blood. Three patients (1.1%) subsequently developedNS relapse. The authors concluded that in a homogeneousroup of DLBCL patients, a relatively low-intensity intrathe-al chemoprophylaxis regimen given according to site-basedisk can be associated with a low risk of CNS relapse [26].
A retrospective study showed that among 65 patients withLBCL and CNS risk factors who were given intravenousethotrexate with R-CHOP, only 2 (3%) had CNS relapse
fter median follow up of 33 months [65]. Tilly et al. studiedCVBP versus CHOP regimens in aggressive lymphomas inlderly patients. The ACVBP regimen consisted of induc-ion courses of doxorubicin, cyclophosphamide, vindesin,leomycin, prednisone and intrathecal methotrexate followedy consolidation with intravenous methotrexate, etoposide,fosfamide and cytosine-arabinoside. There was a 2.8% ratef CNS relapse in the ACVBP group versus 8.3% in theHOP group with 5-year overall survival rates of 46% and8%, respectively (P = 0.036) [25]. A recent phase 2 study
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
n 156 high risk DLBCL and grade 3 Follicular lymphomaatients < 65 years age, treated with dose dense R-CHOEPhemotherapy and systemic CNS prophylaxis with IV cytara-ine and methotrexate showed a CNS relapse rate of 4.5%
72]. These studies do suggest a potential role, although smallor systemic chemoprophylaxis in the high risk patients.
Intrathecal chemoprophylaxis alone or in combinationith high dose intravenous methotrexate therapy and irra-iation of contralateral testis following orchiectomy isommonly used for patients with primary testicular lym-homa [27,93,94]. Two small studies suggested no benefitrom IT chemoprophylaxis alone in preventing CNS recur-ence [95,96]. In a study by Aviles et al., 34 patients withesticular lymphoma were treated with high dose methotrex-te 6 g/m2, and 6 cycles of anthracycline-based chemotherapylong with local irradiation. There were no instances of CNSelapse after a median follow up of 74 months, although thereas higher toxicity with methotrexate [97]. Studies have
hown that intrathecal therapy alone decreases the risk ofNS relapse in patients with primary testicular lymphoma,lthough it does not eliminate the risk completely [98,99]. Inur practice we recommend combination of intrathecal andystemic chemoprophylaxis to most patients with testicularnvolvement.
Although studies have shown high risk of CNS involve-ent in patients carrying the myc oncogene rearrangement
r both myc and bcl2 rearrangement, no conclusive evidences available regarding the effectiveness of CNS prophylaxisn these patients. As per NCCN guidelines, it is not unrea-onable to treat these double hit lymphomas with a moreggressive regimen. Hence it can be postulated that CNS pro-
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
hylaxis is needed to be included in the treatment regimen.urther studies are necessary to establish the usefulness ofNS prophylaxis in this population.
nda
Fig. 1. Suggested algorithm for proph
gy/Hematology xxx (2014) xxx–xxx
. Conclusion
Studies in the pre-rituximab era have shown conflictingvidence on the role of intrathecal CNS prophylaxis in high-isk patients with DLBCL, except in patients with testicularnvolvement. Large studies like the SWOG 8516 showedo added benefit from CNS prophylaxis with intrathecalethotrexate, cytarabine or whole brain irradiation. In the
ituximab era, studies have shown decreased CNS relapse,ikely due to better systemic disease control as rituximab doesot cross the blood brain barrier.
We need to better identify patients at high-risk of CNSelapse or occult CNS involvement using appropriate CNStaging, and treat these patients preferably with a combina-ion of intrathecal and high-dose intravenous CNS directedherapy to improve their outcomes. Patients with a combina-ion of the following variables can be considered high risk forNS relapse: higher IPI scores, elevated LDH, involvementf >1 extra nodal site, involvement of testes, breast, paranasalinuses, parameninges, bone, bone marrow, kidneys, adrenallands, or retroperitoneal lymph nodes.
National Comprehensive Cancer Network (NCCN) guide-ines recommend that when patients are considered for CNSrophylaxis, possible options include 4–8 doses of intrathe-al methotrexate and/or cytarabine, or systemic methotrexate–3.5 g/m2 during the course of treatment. We propose achema (Figure 1) that is designed to avoid exposing a large
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
umber of patients to the toxicities associated with CNSirected therapies who will not benefit from the treatment,nd to provide appropriate CNS directed therapy to patients
ho are at increased risk for developing CNS involvement.here still exist groups that are considered high-risk basedn conventional clinical features, but for whom benefit ofNS directed chemoprophylaxis is uncertain due to insuf-cient evidence in the rituximab era. These patients can be
reated by systemic chemoprophylaxis with or without ITrophylaxis on an individual basis especially when combi-ations of risk factors are present. The expertise/experiencef the treating physician and the institution should be takennto account when considering systemic chemoprophylaxis,s it requires close monitoring of drug levels, toxicities andiving timely leucovorin rescue. The role of CNS directedherapy for patients carrying high-risk biologic markers likeyc translocation needs to be studied further, as some small
tudies have suggested a role for more intensive systemicherapy like ACVBP, R-CHOEP, or systemic methotrexaten these high risk patients. Large scale randomized clinicalrials are needed to validate these approaches.
uthor contributions
Dr. A. Ghose did the review of literature, wrote the paper,reated the table, and helped with submission. Dr. R. Kunduid the review, helped in writing the paper and table. Dr. T.atif conceptualized the design, did the review, helped write
he paper and submitted paper as corresponding author.
onflict of interest
There is no conflict of interest nor any other disclosures.
unding
No funding received for this work.
eviewers
Assistant Professor Richard Curry, MD, The Vontz Centeror Molecular Studies, 3125 Eden Ave, RM 1330, ML 0562,incinnati, OH 45267, United States.
Professor Lorenz Trümper, Chairman, Georg-August Uni-ersity, Göttingen, Dept. of Hematology and Oncology,obert-Koch-Str. 40, D-37099 Göttingen, Germany.
cknowledgement
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
We appreciate the help of Judy Racadio in scientific editingf the manuscript.
[
gy/Hematology xxx (2014) xxx–xxx 9
eferences
[1] Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The2008 WHO classification of lymphoid neoplasms and beyond: evolvingconcepts and practical applications. Blood 2011;117:5019–32.
[2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA CancerJ Clin 2013;63:11–30.
[3] Ziepert M, Hasenclever D, Kuhnt E, et al. Standard international pro-gnostic index remains a valid predictor of outcome for patients withaggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol2010;28:2373–80.
[4] Recht L, Straus DJ, Cirrincione C, Thaler HT, Posner JB. Central ner-vous system metastases from non-Hodgkin’s lymphoma: treatment andprophylaxis. Am J Med 1988;84:425–35.
[5] Bashir RM, Bierman PJ, Vose JM, Weisenburger DD, Armitage JO.Central nervous system involvement in patients with diffuse aggressivenon-Hodgkin’s lymphoma. Am J Clin Oncol 1991;14:478–82.
[6] Zinzani PL, Magagnoli M, Frezza G, et al. Isolated central nervoussystem relapse in aggressive non-Hodgkin’s lymphoma: the Bolognaexperience. Leuk Lymphoma 1999;32:571–6.
[7] Tomita N, Kodama F, Sakai R, et al. Predictive factors for centralnervous system involvement in non-Hodgkin’s lymphoma: signifi-cance of very high serum LDH concentrations. Leuk Lymphoma2000;38:335–43.
[8] Jahnke K, Thiel E, Martus P, Schwartz S, Korfel A. Retrospective studyof prognostic factors in non-Hodgkin lymphoma secondarily involvingthe central nervous system. Ann Hematol 2006;85:45–50.
[9] Bjorkholm M, Hagberg H, Holte H, et al. Central nervous system occur-rence in elderly patients with aggressive lymphoma and a long-termfollow-up. Ann Oncol 2007;18:1085–9.
10] Feugier P, Virion JM, Tilly H, et al. Incidence and risk factors for centralnervous system occurrence in elderly patients with diffuse large-B-celllymphoma: influence of rituximab. Ann Oncol 2004;15:129–33.
11] Bollen EL, Brouwer RE, Hamers S, et al. Central nervous systemrelapse in non-Hodgkin lymphoma. A single-center study of 532patients. Arch Neurol 1997;54:854–9.
12] Hollender A, Kvaloy S, Lote K, Nome O, Holte H. Prognostic factorsin 140 adult patients with non-Hodgkin’s lymphoma with systemiccentral nervous system (CNS) involvement. A single centre analysis.Eur J Cancer 2000;36:1762–8.
13] Gleissner B, Chamberlain M. Treatment of CNS dissemination in sys-temic lymphoma. J Neurooncol 2007;84:107–17.
14] Villa D, Connors JM, Shenkier TN, Gascoyne RD, Sehn LH, SavageKJ. Incidence and risk factors for central nervous system relapse inpatients with diffuse large B-cell lymphoma: the impact of the additionof rituximab to CHOP chemotherapy. Ann Oncol 2010;21:1046–52.
15] Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M.CNS events in elderly patients with aggressive lymphoma treatedwith modern chemotherapy (CHOP-14) with or without rituximab:an analysis of patients treated in the RICOVER-60 trial of the Ger-man High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).Blood 2009;113:3896–902.
16] Bierman P, Giglio P. Diagnosis and treatment of central nervous systeminvolvement in non-Hodgkin’s lymphoma. Hematol Oncol Clin NorthAm 2005;19:597–609, v.
17] Hegde U, Filie A, Little RF, et al. High incidence of occult lep-tomeningeal disease detected by flow cytometry in newly diagnosedaggressive B-cell lymphomas at risk for central nervous systeminvolvement: the role of flow cytometry versus cytology. Blood2005;105:496–502.
18] Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Cen-tral nervous system involvement following diagnosis of non-Hodgkin’slymphoma: a risk model. Ann Oncol 2002;13:1099–107.
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
19] Kumar A, Vanderplas A, LaCasce AS, et al. Lack of benefit of cen-tral nervous system prophylaxis for diffuse large B-cell lymphomain the rituximab era: findings from a large national database. Cancer2012;118:2944–51.
20] Tomita N, Yokoyama M, Yamamoto W, et al. Central nervous systemevent in patients with diffuse large B-cell lymphoma in the rituximabera. Cancer Sci 2012;103:245–51.
21] Lim HY, Thiel E, Glantz MJ. To protect and defend: central nervoussystem prophylaxis in patients with non-Hodgkin’s lymphoma. CurrOpin Oncol 2008;20:495–501.
22] Perez-Soler R, Smith TL, Cabanillas F. Central nervous system prophy-laxis with combined intravenous and intrathecal methotrexate in diffuselymphoma of aggressive histologic type. Cancer 1986;57:971–7.
23] Chua SL, Seymour JF, Streater J, Wolf MM, Januszewicz EH, PrinceHM. Intrathecal chemotherapy alone is inadequate central nervous sys-tem prophylaxis in patients with intermediate-grade non-Hodgkin’slymphoma. Leuk Lymphoma 2002;43:1783–8.
24] Tomita N, Kodama F, Kanamori H, Motomura S, Ishigatsubo Y. Pro-phylactic intrathecal methotrexate and hydrocortisone reduces centralnervous system recurrence and improves survival in aggressive non-hodgkin lymphoma. Cancer 2002;95:576–80.
25] Tilly H, Lepage E, Coiffier B, et al. Intensive conventionalchemotherapy (ACVBP regimen) compared with standard CHOPfor poor-prognosis aggressive non-Hodgkin lymphoma. Blood2003;102:4284–9.
26] Arkenau HT, Chong G, Cunningham D, et al. The role of intrathecalchemotherapy prophylaxis in patients with diffuse large B-cell lym-phoma. Ann Oncol 2007;18:541–5.
27] Zucca E, Conconi A, Mughal TI, et al. Patterns of outcome and pro-gnostic factors in primary large-cell lymphoma of the testis in a surveyby the International Extranodal Lymphoma Study Group. J Clin Oncol2003;21:20–7.
28] Herrlinger U, Glantz M, Schlegel U, Gisselbrecht C, Cavalli F. Shouldintra-cerebrospinal fluid prophylaxis be part of initial therapy forpatients with non-Hodgkin lymphoma: what we know, and how wecan find out more. Semin Oncol 2009;36:S25–34.
29] Hill QA, Owen RG. CNS prophylaxis in lymphoma: who to target andwhat therapy to use. Blood Rev 2006;20:319–32.
30] Smith JA, Glantz M. Statistical and trial design considerations in centralnervous system prophylaxis studies. Semin Oncol 2009;36:S69–76.
31] Shimazu Y, Notohara K, Ueda Y. Diffuse large B-cell lymphoma withcentral nervous system relapse: prognosis and risk factors according toretrospective analysis from a single-center experience. Int J Hematol2009;89:577–83.
32] Yamamoto W, Tomita N, Watanabe R, et al. Central nervous sys-tem involvement in diffuse large B-cell lymphoma. Eur J Haematol2010;85:6–10.
33] Tai WM, Chung J, Tang PL, et al. Central nervous system (CNS) relapsein diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab.Ann Hematol 2011;90:809–18.
34] Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cyclesof bi-weekly CHOP-14 with or without rituximab in elderly patientswith aggressive CD20+ B-cell lymphomas: a randomised controlledtrial (RICOVER-60). Lancet Oncol 2008;9:105–16.
35] Levitt LJ, Dawson DM, Rosenthal DS, Moloney WC. CNS involvementin the non-Hodgkin’s lymphomas. Cancer 1980;45:545–52.
36] Keldsen N, Michalski W, Bentzen SM, Hansen KB, Thorling K.Risk factors for central nervous system involvement in non-Hodgkins-lymphoma—a multivariate analysis. Acta Oncol 1996;35:703–8.
37] Bos GM, van Putten WL, van der Holt B, van den Bent M, Verdonck LF,Hagenbeek A. For which patients with aggressive non-Hodgkin’s lym-phoma is prophylaxis for central nervous system disease mandatory?Dutch HOVON Group. Ann Oncol 1998;9:191–4.
38] Ersboll J, Schultz HB, Thomsen BL, Keiding N, Nissen NI. Meningealinvolvement in non-Hodgkin’s lymphoma: symptoms, incidence, riskfactors and treatment. Scand J Haematol 1985;35:487–96.
39] Wolf MM, Olver IN, Ding JC, Cooper IA, Liew KH, Madigan JP. Non-
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
Hodgkin’s lymphoma involving the central nervous system. Aust N ZJ Med 1985;15:16–21.
40] van Besien K, Ha CS, Murphy S, et al. Risk factors, treat-ment, and outcome of central nervous system recurrence in
[
gy/Hematology xxx (2014) xxx–xxx
adults with intermediate-grade and immunoblastic lymphoma. Blood1998;91:1178–84.
41] Haioun C, Besson C, Lepage E, et al. Incidence and risk factors of cen-tral nervous system relapse in histologically aggressive non-Hodgkin’slymphoma uniformly treated and receiving intrathecal central nervoussystem prophylaxis: a GELA study on 974 patients. Groupe d’Etudesdes Lymphomes de l’Adulte. Ann Oncol 2000;11:685–90.
42] Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lym-phomas. Blood 2011;117:2319–31.
43] Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rear-rangements are associated with a poor prognosis in diffuse largeB-cell lymphoma patients treated with R-CHOP chemotherapy. Blood2009;114:3533–7.
44] Kramer MH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2,BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.Blood 1998;92:3152–62.
45] Guirguis HR, Cheung MC, Mahrous M, et al. Impact of central nervoussystem (CNS) prophylaxis on the incidence and risk factors for CNSrelapse in patients with diffuse large B-cell lymphoma treated in therituximab era: a single centre experience and review of the literature.Br J Haematol 2012;159:39–49.
46] Stein H. The new WHO classification of malignant lymphoma. After“REAL” a further step on the road to a worldwide consensus. DerPathologe 2000;21:101–5.
47] Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM.A gene expression-based method to diagnose clinically distinct sub-groups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA2003;100:9991–6.
48] Montesinos-Rongen M, Brunn A, Bentink S, et al. Gene expressionprofiling suggests primary central nervous system lymphomas to bederived from a late germinal center B cell. Leukemia 2008;22:400–5.
49] Kridel R, Dietrich PY. Prevention of CNS relapse in diffuse large B-celllymphoma. Lancet Oncol 2011;12:1258–66.
50] Bernstein SH, Unger JM, Leblanc M, Friedberg J, Miller TP, FisherRI. Natural history of CNS relapse in patients with aggressivenon-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG8516—the Southwest Oncology Group. J Clin Oncol 2009;27:114–9.
51] Fonseca R, Habermann TM, Colgan JP, et al. Testicular lymphomais associated with a high incidence of extranodal recurrence. Cancer2000;88:154–61.
52] Doolittle ND, Abrey LE, Shenkier TN, et al. Brain parenchymainvolvement as isolated central nervous system relapse of systemicnon-Hodgkin lymphoma: an International Primary CNS LymphomaCollaborative Group report. Blood 2008;111:1085–93.
53] Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells incerebrospinal fluid (CSF): the meaning of a positive CSF cytology.Neurology 1979;29:1369–75.
54] Ward MS. The use of flow cytometry in the diagnosis and monitoringof malignant hematological disorders. Pathology 1999;31:382–92.
55] French CA, Dorfman DM, Shaheen G, Cibas ES. Diagnosinglymphoproliferative disorders involving the cerebrospinal fluid:increased sensitivity using flow cytometric analysis. Diagn Cytopathol2000;23:369–74.
56] Bromberg JE, Breems DA, Kraan J, et al. CSF flow cytometry greatlyimproves diagnostic accuracy in CNS hematologic malignancies. Neu-rology 2007;68:1674–9.
57] Quijano S, Lopez A, Manuel Sancho J, et al. Identification of lep-tomeningeal disease in aggressive B-cell non-Hodgkin’s lymphoma:improved sensitivity of flow cytometry. J Clin Oncol 2009;27:1462–9.
58] Roma AA, Garcia A, Avagnina A, Rescia C, Elsner B. Lymphoidand myeloid neoplasms involving cerebrospinal fluid: comparison ofmorphologic examination and immunophenotyping by flow cytometry.Diagn Cytopathol 2002;27:271–5.
60] Kros JM, Bagdi EK, Zheng P, et al. Analysis of immunoglobulin Hgene rearrangement by polymerase chain reaction in primary centralnervous system lymphoma. J Neurosurg 2002;97:1390–6.
61] Ekstein D, Ben-Yehuda D, Slyusarevsky E, Lossos A, Linetsky E,Siegal T. CSF analysis of IgH gene rearrangement in CNS lym-phoma: relationship to the disease course. J Neurol Sci 2006;247:39–46.
62] Bartel DP. MicroRNAs: target recognition and regulatory functions.Cell 2009;136:215–33.
63] Baraniskin A, Kuhnhenn J, Schlegel U, et al. Identification of microR-NAs in the cerebrospinal fluid as marker for primary diffuse largeB-cell lymphoma of the central nervous system. Blood 2011;117:3140–6.
64] Gokbuget N, Hartog CM, Bassan R, et al. Liposomal cytarabine is effec-tive and tolerable in the treatment of central nervous system relapse ofacute lymphoblastic leukemia and very aggressive lymphoma. Haema-tologica 2011;96:238–44.
65] Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrexateas central nervous system (CNS) prophylaxis is associated with a lowrisk of CNS recurrence in high-risk patients with diffuse large B-celllymphoma. Cancer 2010;116:4283–90.
66] Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intra-ventricular administration of chemotherapy in patients with neoplasticmeningitis. Clin Pharmacokinet 2005;44:1–31.
67] Cheung CW, Burton C, Smith P, Linch DC, Hoskin PJ, Ardeshna KM.Central nervous system chemoprophylaxis in non-Hodgkin lymphoma:current practice in the UK. Br J Haematol 2005;131:193–200.
68] Vassal G, Valteau D, Bonnay M, Patte C, Aubier F, Lemerle J. Cere-brospinal fluid and plasma methotrexate levels following high-doseregimen given as a 3-hour intravenous infusion in children with non-Hodgkin’s lymphoma. Pediatr Hematol Oncol 1990;7:71–7.
69] Lippens RJ, Winograd B. Methotrexate concentration levels in the cere-brospinal fluid during high-dose methotrexate infusions: an unreliableprediction. Pediatr Hematol Oncol 1988;5:115–24.
70] Lin XB, Zhou NN, Li S, et al. Effects of infusion duration of high-dosemethotrexate on cerebrospinal fluid drug levels in lymphoma patients.Ai Zheng 2008;27:1100–5.
71] Millot F, Rubie H, Mazingue F, Mechinaud F, Thyss A. Cerebrospinalfluid drug levels of leukemic children receiving intravenous 5 g/m2
methotrexate. Leuk Lymphoma 1994;14:141–4.72] Holte H, Leppa S, Bjorkholm M, et al. Dose-densified chemoim-
munotherapy followed by systemic central nervous system prophylaxisfor younger high-risk diffuse large B-cell/follicular grade 3 lymphomapatients: results of a phase II Nordic Lymphoma Group study. AnnOncol 2013;24:1385–92.
74] Chamberlain MC, Kormanik P, Howell SB, Kim S. Pharmacokinetics ofintralumbar DTC-101 for the treatment of leptomeningeal metastases.Arch Neurol 1995;52:912–7.
76] Rubenstein JL, Combs D, Rosenberg J, et al. Rituximab therapy forCNS lymphomas: targeting the leptomeningeal compartment. Blood2003;101:466–8.
77] Schulz H, Pels H, Schmidt-Wolf I, Zeelen U, Germing U, EngertA. Intraventricular treatment of relapsed central nervous systemlymphoma with the anti-CD20 antibody rituximab. Haematologica2004;89:753–4.
78] Antonini G, Cox MC, Montefusco E, et al. Intrathecal anti-CD20 anti-body: an effective and safe treatment for leptomeningeal lymphoma. JNeurooncol 2007;81:197–9.
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
79] Pels H, Schulz H, Manzke O, Hom E, Thall A, Engert A. Intraventricularand intravenous treatment of a patient with refractory primary CNSlymphoma using rituximab. J Neurooncol 2002;59:213–6.
gy/Hematology xxx (2014) xxx–xxx 11
80] Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraven-tricular administration of rituximab in patients with recurrent CNS andintraocular lymphoma. J Clin Oncol 2007;25:1350–6.
81] Rubenstein JL, Li J, Chen L, et al. Multicenter phase 1 trial of intra-ventricular immunochemotherapy in recurrent CNS lymphoma. Blood2013;121:745–51.
82] Said JA, Waters BG, Cousens P, Stevens MM. Neuropsychologi-cal sequelae of central nervous system prophylaxis in survivors ofchildhood acute lymphoblastic leukemia. J Consult Clin Psychol1989;57:251–6.
83] Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults.Semin Oncol 2004;31:702–13.
84] Tucker J, Prior PF, Green CR, et al. Minimal neuropsychologi-cal sequelae following prophylactic treatment of the central nervoussystem in adult leukaemia and lymphoma. Br J Cancer 1989;60:775–80.
85] Armon C, Evans RW. Therapeutics, Technology Assessment Subcom-mittee of the American Academy of N. Addendum to assessment:prevention of post-lumbar puncture headaches: report of the Thera-peutics and Technology Assessment Subcommittee of the AmericanAcademy of Neurology. Neurology 2005;65:510–2.
86] Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med2005;352:1791–8.
87] Blaney SM, Poplack DG, Godwin K, McCully CL, Murphy R, BalisFM. Effect of body position on ventricular CSF methotrexate concen-tration following intralumbar administration. J Clin Oncol 1995;13:177–9.
88] Boehme V, Zeynalova S, Kloess M, et al. Incidence and risk factorsof central nervous system recurrence in aggressive lymphoma—a sur-vey of 1693 patients treated in protocols of the German High-GradeNon-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol2007;18:149–57.
89] Buckstein R, Lim W, Franssen E, Imrie KL. CNS prophylaxis and treat-ment in non-Hodgkin’s lymphoma: variation in practice and lessonsfrom the literature. Leuk Lymphoma 2003;44:955–62.
90] MacKintosh FR, Colby TV, Podolsky WJ, et al. Central nervous systeminvolvement in non-Hodgkin’s lymphoma: an analysis of 105 cases.Cancer 1982;49:586–95.
91] Schmitz N, Zeynalova S, Glass B, et al. CNS disease in younger patientswith aggressive B-cell lymphoma: an analysis of patients treatedon the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Ann Oncol 2012;23:1267–73.
92] Brugieres L, Le Deley MC, Rosolen A, et al. Impact of the methotrexateadministration dose on the need for intrathecal treatment in chil-dren and adolescents with anaplastic large-cell lymphoma: results ofa randomized trial of the EICNHL Group. J Clin Oncol 2009;27:897–903.
93] Shahab N, Doll DC. Testicular lymphoma. Semin Oncol1999;26:259–69.
94] Ahmad SS, Idris SF, Follows GA, Williams MV. Primary testicularlymphoma. Clin Oncol (R Coll Radiol) 2012;24:358–65.
95] Zouhair A, Weber D, Belkacemi Y, et al. Outcome and patterns of failurein testicular lymphoma: a multicenter Rare Cancer Network study. IntJ Radiat Oncol Biol Phys 2002;52:652–6.
96] Seymour JF, Solomon B, Wolf MM, Janusczewicz EH, Wirth A, PrinceHM. Primary large-cell non-Hodgkin’s lymphoma of the testis: a ret-rospective analysis of patterns of failure and prognostic factors. ClinLymphoma 2001;2:109–15.
97] Aviles A, Neri N, Huerta-Guzman J, Perez F, Fernandez R. Testi-cular lymphoma: organ-specific treatment did not improve outcome.Oncology 2004;67:211–4.
98] Vitolo U, Chiappella A, Ferreri AJ, et al. First-line treatment for pri-
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
mary testicular diffuse large B-cell lymphoma with rituximab-CHOP,CNS prophylaxis, and contralateral testis irradiation: final results of aninternational phase II trial. J Clin Oncol 2011;29:2766–72.
dassistant in the Division of Hematology/Oncology, Univer-sity of Cincinnati. Her academic interest is clinical researchin malignant hematology.
2 A. Ghose et al. / Critical Reviews in
99] Park BB, Kim JG, Sohn SK, et al. Consideration of aggressive ther-apeutic strategies for primary testicular lymphoma. Am J Hematol2007;82:840–5.
iographies
Tahir Latif, MBBS, MBA, is Interim Chief of the Divi-ion of Hematology/Oncology and Associate Professor atniversity of Cincinnati College of Medicine. His academic
nterests include clinical and translational research in malig-
Please cite this article in press as: Ghose A, et al. Prophylactic CNS direOncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.02.0
ant hematology and GI malignancies, process improvementn health care delivery especially chemotherapy infusion, andesidency/fellowship education.
gy/Hematology xxx (2014) xxx–xxx
Abhimanyu Ghose, MBBS, MD is a fellow physiciann the Division of Hematology/Oncology at University ofincinnati with academic interest in malignant hematologyspecially clinical and translational research in lymphoma,eukemia and myeloma.
Ria Kundu, MBBS, MD, is an internal medicine resi-ent in Good Samaritan Hospital, Cincinnati, and research
cted therapy in systemic diffuse large B cell lymphoma. Crit Rev06
