Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis.

Non-Hodgkin lymphomas are biologically and clinically diverse hematological malignancies. Treatment is influenced by patient fitness, disease biology, and tumor burden. Identifying patients at high risk of central nervous system (CNS) relapse is important as the outcome of secondary CNS lymphoma is poor.1-4  Risk of CNS progression is influenced by histologic subtype and subtype-specific clinicopathologic features (eg, site of involvement, protein expression, or gene rearrangements). Patients with highly aggressive lymphomas (eg, lymphoblastic, Burkitt lymphoma) are at high risk and frontline protocols include CNS-directed prophylaxis. In contrast, indolent lymphomas rarely involve the CNS and CNS prophylaxis is not required. Between these extremes fall diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL) with MYC and BCL2 or BCL6 rearrangements, so-called “double-hit” lymphomas (HGBL-DH), and (nodal) peripheral T-cell lymphomas (PTCLs). The addition of rituximab has slightly reduced CNS relapse in DLBCL, probably through superior systemic control as there is negligible CNS penetration of the drug across the intact blood-brain barrier.1,5  However, ∼4% of unselected patients with DLBCL treated with prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-CHOP) experience CNS relapse,6,7  and considerable efforts have been made to identify those at greatest risk. In this review, we will summarize our approach to this problem with case vignettes drawn from our practice.

Many investigators have examined risk factors for CNS relapse, but studies have yielded inconsistent results, due to heterogeneity in patient populations, treatment, and/or limited sample size.8-16  To address some of these limitations, Schmitz et al developed a 6-point score from 2164 patients treated on prospective German studies and validated in 1597 patients with DLBCL treated with R-CHOP in the British Columbia Cancer Agency (BCCA) Lymphoid Malignancies Database.6  The components of the score were the International Prognostic Index (IPI) factors: age > 60 years, elevated serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) status > 1, stage III/IV, >1 extranodal site, with the addition of kidney/adrenal involvement. The resulting “CNS-IPI” separates patients into low- (0-1 factor), intermediate- (2-3), and high- (4+) risk groups with 2-year CNS relapse rates of 0.6%, 3.4%, and 10.2%, respectively. This provides a robust and readily calculable risk estimate in patients with DLBCL that has been externally validated in another independent cohort of 1532 patients with similar results (Figure 1A).7  Despite its strengths, it remains imperfect with low positive predictive value (10%-12%). Thus, if used to select patients for prophylaxis, most patients unnecessarily receive CNS prophylaxis. Other factors including the involvement of other specific anatomic sites (Figure 2) and biologic factors have been identified in separate studies as predictive of CNS relapse and warrant specific consideration. A summary of the factors we consider when assessing CNS risk is presented in Table 1.6,16-29 

Figure 1.

Cumulative incidence of CNS relapse among 1532 patients with DLBCL. (A) Patients were treated with R-CHOP–like regimens according to CNS-IPI and (B) number of extranodal sites was determined by PET-CT. Reprinted from El-Galaly et al7  with permission.

Figure 1.

Cumulative incidence of CNS relapse among 1532 patients with DLBCL. (A) Patients were treated with R-CHOP–like regimens according to CNS-IPI and (B) number of extranodal sites was determined by PET-CT. Reprinted from El-Galaly et al7  with permission.

Figure 2.

Specific extranodal sites associated with increased risk of CNS relapse.

Figure 2.

Specific extranodal sites associated with increased risk of CNS relapse.

Table 1.

Risk stratification for secondary CNS involvement in non-Hodgkin lymphoma integrating histologic, clinical, and molecular factors

Histologic subtypeHistologic subtype-specific risk factorsApproximate CNS relapse risk
DLBCL CNS-IPI ≥ 46  10% at 2 y 
or involvement of breast,17  testis,18  uterus,19  epidural,20,21  kidney/adrenals6,16  Varies by site 
MYC/BCL2 DE DLBCL, particularly if ABC subtype22  10% at 2 y (15% if ABC COO) 
CD5+ DLBCL23  12.7% at 2 y 
Intravascular large B-cell lymphoma24  25% at 3 y 
IgM-secreting DLBCL25  41% cumulative incidence (7 of 17) 
HGBL with MYC and BCL2 and/or BCL6 rearrangements26   13% at 3 y 
MCL Blastoid histology or Ki-67 ≥ 30%27  25.4% at 2 y 
PTCL (PTCL-NOS, AITL, ALCL) >1 extranodal site, skin or gastrointestinal involvement28  ∼10% at 2 y 
ALK+ ALCL >1 extranodal site29  1-y 15% 
Histologic subtypeHistologic subtype-specific risk factorsApproximate CNS relapse risk
DLBCL CNS-IPI ≥ 46  10% at 2 y 
or involvement of breast,17  testis,18  uterus,19  epidural,20,21  kidney/adrenals6,16  Varies by site 
MYC/BCL2 DE DLBCL, particularly if ABC subtype22  10% at 2 y (15% if ABC COO) 
CD5+ DLBCL23  12.7% at 2 y 
Intravascular large B-cell lymphoma24  25% at 3 y 
IgM-secreting DLBCL25  41% cumulative incidence (7 of 17) 
HGBL with MYC and BCL2 and/or BCL6 rearrangements26   13% at 3 y 
MCL Blastoid histology or Ki-67 ≥ 30%27  25.4% at 2 y 
PTCL (PTCL-NOS, AITL, ALCL) >1 extranodal site, skin or gastrointestinal involvement28  ∼10% at 2 y 
ALK+ ALCL >1 extranodal site29  1-y 15% 

ABC, activated B cell; AITL, angiommunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; HGBL, high-grade B-cell lymphoma; IgM, immunoglobulin M; MCL, mantle cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified.

Case 1

Presentation.

A 78-year-old retired nurse presented with hematemesis. At endoscopy, a gastric tumor was biopsied and showed non–germinal center B-cell (GCB) DLBCL (by Hans algorithm).30  A staging positron emission tomography with computed tomography (PET-CT) scan identified widespread lymphadenopathy and involvement of the adrenal glands, kidneys, and bone. She did not have signs or symptoms suggestive of CNS involvement. Her ECOG was 2 and LDH elevated (IPI = 5, CNS-IPI = 6). Examination of the blood film and peripheral blood lymphocyte immunophenotyping excluded circulating lymphoma cells. Cerebrospinal fluid (CSF) cytology (CC) and flow cytometry (FCM) were negative for lymphoma.

Discussion.

The decision to offer CNS prophylaxis to this patient was straightforward. Her predicted 2-year CNS risk of 10.2% using the CNS-IPI model was likely an underestimate. In fact, for the 0.6% of patients with the maximum CNS-IPI score of 6, the 2-year risk of CNS relapse was 32.5%.6  We always send CSF for CC and FCM as the use of FCM increases the sensitivity of detecting lymphoma in this compartment.31  Occult leptomeningeal disease (CC/FCM+) is associated with markedly increased risk of frank CNS progression and warrants aggressive CNS-directed therapy.32,33 

Outcome.

We commenced prephase prednisone followed by R-CHOP given every 21 days (R-CHOP21) for 6 cycles with 1 dose of intrathecal methotrexate (IT MTX) per cycle. In addition, 2 cycles of systemic MTX were administered (with rituximab, total of 8 doses) at a reduced dose of 1 g/m2 due to her age. She achieved complete metabolic response (CMR) at the end of treatment, but unfortunately experienced nodal disease relapse with B symptoms and retroperitoneal and mediastinal lymphadenopathy 9 months later. Her disease was refractory to second-line chemotherapy. She was offered participation in a clinical trial and remains on study with stable disease after 4 months on the investigational agent.

Case 2

Presentation.

A 45-year-old female lawyer presented with a painless right breast lump and subsequently underwent a core biopsy. Histopathology confirmed DLBCL with non-GCB phenotype (by Hans algorithm). The contralateral breast was normal by clinical examination and ultrasound; PET-CT confirmed ipsilateral breast involvement only (stage IAE or primary breast lymphoma). Her ECOG status was 0, LDH normal (IPI = 0 and CNS-IPI = 0).

Discussion.

Certain anatomic sites of extranodal involvement of DLBCL are strongly associated with CNS relapse, even when the CNS-IPI is low.34  Although the kidney/adrenals were independent predictors in the CNS-IPI, extranodal sites identified in other datasets (epidural, breast, uterus, and testes) were not. This is probably explained by underrepresentation of such patients from prospective studies. For instance, many patients with epidural involvement require emergent radiotherapy to treat impending spinal cord compression precluding clinical trial participation, and patients with stage IE lymphomas are excluded from many protocols. The propensity for primary testicular lymphoma to disseminate to the CNS is well described18,35,36 ; a specific treatment protocol was shown in a prospective phase 2 study to result in an apparent reduction in CNS risk relative to historic controls.37  In contrast, the association between primary breast lymphoma and CNS relapse is underappreciated, despite data suggesting crude incidence of 12% to 16%.17,38,39  Stage IIE disease,17  stage-modified IPI ≥ 2,17  bilateral breast involvement,40  and tumor > 5 cm41  have all been observed in individual studies to be potential risk factors for CNS involvement, but the findings have not been consistently replicated. Epidural involvement was associated with increased CNS risk in prerituximab case series,42-45  however, contemporary data are lacking. Sinus involvement was associated with marginally increased CNS risk (6% in the prerituximab era) which was reduced to 1.6% when rituximab was incorporated into primary therapy.46,47  El-Galaly et al identified a strong association between uterine (but not ovarian) involvement with DLBCL and CNS risk (hazard ratio, 14.1) by multivariate analysis, independent of the CNS-IPI.19  We offer patients with breast, uterine, testicular, and epidural involvement CNS prophylaxis, irrespective of their CNS-IPI.

Outcome.

Despite the CNS-IPI of 0, we treated this patient with 6 cycles of R-CHOP21 with IT MTX and 2 cycles of high-dose MTX (HD-MTX; 3 g/m2). Consolidative radiotherapy was delivered to the ipsilateral breast and she remains in ongoing remission 4 years from initial presentation.

Case 3

Presentation.

A 68-year-old retired truck driver with comorbidities including chronic obstructive pulmonary disease and ischemic cardiomyopathy (ejection fraction, 35%) presented with asymptomatic lymphadenopathy. Biopsy showed both grade 3B follicular and DLBCL in the same specimen. PET-CT identified widespread lymphadenopathy with bone marrow the only apparent site of extranodal involvement. He had no antecedent history of indolent lymphoma. The ECOG was 0 and LDH normal. He therefore had stage IVA composite lymphoma (IPI = 2, CNS-IPI = 2). However, fluorescence in situ hybridization confirmed rearrangements in MYC, BCL2, and BCL6, that is, “triple-hit” lymphoma. CSF was negative for lymphoma (CC/FCM).

Discussion.

MYC-rearranged non-Burkitt lymphomas have aggressive behavior and poor outcomes with R-CHOP.48  Aggressive lymphomas bearing rearrangements in MYC and BCL2 and/or BCL6 were previously termed “double-hit” lymphomas (DHLs) or “triple-hit” lymphomas with a spectrum in morphology from DLBCL to Burkitt lymphoma. In the World Health Organization (WHO) 2008 classification, many were captured under the provisional entity of “B-cell lymphoma, unclassifiable (BCL-U), with features intermediate between DLCBL and Burkitt lymphoma.”49  In the 2017 update, all aggressive lymphomas (except those with lymphoblastic or follicular lymphoma morphology) bearing rearrangements in MYC and BCL2 and/or BCL6 were reclassified as “high-grade B-cell lymphoma, with MYC and/or BCL2 or BCL6 rearrangements” (HGBL-DH). Although early studies of patients with DLBCL bearing MYC and/or BCL2 rearrangements indicated markedly increased risk of CNS involvement at diagnosis of up to 44%,50,51  2 larger retrospective studies indicated that 4% to 7% of patients had CNS involvement at diagnosis with a 3-year cumulative CNS risk of 13%.26,52  Both studies also suggested use of CNS prophylaxis may improve outcomes: in the first, IT MTX prophylaxis was associated with a reduction in CNS progression (3-year incidence, 5% v 15%; P = .017)26 ; in the second, use of CNS prophylaxis was associated with improvement in overall survival.52  We therefore consider HGBL-DH at high risk of CNS involvement and consider these patients for CNS-directed prophylaxis. The 2017 WHO categories of HGBL-DH and HGBL not otherwise specified (HGBL-NOS) have created difficulty in applying evidence from older datasets (based on the superseded BCL-U). We are unaware of specific data examining the risk of CNS progression in HGBL-NOS (ie, without MYC translocations). However, we continue to recommend CNS prophylaxis for patients with HGBL-NOS based on the increased risk observed in BCL-U and Burkitt lymphoma; in retrospective series, many patients with BCL-U morphology presented with IPI 3 to 5 even in the absence of MYC translocations.53,54  However, this issue clearly warrants further study in larger datasets with central pathology review.

Outcome.

We favor dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for fit patients with HGBL-DH based on retrospective26,52,55  and prospective data.56  However, given substantial comorbidities including cardiac dysfunction, we used 6 cycles of cyclophosphamide, etoposide, prednisone, vincristine, and rituximab (R-CEOP; anthracycline substituted for etoposide). We administered IT MTX 12 mg with each cycle of the first 4 cycles of chemoimmunotherapy. After the fourth cycle, he developed severe post–lumbar puncture headache unresponsive to simple analgesia and caffeine. As all CSF assessments had been negative, further IT prophylaxis was abandoned. On completion of chemoimmunotherapy, after 2 cycles of HD-MTX (3 g/m2) in addition with rituximab (to complete 8 doses), the end of treatment PET-CT demonstrated a “near” CMR (Deauville 3, with residual low-grade uptake at a periportal node unsafe to rebiopsy). The node remains unchanged in size and avidity 3 months later and he remains in clinical remission at 8 months follow-up.

Case 4

Presentation.

A 67-year-old male office worker presented with abdominal discomfort, night sweats, and hypercalcemia. CT-guided core biopsy of retroperitoneal lymphadenopathy showed DLBCL with non-GCB phenotype (by Hans algorithm); cells expressed both MYC (70%) and BCL2 (60%) by immunohistochemistry. MYC–fluorescence in situ hybridization was negative. PET-CT revealed extensive nodal disease and involvement of the liver, multiple bone lesions, and muscle. CSF analysis was negative. His stage was IVB, ECOG was 0, and serum LDH (surprisingly) was not elevated (IPI = 3, CNS-IPI = 3).

Discussion.

Although not fulfilling CNS-IPI criteria for high risk, we assessed the patient to be at high risk of CNS relapse for 2 reasons. First, data from Vancouver suggest MYC and BCL2 protein dual expressers (DEs) are at increased risk of CNS relapse. Savage et al examined the correlation between DE status, cell of origin (COO; Lymph2Cx nanostring57  and Hans algorithm), and CNS relapse in 428 patients with de novo DLBCL treated with R-CHOP (largely without CNS prophylaxis).22  DE patients were more likely to experience CNS relapse than non-DE (2-year CNS relapse risk, 9.7% v 2.2%; P = .001). Activated B-cell (ABC) COO was also associated with increased CNS relapse risk (9.4% v 2.2%; P = .02). However, by multivariate analysis, only DE status (hazard ratio, 3.68) and CNS-IPI (hazard ratio, 5.21) remained significant predictors of CNS relapse.22  Patients whose tumors were both DE and ABC COO had a 2-year CNS relapse risk of 15.3%. The study was important as DEs account for around 30% of DLBCL (around 6 times more frequent than MYC/BCL2-rearranged lymphomas)48,58,59  and around two-thirds of DE are ABC COO. In contrast, HGBL-DH typically arise in tumors with GCB phenotype, acknowledging that COO nomenclature is limited to pure cases of DLBCL in the revised 2017 WHO category.60-62 

The second reason we would have administered CNS prophylaxis independent of DE status is the involvement of 3 extranodal sites on PET-CT. El-Galaly et al studied an independent cohort of 1532 DLBCL patients staged with PET-CT and treated with R-CHOP21 (or similar) and observed a striking correlation between the absolute number of extranodal sites and risk of CNS progression.7  Multiple areas of involvement within 1 organ or tissue (eg, multifocal bone involvement) only counted for 1 site. Patients with ≥3 extranodal sites comprised 9.5% of the cohort and had a 2-year CNS relapse risk of 15.2% (Figure 1B). The authors explored the “≥3 extranodal sites” model further, and compared with the CNS-IPI, it identified fewer patients as high risk (9.5% vs 19.2%; P = .005) and as a result was less sensitive (35.5% vs 55.7%; P < .001), more specific (91.7% vs 82.3%; P < .001), and more accurate (89.4% vs 81.2%; P = .001), but had similar positive predictive value (15.3% vs 11.2%; P = .1). Although both models offer an excellent negative predictive value (∼97%), the ≥3 extranodal sites model has the potential advantages of being easier to remember and resulting in fewer patients being exposed to CNS prophylaxis (at the cost of decreased sensitivity). The model should be validated in an external cohort; however, at present, we consider patients with ≥3 extranodal sites for CNS prophylaxis even if they are not “high risk” by CNS-IPI.

Outcome.

Based on DE status and involvement of ≥3 extranodal sites, we estimated the patient’s 2-year risk of CNS relapse to be ∼15% despite the CNS-IPI score of 3 (intermediate). We commenced treatment with DA-EPOCH-R with 1 dose of IT MTX per cycle, followed by 2 cycles of systemic MTX following the completion of chemoimmunotherapy. End of treatment PET-CT demonstrated CMR and remains in remission 16 months after completion of therapy. We should highlight that in contrast to DHL, there are fewer data supporting DA-EPOCH-R in DE lymphoma. A small retrospective series from MD Anderson Cancer Center (MDACC) suggested a potential benefit,63  however, this remains to be confirmed in larger, prospective series. Furthermore, overall results from the CALGB 50303 study (the only phase 3 randomized comparison of R-CHOP vs DA-EPOCH-R) was negative for cohort overall, although results from biologic subgroups including COO, DEs, and DHLs are awaited.64 

Case 5

Presentation.

A 32-year-old engineer presented with widespread lymphadenopathy and fevers. Biopsy showed anaplastic lymphoma kinase–positive (ALK+) anaplastic large cell lymphoma (ALCL). PET-CT identified involvement of the liver, spleen, and multifocal bone lesions. This patient had stage IVB disease, ECOG of 1, and elevated LDH (IPI = 3, CNS-IPI = 3). Treatment with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) was commenced at another institution. He attended our institution for a second opinion after completing the first cycle of therapy.

Discussion.

Applying the CNS-IPI (derived largely from patients with DLBCL), the risk would be intermediate (∼3%), not warranting CNS-directed prophylaxis. However, investigators have studied PTCL separate from DLBCL to better refine risk factors for CNS involvement. Ellin et al reported that 28 of 625 patients with PTCL (4.5%) in a Swedish population-based study developed CNS relapse with >1 extranodal site, skin, and gastrointestinal involvement associated with CNS risk by multivariate analysis.28  In a Korean study of 228 patients, Yi et al identified elevated LDH and paranasal sinus involvement as associated with CNS relapse.65  In both studies, all PTCL subtypes were considered together to derive risk factors. Of specific relevance to this patient, Chihara et al analyzed CNS risk according to PTCL subtype in 616 patients treated at MDACC: among 76 patients with ALK+ ALCL, the 5-year risk of CNS relapse was 5.3%; however, among ALK+ ALCL and >1 extranodal site the 1-year CNS relapse was 15%.29  Due to the rarity and heterogeneity of PTCL, interpretation of these studies presents a challenge, but the involvement of multiple extranodal sites appears a recurrent risk factor. Therefore, for this patient with ALK+ ALCL and 2 extranodal sites (liver and bone; we do not consider spleen to be extranodal for the purposes of determining CNS risk), we estimated the 1-year CNS risk for this patient to be 15%.

Mantle cell lymphoma (MCL) is another aggressive histologic subtype where the role of CNS prophylaxis remains controversial. Unselected patients with MCL have an estimated CNS relapse rate of 5.4%, with high-risk features including Ki-67 >30% associated with increased risk (hazard ratio, 6.03; P = .003).27  There are limited data supporting a role for CNS prophylaxis. Outside of clinical trials, in transplant-eligible patients we use high-dose cytarabine-based induction followed by autologous stem cell transplant; in elderly patients, we use bendamustine-rituximab, but we do not specifically add CNS-directed prophylaxis in either setting. However, most patients with MCL at our institution are offered participation in investigational protocols incorporating Bruton tyrosine kinase inhibitors; there are data suggesting the first-in-class agent, ibrutinib, penetrates the CNS66  and may be effective in MCL with CNS involvement.67  We have not observed any CNS relapses in our MCL patients treated with Bruton tyrosine kinase inhibitors (C.Y.C., pooled analysis of patients with MCL treated on phase 1-3 studies with BTK inhibitors as single agents or in combination with chemotherapy, unpublished data). However, larger datasets are required to confirm this observation.

Outcome.

Although there are scarce data among patients with PTCL, by extrapolation from DLBCL we added IT MTX with each cycle of chemotherapy followed by 2 cycles of systemic MTX at the completion of CHOEP. This patient achieved a CMR at the completion of therapy and remains in remission at 12 months follow-up.

How I deliver CNS prophylaxis

The optimal method for administration of CNS-directed prophylaxis is unknown. Even among high-risk patients, only a minority develop CNS recurrence, making adequately powered prospective randomized studies to address this question challenging. The regimen we have outlined is adapted from an approach developed at the Peter MacCallum Cancer Centre, Melbourne, Australia.68  IT MTX is administered once per chemoimmunotherapy cycle (total of 6). Three to 4 weeks after the completion of chemoimmunotherapy, 2 cycles of systemic MTX are administered, 2 to 3 weeks apart. We discontinue medications that may interfere with MTX clearance (eg, cotrimoxazole, proton pump inhibitors) at least 3 days prior to admission for IV MTX. We admit patients the afternoon before scheduled MTX and alkalinize the urine with IV fluids containing sodium bicarbonate, with careful attention to clinical assessment of fluid status (weighing patients twice daily) and using diuretics as needed to prevent fluid overload. We administer MTX at a target dose of 3 g/m2 over 4 hours with leucovorin rescue commencing 24 hours later. In patients with mild to moderate renal impairment, or those aged >70 years, we reduce the dose of IV MTX to 1 g/m2 to 1.5 g/m2.

IT MTX as CNS prophylaxis in aggressive lymphoma was extrapolated from acute lymphoblastic leukemia, where CNS recurrence is usually leptomeningeal. In contrast, CNS relapse in DLBCL usually has a parenchymal component4  and the limited ability of cytotoxic drugs administered by IT injection to penetrate into deep brain tissue is problematic, with data suggesting minimal impact on CNS progression.1,13,69,70  Systemic therapy with CNS penetration is therefore paramount and an essential component for all prophylactic regimens. Systemic HD-MTX achieves tumoricidal levels in brain parenchyma at doses ≥1 g/m2 and leptomeningeal penetration at doses ≥3 g/m2.71-74  A French randomized study (prerituximab) compared doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone with a consolidation phase containing etoposide, ifosfamide, cytarabine, 4 doses of IT MTX, and 2 cycles of systemic MTX 3 g/m2 (ACVBP) with CHOP (which contained no CNS prophylaxis).75  The CNS relapse rate was lower in the arm treated with IT and IV MTX (2.7% vs 8%; P = .02), acknowledging that other CNS-penetrating agents were used in the MTX arm. Several subsequent retrospective68,76,77  and 2 prospective studies also support a potential benefit for high-dose systemic MTX in this setting.78,79  However, these studies are limited by small numbers and nonrandomized and retrospective study designs, with the prospective studies using other CNS-penetrating agents in combination with MTX. There remains lack of consensus regarding a systemic MTX-dosing regimen, number of cycles, and whether IT prophylaxis has any role or not. No randomized study exists to show that IT prophylaxis is effective, with only small retrospective, single-arm, or nonrandomized studies in combination with systemic therapy providing limited evidence for a reduction in CNS risk.10,37,80,81  Given that 20% of CNS progression occurs during primary therapy,3  delaying all CNS-directed measures until completion of chemoimmunotherapy is too late. Accordingly, some groups are using systemic MTX either before chemoimmunotherapy or intercalated between cycles. Although this is entirely rational with regard to prevention of early CNS progression, high-dose systemic MTX can be associated with toxicity, most notably renal impairment, which occurs in up to 9% of cycles.82  This could potentially interrupt the primary (curative intent) chemoimmunotherapy.83  We recognize that the quality of data supporting these approaches are suboptimal and prospective studies should guide the ideal strategy.

It is noteworthy that several groups have explored dose-intensified regimens for younger patients with DLBCL and poor prognostic features in nonrandomized studies. Dunleavy et al used DA-EPOCH-R with IT MTX as the sole form of CNS prophylaxis in 52 patients with aggressive MYC-rearranged B-cell lymphoma, 65% with IPI ≥ 3.56  To date, no CNS progressions have occurred, though final results are awaited (K. Dunleavy, George Washington University, e-mail, March 2016). The numbers of patients treated remain relatively small, though the CNS progression rate in the phase 2 study using the same regimen in low-risk Burkitt lymphoma appeared to prevent CNS relapse.84  In contrast, investigators from Chicago retrospectively examined 117 patients with DLBCL treated with DA-EPOCH-R, 62 of whom received IT MTX and 55 of whom did not.85  The crude incidence of CNS relapse was 7 of 117 (6%) and IT MTX did not appear to be associated with reduction in risk. Limitations of retrospective design notwithstanding, these data highlight that CNS progression in patients receiving DA-EPOCH-R and IT MTX can occur. When we use DA-EPOCH-R, if CNS prophylaxis is indicated, we add 2 cycles of high-dose IV MTX after the last cycle of chemoimmunotherapy, as in case 4. This shares some similarities with the Nordic approach. Holte et al used dose-dense rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone delivered in 14-day cycles, followed by intensification with high-dose cytarabine and HD-MTX in 156 patients with DLBCL aged 18 to 65 years with age-adjusted IPI 2-3.79  Apart from 1 dose of IT MTX on baseline lumbar puncture, IT chemotherapy prophylaxis was not given. CNS relapses occurred in 7 patients (4.4%), all within 6 months of study entry, again highlighting the need to provide some form of prophylaxis early during treatment. Finally, Phillips et al reported CNS outcomes from the UK National Cancer Research Institute phase 2 study of rituximab, cyclophosphamide, doxorubicin, vincristine, high-dose methotrexate, followed by ifosfamide, etoposide, high-dose cytarabine, rituximab with intrathecal methotrexate and cytarabine in intermediate-high risk DLBCL.78  Among the 55 patients with high-risk CNS-IPI, the 2-year CNS relapse rate was lower than expected at 6.2%. This observation suggests a potential benefit from the early inclusion of HD-MTX used in this regimen, however, confirmation of this finding in larger, randomized studies is needed.

Although the case vignettes detailing our approach to CNS prophylaxis have been successful, it is important to acknowledge that failures may still occur. This highlights the need for further studies to better identify high-risk patients; better prophylactic strategies are needed as well. Novel agents such as ibrutinib and lenalidomide cross the blood-brain barrier67,86  and are active in both systemic ABC DLBCL87,88  and CNS lymphomas.89-91  In a recent pooled analysis of 2 prospective studies using R-CHOP plus lenalidomide in 136 patients (18% CNS-IP I ≥ 4) with a median follow-up of 48 months, only 1 patient (0.7%) developed isolated CNS relapse despite minimal use of CNS prophylaxis with IT (15%) or IV (0%) MTX.92  Randomized phase 3 studies comparing R-CHOP ± ibrutinib (NCT01855750) and R-CHOP ± lenalidomide (NCT01856192; NCT02285062) in DLBCL will hopefully answer the question of whether these agents can replace existing CNS prophylactic strategies.

Until then, we suggest that careful assessment for CNS recurrence be integrated into routine therapeutic decision-making for patients with aggressive lymphomas.

C.Y.C. acknowledges the mentorship of John Seymour over many years, particularly in relation to the subject of this review.

Contribution: C.K.C. performed the literature review and wrote the first draft of the manuscript, and C.Y.C. designed the paper and reviewed and cowrote the manuscript.

Conflict-of-interest disclosure: C.Y.C. received research funding from Celgene and Roche; was on the speakers bureau for Roche, Janssen-Cilag, and Takeda; was an advisory board member for Janssen-Cilag and Bristol-Myers Squibb; and received travel expenses from Bristol-Myers Squibb. C.K.C. declares no competing financial interests.

Correspondence: Chan Yoon Cheah, Department of Haematology, Sir Charles Gairdner Hospital, Ground Floor, B Block, Hospital Ave, Nedlands, WA 6009, Australia; e-mail: chan.cheah@health.wa.gov.au.

1.
Boehme
V
,
Schmitz
N
,
Zeynalova
S
,
Loeffler
M
,
Pfreundschuh
M
.
CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
.
Blood
.
2009
;
113
(
17
):
3896
-
3902
.
2.
Bernstein
SH
,
Unger
JM
,
Leblanc
M
,
Friedberg
J
,
Miller
TP
,
Fisher
RI
.
Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG 8516 -- the Southwest Oncology Group
.
J Clin Oncol
.
2009
;
27
(
1
):
114
-
119
.
3.
El-Galaly
TC
,
Cheah
CY
,
Bendtsen
MD
,
Thanarasjasingam
G
,
Villa
D
.
An international collaborative study of outcome and prognostic factors in patients with secondary CNS involvement by diffuse large B-cell lymphoma
.
In: Proceedings from the American Society of Hematology 58th Annual Meeting & Exposition; 3 December 2016; San Diego, CA
.
4.
Kansara
R
,
Villa
D
,
Gerrie
AS
, et al
.
Site of central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) by the CNS-IPI risk model
.
Br J Haematol
.
2016
.
5.
Zhang
J
,
Chen
B
,
Xu
X
.
Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis
.
Leuk Lymphoma
.
2014
;
55
(
3
):
509
-
514
.
6.
Schmitz
N
,
Zeynalova
S
,
Nickelsen
M
, et al
.
CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP
.
J Clin Oncol
.
2016
;
34
(
26
):
3150
-
3156
.
7.
El-Galaly
TC
,
Villa
D
,
Michaelsen
TY
, et al
.
The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: an international multicenter study of 1532 patients treated with chemoimmunotherapy
.
Eur J Cancer
.
2017
;
75
:
195
-
203
.
8.
Feugier
P
,
Virion
JM
,
Tilly
H
, et al
.
Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab
.
Ann Oncol
.
2004
;
15
(
1
):
129
-
133
.
9.
Hollender
A
,
Kvaloy
S
,
Nome
O
,
Skovlund
E
,
Lote
K
,
Holte
H
.
Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model
.
Ann Oncol
.
2002
;
13
(
7
):
1099
-
1107
.
10.
Haioun
C
,
Besson
C
,
Lepage
E
, et al
.
Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d’Etudes des Lymphomes de l’Adulte
.
Ann Oncol
.
2000
;
11
(
6
):
685
-
690
.
11.
van Besien
K
,
Ha
CS
,
Murphy
S
, et al
.
Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma
.
Blood
.
1998
;
91
(
4
):
1178
-
1184
.
12.
Tomita
N
,
Yokoyama
M
,
Yamamoto
W
, et al
.
Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era
.
Cancer Sci
.
2012
;
103
(
2
):
245
-
251
.
13.
Guirguis
HR
,
Cheung
MC
,
Mahrous
M
, et al
.
Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature
.
Br J Haematol
.
2012
;
159
(
1
):
39
-
49
.
14.
Tai
WM
,
Chung
J
,
Tang
PL
, et al
.
Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab
.
Ann Hematol
.
2011
;
90
(
7
):
809
-
818
.
15.
Chihara
D
,
Oki
Y
,
Matsuo
K
, et al
.
Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: analyses with competing risk regression model
.
Leuk Lymphoma
.
2011
;
52
(
12
):
2270
-
2275
.
16.
Villa
D
,
Connors
JM
,
Shenkier
TN
,
Gascoyne
RD
,
Sehn
LH
,
Savage
KJ
.
Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy
.
Ann Oncol
.
2010
;
21
(
5
):
1046
-
1052
.
17.
Hosein
PJ
,
Maragulia
JC
,
Salzberg
MP
, et al
.
A multicentre study of primary breast diffuse large B-cell lymphoma in the rituximab era
.
Br J Haematol
.
2014
;
165
(
3
):
358
-
363
.
18.
Zucca
E
,
Conconi
A
,
Mughal
TI
, et al
;
International Extranodal Lymphoma Study Group
.
Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group
.
J Clin Oncol
.
2003
;
21
(
1
):
20
-
27
.
19.
El-Galaly
TC
,
Cheah
CY
,
Hutchings
M
, et al
.
Uterine, but not ovarian, female reproductive organ involvement at presentation by diffuse large B-cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement
.
Br J Haematol
.
2016
;
175
(
5
):
876
-
883
.
20.
McDonald
AC
,
Nicoll
JA
,
Rampling
RP
.
Non-Hodgkin’s lymphoma presenting with spinal cord compression; a clinicopathological review of 25 cases
.
Eur J Cancer
.
2000
;
36
(
2
):
207
-
213
.
21.
Eeles
RA
,
O’Brien
P
,
Horwich
A
,
Brada
M
.
Non-Hodgkin’s lymphoma presenting with extradural spinal cord compression: functional outcome and survival
.
Br J Cancer
.
1991
;
63
(
1
):
126
-
129
.
22.
Savage
KJ
,
Slack
GW
,
Mottok
A
, et al
.
Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL
.
Blood
.
2016
;
127
(
18
):
2182
-
2188
.
23.
Miyazaki
K
,
Yamaguchi
M
,
Suzuki
R
, et al
.
CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab
.
Ann Oncol
.
2011
;
22
(
7
):
1601
-
1607
.
24.
Shimada
K
,
Murase
T
,
Matsue
K
, et al
;
IVL Study Group in Japan
.
Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients
.
Cancer Sci
.
2010
;
101
(
6
):
1480
-
1486
.
25.
Cox
MC
,
Di Napoli
A
,
Scarpino
S
, et al
.
Clinicopathologic characterization of diffuse-large-B-cell lymphoma with an associated serum monoclonal IgM component
.
PLoS One
.
2014
;
9
(
4
):
e93903
.
26.
Oki
Y
,
Noorani
M
,
Lin
P
, et al
.
Double hit lymphoma: the MD Anderson Cancer Center clinical experience
.
Br J Haematol
.
2014
;
166
(
6
):
891
-
901
.
27.
Chihara
D
,
Asano
N
,
Ken
O
, et al
.
Ki-67 is a strong predictor for central nervous system relapse in patients with mantle cell lymphoma (MCL)
.
Ann Oncol
.
2015
;
26
(
5
):
966
-
973
.
28.
Ellin
F
,
Landström
J
,
Jerkeman
M
,
Relander
T
.
Central nervous system relapse in peripheral T-cell lymphomas: a Swedish Lymphoma Registry study
.
Blood
.
2015
;
126
(
1
):
36
-
41
.
29.
Chihara
D
,
Fanale
MA
,
Miranda
RN
, et al
.
The risk of central nervous system (CNS) relapses in patients with peripheral T-cell lymphoma [abstract]
.
Blood
.
2016
;
128
(
22
).
Abstract 4153
.
30.
Hans
CP
,
Weisenburger
DD
,
Greiner
TC
, et al
.
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray
.
Blood
.
2004
;
103
(
1
):
275
-
282
.
31.
Quijano
S
,
López
A
,
Manuel Sancho
J
, et al
;
Spanish Group for the Study of CNS Disease in NHL
.
Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin’s lymphoma: improved sensitivity of flow cytometry
.
J Clin Oncol
.
2009
;
27
(
9
):
1462
-
1469
.
32.
Wilson
WH
,
Bromberg
JE
,
Stetler-Stevenson
M
, et al
.
Detection and outcome of occult leptomeningeal disease in diffuse large B-cell lymphoma and Burkitt lymphoma
.
Haematologica
.
2014
;
99
(
7
):
1228
-
1235
.
33.
Benevolo
G
,
Stacchini
A
,
Spina
M
, et al
;
Fondazione Italiana Linfomi
.
Final results of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination
.
Blood
.
2012
;
120
(
16
):
3222
-
3228
.
34.
Cheah
CY
,
Seymour
JF
.
Central nervous system prophylaxis in non-Hodgkin lymphoma: who, what, and when?
Curr Oncol Rep
.
2015
;
17
(
6
):
25
.
35.
Fonseca
R
,
Habermann
TM
,
Colgan
JP
, et al
.
Testicular lymphoma is associated with a high incidence of extranodal recurrence
.
Cancer
.
2000
;
88
(
1
):
154
-
161
.
36.
Cheah
CY
,
Wirth
A
,
Seymour
JF
.
Primary testicular lymphoma
.
Blood
.
2014
;
123
(
4
):
486
-
493
.
37.
Vitolo
U
,
Chiappella
A
,
Ferreri
AJ
, et al
.
First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial
.
J Clin Oncol
.
2011
;
29
(
20
):
2766
-
2772
.
38.
Jeanneret-Sozzi
W
,
Taghian
A
,
Epelbaum
R
, et al
.
Primary breast lymphoma: patient profile, outcome and prognostic factors. A multicentre Rare Cancer Network study
.
BMC Cancer
.
2008
;
8
:
86
.
39.
Yhim
HY
,
Kang
HJ
,
Choi
YH
, et al
.
Clinical outcomes and prognostic factors in patients with breast diffuse large B cell lymphoma; Consortium for Improving Survival of Lymphoma (CISL) study
.
BMC Cancer
.
2010
;
10
:
321
.
40.
Guo
H-Y
,
Zhao
X-M
,
Li
J
,
Hu
X-C
.
Primary non-Hodgkin’s lymphoma of the breast: eight-year follow-up experience
.
Int J Hematol
.
2008
;
87
(
5
):
491
-
497
.
41.
Fukuhara
S
,
Watanabe
T
,
Munakata
W
, et al
.
Bulky disease has an impact on outcomes in primary diffuse large B-cell lymphoma of the breast: a retrospective analysis at a single institution
.
Eur J Haematol
.
2011
;
87
(
5
):
434
-
440
.
42.
Di Marco
A
,
Campostrini
F
,
Garusi
GF
.
Non-Hodgkin lymphomas presenting with spinal epidural involvement
.
Acta Oncol
.
1989
;
28
(
4
):
485
-
488
.
43.
Lyons
MK
,
O’Neill
BP
,
Marsh
WR
,
Kurtin
PJ
.
Primary spinal epidural non-Hodgkin’s lymphoma: report of eight patients and review of the literature
.
Neurosurgery
.
1992
;
30
(
5
):
675
-
680
.
44.
Rathmell
AJ
,
Gospodarowicz
MK
,
Sutcliffe
SB
,
Clark
RM
;
The Princess Margaret Hospital Lymphoma Group
.
Localized extradural lymphoma: survival, relapse pattern and functional outcome
.
Radiother Oncol
.
1992
;
24
(
1
):
14
-
20
.
45.
Salvati
M
,
Cervoni
L
,
Artico
M
,
Raco
A
,
Ciappetta
P
,
Delfini
R
.
Primary spinal epidural non-Hodgkin's lymphomas: a clinical study
.
Surg Neurol
.
1996
;
46
(
4
):
339
-
343
;
discussion 343-334
.
46.
Mian
M
,
Capello
D
,
Ventre
MB
, et al
;
International Extranodal Lymphoma Study Group (IELSG)
.
Early-stage diffuse large B cell lymphoma of the head and neck: clinico-biological characterization and 18 year follow-up of 488 patients (IELSG 23 study)
.
Ann Hematol
.
2014
;
93
(
2
):
221
-
231
.
47.
Murawski
N
,
Held
G
,
Ziepert
M
, et al
.
The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas
.
Blood
.
2014
;
124
(
5
):
720
-
728
.
48.
Johnson
NA
,
Slack
GW
,
Savage
KJ
, et al
.
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone
.
J Clin Oncol
.
2012
;
30
(
28
):
3452
-
3459
.
49.
Swerdlow
SH
,
Campo
E
,
Harris
N
, et al
.
WHO Classification of Tumours of the Haematopoeitic and Lymphoid Tissues
.
Lyon, France
:
IARC
;
2008
.
50.
Niitsu
N
,
Okamoto
M
,
Miura
I
,
Hirano
M
.
Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations
.
Leukemia
.
2009
;
23
(
4
):
777
-
783
.
51.
Snuderl
M
,
Kolman
OK
,
Chen
YB
, et al
.
B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma
.
Am J Surg Pathol
.
2010
;
34
(
3
):
327
-
340
.
52.
Petrich
AM
,
Gandhi
M
,
Jovanovic
B
, et al
.
Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis
.
Blood
.
2014
;
124
(
15
):
2354
-
2361
.
53.
Lin
P
,
Dickason
TJ
,
Fayad
LE
, et al
.
Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma
.
Cancer
.
2012
;
118
(
6
):
1566
-
1573
.
54.
Perry
AM
,
Crockett
D
,
Dave
BJ
, et al
.
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma: study of 39 cases
.
Br J Haematol
.
2013
;
162
(
1
):
40
-
49
.
55.
Sathyanarayanan
V
,
Oki
Y
,
Issa
AK
, et al
.
High risk diffuse large B cell lymphoma: a comparison of aggressive subtypes treated with dose adjusted chemotherapy - the University of Texas MD Anderson experience [abstract]
.
Blood
.
2016
;
128
(
22
).
Abstract 106
.
56.
Dunleavy
K
,
Fanale
M
,
LaCasce
A
, et al
.
Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma [abstract]
.
Blood
.
2014
;
124
(
21
).
Abstract 395
.
57.
Scott
DW
,
Wright
GW
,
Williams
PM
, et al
.
Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue
.
Blood
.
2014
;
123
(
8
):
1214
-
1217
.
58.
Hu
S
,
Xu-Monette
ZY
,
Tzankov
A
, et al
.
MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program
.
Blood
.
2013
;
121
(
20
):
4021
-
4031
,
quiz 4250
.
59.
Horn
H
,
Ziepert
M
,
Becher
C
, et al
;
German High-Grade Non-Hodgkin Lymphoma Study Group
.
MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma
.
Blood
.
2013
;
121
(
12
):
2253
-
2263
.
60.
Savage
KJ
,
Johnson
NA
,
Ben-Neriah
S
, et al
.
MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy
.
Blood
.
2009
;
114
(
17
):
3533
-
3537
.
61.
Barrans
S
,
Crouch
S
,
Smith
A
, et al
.
Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab
.
J Clin Oncol
.
2010
;
28
(
20
):
3360
-
3365
.
62.
Visco
C
,
Tzankov
A
,
Xu-Monette
ZY
, et al
.
Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study
.
Haematologica
.
2013
;
98
(
2
):
255
-
263
.
63.
Sathyanarayanan
V
,
Oki
Y
,
Issa
A
, et al
.
High risk diffuse large B cell lymphoma: a comparison of aggressive subtypes treated with dose adjusted chemotherapy—the University of Texas MD Anderson experience
. In: Proceedings from the American Society of Hematology 58th Annual Meeting & Exposition; 3 December 2016; San Diego, CA.
64.
Wilson
WH
,
Jung
SH
,
Porcu
P
, et al
;
Cancer Leukemia Group B
.
A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype
.
Haematologica
.
2012
;
97
(
5
):
758
-
765
.
65.
Yi
JH
,
Kim
JH
,
Baek
KK
, et al
.
Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma
.
Ann Oncol
.
2011
;
22
(
7
):
1636
-
1643
.
66.
Pouzoulet
F
,
Rezai
K
,
Li
Z
, et al
.
Preclinical evaluation of ibrutinib for central nervous system lymphoma [abstract]
.
Blood
.
2016
;
128
(
22
).
Abstract 4170
.
67.
Bernard
S
,
Goldwirt
L
,
Amorim
S
, et al
.
Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse
.
Blood
.
2015
;
126
(
14
):
1695
-
1698
.
68.
Cheah
CY
,
Herbert
KE
,
O’Rourke
K
, et al
.
A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma
.
Br J Cancer
.
2014
;
111
(
6
):
1072
-
1079
.
69.
Chua
SL
,
Seymour
JF
,
Streater
J
,
Wolf
MM
,
Januszewicz
EH
,
Prince
HM
.
Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediate-grade non-Hodgkin’s lymphoma
.
Leuk Lymphoma
.
2002
;
43
(
9
):
1783
-
1788
.
70.
Kumar
A
,
Vanderplas
A
,
LaCasce
AS
, et al
.
Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database
.
Cancer
.
2012
;
118
(
11
):
2944
-
2951
.
71.
Kimelberg
HK
,
Biddlecome
SM
,
Bourke
RS
.
Distribution and degradation of [3H]methotrexate after intravenous and cerebral intraventricular injection in primates
.
Cancer Res
.
1977
;
37
(
1
):
157
-
165
.
72.
DeAngelis
LM
,
Yahalom
J
,
Thaler
HT
,
Kher
U
.
Combined modality therapy for primary CNS lymphoma
.
J Clin Oncol
.
1992
;
10
(
4
):
635
-
643
.
73.
Morris
PG
,
Abrey
LE
.
Therapeutic challenges in primary CNS lymphoma
.
Lancet Neurol
.
2009
;
8
(
6
):
581
-
592
.
74.
Batchelor
T
,
Carson
K
,
O’Neill
A
, et al
.
Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07
.
J Clin Oncol
.
2003
;
21
(
6
):
1044
-
1049
.
75.
Tilly
H
,
Lepage
E
,
Coiffier
B
, et al
;
Groupe d’Etude des Lymphomes de l’Adulte
.
Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma
.
Blood
.
2003
;
102
(
13
):
4284
-
4289
.
76.
Abramson
JS
,
Hellmann
M
,
Barnes
JA
, et al
.
Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma
.
Cancer
.
2010
;
116
(
18
):
4283
-
4290
.
77.
Ferreri
AJ
,
Bruno-Ventre
M
,
Donadoni
G
, et al
.
Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era
.
Br J Haematol
.
2015
;
168
(
5
):
654
-
662
.
78.
Phillips
EH
,
Kirkwood
AA
,
Lawrie
A
, et al
.
Low rates of CNS relapse in high risk DLBCL patients treated with R-CODOX-M and R-IVAC: results from a phase 2 UK NCRI/Bloodwise trial [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 1855.
79.
Holte
H
,
Leppä
S
,
Björkholm
M
, et al
.
Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study
.
Ann Oncol
.
2013
;
24
(
5
):
1385
-
1392
.
80.
Arkenau
HT
,
Chong
G
,
Cunningham
D
, et al
.
The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma
.
Ann Oncol
.
2007
;
18
(
3
):
541
-
545
.
81.
Tomita
N
,
Kodama
F
,
Kanamori
H
,
Motomura
S
,
Ishigatsubo
Y
.
Prophylactic intrathecal methotrexate and hydrocortisone reduces central nervous system recurrence and improves survival in aggressive non-hodgkin lymphoma
.
Cancer
.
2002
;
95
(
3
):
576
-
580
.
82.
May
J
,
Carson
KR
,
Butler
S
,
Liu
W
,
Bartlett
NL
,
Wagner-Johnston
ND
.
High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis
.
Leuk Lymphoma
.
2014
;
55
(
6
):
1345
-
1349
.
83.
McMillan
A
,
Ardeshna
KM
,
Cwynarski
K
,
Lyttelton
M
,
McKay
P
,
Montoto
S
;
British Committee for Standards in Haematology
.
Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology
.
Br J Haematol
.
2013
;
163
(
2
):
168
-
181
.
84.
Dunleavy
K
,
Pittaluga
S
,
Shovlin
M
, et al
.
Low-intensity therapy in adults with Burkitt’s lymphoma
.
N Engl J Med
.
2013
;
369
(
20
):
1915
-
1925
.
85.
Malecek
MK
,
Rozell
S
,
Chu
BA
, et al
.
Risk factors for CNS relapse among patients with DLBCL treated with EPOCH-R [abstract]
.
Blood
.
2015
;
126
(
23
). Abstract 1500.
86.
Houillier
C
,
Choquet
S
,
Touitou
V
, et al
.
Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma
.
Neurology
.
2015
;
84
(
3
):
325
-
326
.
87.
Wilson
WH
,
Young
RM
,
Schmitz
R
, et al
.
Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma
.
Nat Med
.
2015
;
21
(
8
):
922
-
926
.
88.
Hernandez-Ilizaliturri
FJ
,
Deeb
G
,
Zinzani
PL
, et al
.
Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype
.
Cancer
.
2011
;
117
(
22
):
5058
-
5066
.
89.
Choquet
S
,
Houillier
C
,
Bijou
F
, et al
.
Ibrutinib monotherapy in relapse or refractory primary CNS lymphoma (PCNSL) and primary vitreo-retinal lymphoma (PVRL). Result of the interim analysis of the iLOC phase II study from the Lysa and the French LOC Network [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 784.
90.
Grommes
C
,
Pastore
A
,
Gavrilovic
I
, et al
.
Single-agent ibrutinib in recurrent/refractory central nervous system lymphoma [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 783.
91.
Rubenstein
JL
,
Fraser
E
,
Formaker
P
, et al
.
Phase I investigation of lenalidomide plus rituximab and outcomes of lenalidomide maintenance in recurrent CNS lymphoma [abstract]
.
ASCO Meeting Abstracts
.
2016
;
34
(
suppl 15
):
7502
.
92.
Ayed
AO
,
Chiappella
A
,
Nowakowski
GS
, et al
.
Lenalidomide plus R-CHOP (R2CHOP) in patients with DLBCL is associated with a lower risk of CNS relapse: combined analysis from two phase 2 studies
. In: Proceedings from the American Society of Hematology 58th Annual Meeting & Exposition; 3 December 2016; San Diego, CA.