INTRODUCTION — Central nervous system (CNS) involvement by systemic non-Hodgkin lymphoma (NHL), either at the time of initial lymphoma diagnosis or in the setting of relapse, is an uncommon but clinically challenging event.
The terms primary and secondary CNS lymphoma have traditionally been used to describe any lymphoma subtype that arises exclusively or secondarily within the CNS compartment, respectively. However, these terms fail to recognize significant differences in biology, natural history, and treatment of various lymphoma histologies, many of which influence optimal treatment selection and prognosis.
Among lymphoma subtypes, diffuse large B cell lymphoma (DLBCL) accounts for the majority of cases of both primary and secondary CNS lymphoma [1,2]. Other less common aggressive B cell lymphomas that frequently involve the CNS include Burkitt lymphoma, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and anaplastic large cell lymphoma (ALCL). Rarely, low-grade histologies with typically indolent natural histories involve the CNS, including follicular lymphoma, marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL).
This topic will discuss management of all secondary CNS lymphomas, with an emphasis on secondary DLBCL of the CNS, followed by discussion of other NHL histologies. Other relevant topics on CNS lymphoma include:
PROGNOSIS — Secondary CNS involvement by lymphoma is generally associated with a poor prognosis and limited long-term survival. In most series, median overall survival from time of CNS recurrence is approximately three to five months .
Prolonged survival is possible in selected patients, however. Older series largely include patients treated with conventional therapies before the availability of the anti-CD20 monoclonal antibody rituximab, the use of high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT), and the emergence of novel targeted therapies for certain patient subsets. Therefore, they likely underestimate the opportunity for inducing durable remissions and prolonged survival using contemporary management strategies [2-6].
The most commonly identified positive prognostic factors include:
●Younger age (≤60 years)
●Good performance status (table 1)
●Absence of systemic disease (isolated CNS recurrence)
●Single-compartment disease (eg, parenchymal only)
A simple three-tier score developed for primary CNS lymphoma has prognostic value in patients with secondary CNS diffuse large B cell lymphoma (DLBCL) as well . This score, known as the Memorial Sloan Kettering Cancer Center (MSKCC) score, classifies patients into three risk groups based on age and Karnofsky Performance Status (KPS) (table 2): low risk (patients <50 years of age), intermediate risk (age ≥50 years and KPS ≥70), and high risk (age ≥50 years and KPS <70).
The importance of these factors was illustrated by a multicenter retrospective study of 92 patients with secondary CNS lymphoma treated between 2000 and 2010 . The median age was 58 years and the most common lymphoma subtype was DLBCL (76 percent). Median overall survival was seven months. On multivariable analysis, predictors of improved outcome included receipt of HCT and MSKCC prognostic score. Median overall survival for MSKCC low-, intermediate-, and high-risk patients was 16, 9, and 2 months, respectively.
PRETREATMENT CONSIDERATIONS — Optimal management of secondary CNS lymphoma is individualized based on numerous patient- and disease-specific variables.
●Patient age, fitness, and medical comorbidities – Fitness for standard-dose and high-dose chemotherapy is a dominant management consideration. Preferred induction chemotherapy for most patients includes a methotrexate-based regimen, and patients should be assessed for appropriate age, fitness, renal function, and presence of ascites or effusions, which would increase risk for toxicity. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Pretreatment assessment'.)
Assessment of age, fitness, and organ function will also determine a patient's candidacy for consolidative therapy with high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT). (See "Determining eligibility for autologous hematopoietic cell transplantation".)
●Prior lymphoma therapy – Patients with secondary CNS lymphoma may present with CNS disease at the time of relapse after receiving initial therapy for systemic lymphoma, or less commonly at the time of initial presentation with concurrent systemic and CNS involvement.
Patients presenting in the setting of relapse after initial therapy should be assessed for relapsing systemic disease in need of cytoreduction, the type of prior therapy received for their systemic lymphoma, and the quality and duration of initial response.
For patients presenting with de novo systemic and CNS disease, the overall tumor burden and symptoms related to disease in each compartment should be assessed. The acuity and burden of disease influence the timing and order of treatment of the systemic and CNS compartments. Patients with symptomatic CNS disease may require urgent initiation of high-dose methotrexate prior to a first cycle of systemic therapy, for example. (See 'Newly diagnosed DLBCL, synchronous systemic and CNS disease' below.)
●Histology and genetics – The vast majority of secondary CNS lymphomas are diffuse large B cell (DLBCL), and so most data and clinical experience apply to secondary CNS DLBCL. While these data may be extrapolated to other histologies, it is important to avoid a "one size fits all" approach and consider unique biology and treatment options associated with other histologic subtypes.
Within DLBCL, the disease can be further subclassified as germinal center B cell-like (GCB) or activated B cell-like (ABC; also referred to as "non-GCB" if determined based on immunohistochemistry). Knowledge of the subclassification informs whether a patient may be a good candidate for novel agents such as lenalidomide or a Bruton tyrosine kinase (BTK) inhibitor.
Approaches to non-DLBCL histologies are discussed further below. (See 'Other lymphoma histologies' below.)
●Distribution of CNS disease – There are several typical patterns of secondary CNS involvement by lymphoma, although the disease is heterogenous and patterns may be changing as systemic lymphoma therapy evolves. In particular, isolated CNS relapses and parenchymal brain localization have become more common over time. Many other patients have primarily leptomeningeal involvement with cranial neuropathies, radicular nerve pain, and/or cauda equina disease. Disease within the eye can also be seen. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Clinical features'.)
A single focus of disease within the CNS may make the patient a candidate for combined-modality therapy incorporating both chemotherapy and radiation or palliative radiation alone. Isolated disease within the leptomeningeal compartment may prompt consideration of intrathecal (IT) chemotherapy, usually in combination with systemic treatment. Patients with vitreoretinal involvement may receive intravitreal injections of chemotherapy, as well as systemic therapy and consideration of radiation if the disease is localized.
ACUTE SYMPTOM MANAGEMENT — Patients with lymphoma involving the CNS may present with acute neurologic manifestations of the disease, including altered mental status, cranial neuropathies, weakness, headache, seizures, and deterioration of performance status. An initial course of high-dose glucocorticoids and antiseizure drugs, when indicated, often results in significant improvement in symptoms and performance status prior to initiating definitive-dose chemotherapy. (See "Seizures in patients with primary and metastatic brain tumors".)
A typical regimen of glucocorticoids for symptomatic CNS disease is dexamethasone 8 to 16 mg daily, oral or intravenous (IV), divided in one or two [8,9]. Maximal symptomatic effects are typically seen within two to three days. Once lymphoma treatment is initiated, glucocorticoids should be tapered gradually to the lowest effective dose to minimize steroid toxicities.
Pneumocystis pneumonia prophylaxis is particularly important in patients receiving glucocorticoids and concomitant chemotherapy. Trimethoprim-sulfamethoxazole should be avoided in combination with methotrexate, as both drugs affect folate metabolism. Alternative prophylactic regimens are reviewed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
DIFFUSE LARGE B CELL LYMPHOMA — The goal of treatment in patients with diffuse large B cell lymphoma (DLBCL) with secondary CNS involvement is to induce durable disease control in both the systemic and CNS compartments, to improve quality of life, and to prolong progression-free and overall survival.
When an aggressive approach is feasible, treatment consists of induction therapy, usually with a methotrexate-based regimen, followed by consideration of consolidative therapy with high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) in eligible patients. Patients who are not considered chemotherapy candidates, or who relapse after induction and consolidative therapy, are considered for alternative therapies including additional chemotherapy, radiation, novel and targeted agents, and cellular immunotherapy.
Newly diagnosed DLBCL, synchronous systemic and CNS disease — Synchronous systemic DLBCL and CNS involvement at initial diagnosis presents a unique challenge. Optimal disease control requires chemotherapy that eradicates disease in both compartments, but most drugs used with curative intent for DLBCL and other high-grade B cell lymphomas (ie, R-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab] and da-EPOCH-R [dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab]) do not cross the blood-brain barrier.
Curative-intent regimens — While there is no uniformly accepted approach, retrospective and prospective series consistently demonstrate that regimens targeting both the systemic lymphoma and the CNS compartment can achieve durable remissions and even cures in a significant proportion of patients eligible for aggressive treatment. Since these patients have not received prior lymphoma-directed therapy, the disease may be more chemosensitive than in a previously treated patient with relapsed disease.
Our approach in most patients is to use R-CHOP (table 3) combined with high-dose methotrexate (R-CHOP-M), followed by thiotepa-based autologous HCT in sufficiently young, fit patients with responding disease. Other acceptable induction strategies include MATRix-RICE (table 4 and table 5), R-Hyper-CVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine), and R-CODOX-M/IVAC (table 6), with consideration of consolidative high-dose chemotherapy and HCT consolidation for eligible patients .
Not all patients are candidates for these curative-intent approaches. Patients must be sufficiently fit to tolerate intensive induction therapy and have appropriate renal function or have dose reductions of methotrexate as appropriate. All patients receive supportive care with pegfilgrastim or granulocyte colony stimulating factor (G-CSF); hydration, alkalinization, and leucovorin rescue with methotrexate level monitoring; and Pneumocystis pneumonia prophylaxis.
●Administration of R-CHOP-M – We typically administer high-dose methotrexate on day 15 of the 21-day R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) cycle (table 3), for a total of six planned cycles. For patients presenting with significant symptoms related to CNS disease, we start with two to three cycles of high-dose methotrexate with or without rituximab at 14-day intervals for rapid CNS control, and thereafter administer R-CHOP-M together on a 21-day schedule.
The ideal dose of methotrexate for optimal control of CNS lymphoma is unknown. Doses of 3 g/m2 or higher appear to achieve adequate CNS penetration [11-15]. Our typical approach is to use 8 g/m2 of methotrexate in combination with R-CHOP in fit patients with normal creatinine clearance, and to dose reduce for advanced age or impaired renal function.
●Efficacy of R-CHOP-M – Evidence for R-CHOP-M with or without autologous HCT consolidation is derived from several retrospective series.
•A multicenter retrospective study analyzed 60 patients with synchronous CNS and systemic lymphoma at diagnosis . The majority of patients (88 percent) received CHOP-like chemotherapy, 74 percent of whom also received high-dose methotrexate with or without cytarabine. Nearly all patients received rituximab with induction therapy. Nineteen patients proceeded to consolidative high-dose chemotherapy with autologous HCT. The overall and complete response rates after induction therapy were 76 and 68 percent, respectively, and the three-year progression-free survival was 42 percent. Receipt of HCT was associated with improved progression-free and overall survival on multivariable analysis.
•Twenty-one patients were treated with high-dose methotrexate and R-CHOP, with a median of eight methotrexate cycles and four R-CHOP cycles . Whole brain radiation therapy was administered in one-third of patients. The three-year progression-free and overall survival rates were 45 and 49 percent, respectively.
●Alternative regimens – More intensive induction regimens may be considered, which include multiple CNS-penetrating agents such as methotrexate, cytarabine, and thiotepa. However, they have a higher risk of toxicity, and there is no available evidence to show that they are more effective than R-CHOP-M plus autologous HCT in this setting.
•MATRix-RICE – Support for a more intensive CNS regimen comes from the prospective MARIETTA study of MATRix-RICE (methotrexate, cytarabine, thiotepa, and rituximab plus rituximab, ifosfamide, carboplatin, and etoposide), which included 32 patients with synchronous disease at presentation . Patients received three consecutive cycles of MATRix followed by three cycles of RICE followed by autologous HCT; intrathecal (IT) chemotherapy was also included in all induction cycles. The overall response rate in this subset was 84 percent, including complete remissions after MATRix-RICE in 53 percent; the complete response rate increased to 75 percent post-HCT. The two-year progression-free survival was 71 percent in these high-risk patients, confirming that durable remissions can be achieved in patients presenting with synchronous systemic and CNS involvement by DLBCL.
One concern regarding the use of MATRix-RICE at initial DLBCL diagnosis, in addition to toxicity, is that it omits the use of an anthracycline, which is considered essential in optimizing curative-intent treatment of systemic DLBCL.
•R-Hyper-CVAD/MA and R-CODOX-M/IVAC – Eighty patients with synchronous systemic and CNS disease at presentation studied by the Australasian Lymphoma Alliance received intensive CNS-directed therapy with high-dose methotrexate and cytarabine as part of, or in addition to, a systemic lymphoma regimen . Among 38 patients treated with intensive CNS-directed therapy, the majority received R-Hyper-CVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; 66 percent) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, and methotrexate alternating with ifosfamide, etoposide, and cytarabine; 24 percent), both of which include intensive alkylator-based therapy as well as high-dose methotrexate and cytarabine. Among patients treated more conservatively, 83 percent were treated with R-CHOP and 60 percent received high-dose methotrexate.
Receipt of intensified induction therapy including both high-dose methotrexate and cytarabine was associated with an improved complete response rate of 69 percent compared with 51 percent in patients treated less aggressively. Intensive therapy was also associated with improved two-year progression-free and overall survival (50 and 54 percent, respectively) compared with more conservative measures (31 and 44 percent, respectively).
•R-CHOP-M plus cytarabine and/or ifosfamide – In a retrospective multicenter analysis of 44 patients with synchronous systemic and CNS DLBCL , 35 patients (80 percent) received R-CHOP or an R-CHOP-like regimen for four to six cycles along with ≥3 cycles of high-dose methotrexate. Eleven of these patients also received high-dose cytarabine and/or ifosfamide, 28 received IT therapy, and 19 underwent consolidative HCT.
Among 41 patients receiving curative-intent chemotherapy, the overall response rate was 81 percent, with complete responses in 66 percent. Progression-free and overall survival rates in these patients at three years were 46 and 60 percent, respectively. On multivariable analysis, factors associated with improved progression-free and overall survival were receipt of R-CHOP and high-dose methotrexate-based induction therapy, a methotrexate dose of 3.5 g/m2, and achievement of complete response.
Palliative approaches — Patients who are not candidates for curative-intent therapy due to advanced age and medical comorbidities can be treated with lower-intensity approaches with palliative intent. These may include reduced-dose methotrexate, glucocorticoids, radiation therapy, or IT therapy in patients with symptomatic leptomeningeal disease. (See 'Adjunctive and palliative therapies' below.)
Patients with non-germinal center B cell-like (GCB) DLBCL may also be considered for treatment with ibrutinib or lenalidomide with or without rituximab. (See 'Ibrutinib' below and 'Lenalidomide' below.)
Relapsed DLBCL, secondary CNS disease
●Isolated CNS disease – For most patients relapsing with isolated CNS DLBCL in the absence of systemic lymphoma who are candidates for chemotherapy, we suggest treatment extrapolated from primary DLBCL of the CNS, with methotrexate-based induction therapy followed by consolidative autologous HCT after remission has been achieved.
For these patients, high-dose methotrexate may be given as monotherapy at doses of 3.5 to 8 g/m2, either alone or in combination with other agents. Trials from the International Extranodal Lymphoma Study Group (IELSG) in patients with primary CNS lymphoma have shown that methotrexate combined with cytarabine results in higher overall response rate, complete response rate, and progression-free survival compared with methotrexate alone . Therefore, combination regimens are usually preferred when possible. Specific combination regimens are reviewed below. (See 'Methotrexate-based induction regimens' below.)
●Combined CNS and systemic disease – For patients with concurrent CNS and systemic disease at the time of relapse who are candidates for chemotherapy, options to induce durable control of systemic and CNS disease include MATRix-RICE (table 4 and table 5) or MAR (methotrexate, cytarabine, rituximab). Options for patients who are not candidates for methotrexate include RICE (table 5) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin). Eligible patients should proceed to consolidative thiotepa-based HCT if they respond to induction chemotherapy. Selection of a specific regimen is individualized based on patient-, disease-, and prior treatment-related factors. (See 'Pretreatment considerations' above and 'Methotrexate-based induction regimens' below.)
●Medically unfit or chemotherapy refractory – Treatment of medically unfit and/or chemotherapy refractory patients is individualized with a focus on relieving symptoms. Patients with bulky, symptomatic disease at a single site or region (eg, cauda equina, base of skull) may benefit from a short course of palliative radiation, especially when painful radiculopathy is a dominant symptom. Chemotherapy-refractory patients who maintain a reasonable functional status may be eligible for chimeric antigen receptor T (CAR-T) cell therapy or other novel agents. (See 'Medically unfit or chemotherapy refractory' below and 'Adjunctive and palliative therapies' below.)
Route of methotrexate — We administer methotrexate systemically in patients with parenchymal CNS involvement as well as in those with leptomeningeal disease when possible, using doses that are adequate to achieve uniform CNS penetration (eg, 3 to 8 g/m2) [11,13]. Experts vary in the use of IT methotrexate for patients with isolated or concurrent leptomeningeal involvement. We generally reserve IT therapy for patients who fail or cannot receive adequate systemic doses of methotrexate, or in combination with systemic methotrexate for patients with highly symptomatic leptomeningeal disease in hopes of achieving a more rapid symptomatic response. Others may use IT therapy more routinely in combination with systemic therapy for patients with predominant leptomeningeal involvement. (See 'Intrathecal therapy' below.)
Methotrexate-based induction regimens — High-dose methotrexate is the cornerstone of treatment for primary and secondary CNS lymphoma.
Unlike most drugs used to treat systemic lymphoma, high-dose methotrexate (eg, 3 to 8 g/m2) efficiently crosses the blood-brain barrier and distributes throughout the CNS [13,21-23]. In retrospective studies of patients with secondary CNS lymphoma, regimens that include methotrexate are associated with consistently longer survival than those that do not include methotrexate [2,24].
Induction regimens that have been studied prospectively in patients with primary CNS lymphoma and are used primarily in patients with isolated secondary CNS DLBCL include the following:
●MAR and MATRix – In a three-arm IELSG32 phase II trial, methotrexate-cytarabine (MA) was compared with MA plus rituximab (MAR; 375 mg/m2 on days -5 and 0) and MA plus rituximab and thiotepa (30 mg/m2 on day 4) in a third arm (MATRix) (table 4) . The methotrexate dose in all three regimens was 3.5 g/m2 every two weeks, and cytarabine was given at a dose of 2 g/m2 every 12 hours for two days every two weeks. At the end of the first randomization, complete response rates were higher with MAR (30 percent) and MATRix (49 percent) compared with MA alone (23 percent). Grade 4 hematologic toxicity was also highest with MATRix. Patients subsequently underwent a second randomization to consolidative therapy with either high-dose chemotherapy and autologous HCT versus whole brain radiation therapy. (See 'Consolidation chemotherapy with autologous HCT' below.)
●MTR (methotrexate, temozolomide, rituximab) – The Alliance cooperative group in the United States evaluated the MTR regimen (table 4) in previously untreated primary CNS DLBCL . Methotrexate was administered at 8 g/m2 every two weeks with leucovorin rescue for a total of five monthly cycles. No IT chemotherapy was included. The overall and complete response rates to induction therapy were 77 and 66 percent, respectively. All patients subsequently received consolidative therapy with etoposide and cytarabine. At two years, the progression-free survival was 57 percent.
Induction regimens studied prospectively in patients with concurrent CNS and systemic DLBCL at relapse include the following:
●Intensified MAR – A phase II Italian study incorporated sequential high-dose alkylating therapy followed by autologous HCT in 38 patients with secondary CNS DLBCL (median age 58 years, 84 percent with DLBCL, either newly diagnosed or relapsed disease) . Initial treatment consisted of two cycles of MAR (methotrexate 3.5 g/m2 on day 1, cytarabine 2 g/m2 every 12 hours on days 1 to 2, and rituximab 375 mg/m2 on days 3 and 11) on a 21-day schedule . Patients with bulky symptomatic systemic disease could receive one to two lead-in cycles of R-CHOP for systemic cytoreduction. Responding patients proceeded to an intensification phase of sequential high-dose antimetabolites, each combined with two doses of rituximab. All patients also received IT therapy during induction and intensification. Responding patients after intensification then went on to consolidative high-dose carmustine/thiotepa with autologous HCT.
The overall and complete response rates were 74 and 24 percent, respectively, after induction; 63 and 61 percent, respectively, after intensification; and 63 percent for both after all therapy . The five-year event-free and overall survival rates were 40 and 41 percent and were improved among patients who underwent HCT. Among 20 transplanted patients, five-year event-free and overall survival rates were 63 and 68 percent.
●MATRix-RICE – The MARIETTA study of MATRix plus RICE (rituximab, ifosfamide, carboplatin, etoposide) (table 5) followed by autologous HCT included 47 patients up to 70 years old with secondary CNS DLBCL at relapse (either isolated CNS or concurrent systemic disease) and 32 patients with newly diagnosed, synchronous CNS and systemic DLBCL . Treatment consisted of three cycles of MATRix followed by three cycles of RICE; IT chemotherapy was also included in all induction cycles. All responding patients postinduction then received consolidation with high-dose carmustine and thiotepa with autologous HCT.
The overall response rate to MATRix-RICE was 65 percent, with 39 percent of patients achieving complete remission . Progression-free survival at one year was 58 percent and was best in the 32 patients who were enrolled at initial diagnosis and in the 37 patients who proceeded to HCT. Two-year progression-free and overall survival rates were both 46 percent (83 percent among transplanted patients). Survival was similar in patients who had CNS involvement at diagnosis or relapse and in patients with or without concomitant systemic lymphoma involvement.
●R-DHAP-methotrexate – A phase II multicenter trial in the Netherlands (HOVON 80) included 36 patients with secondary CNS DLBCL (median age 57 years) treated with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin) plus methotrexate . Each cycle consisted of dexamethasone 40 mg on days 1 to 4, cisplatin 100 mg/m2 on day 1, cytarabine 2 g/m2 on day 2, rituximab 375 mg/m2 on day 5, and methotrexate 3 g/m2 on day 15. IT rituximab was also included. Patients received up to three 21-day cycles of treatment, and responding patients proceeded to consolidative busulfan/cyclophosphamide high-dose chemotherapy with autologous HCT. The median time from lymphoma diagnosis to CNS relapse was 12 months, and 56 percent of patients had concurrent systemic and CNS disease at relapse.
The overall and complete response rates after two cycles of R-DHAP-M were 53 and 22 percent, respectively, and 42 percent proceeded to autologous HCT. At one year, the progression-free and overall survival rates were a disappointing 19 and 25 percent, respectively. Patients with concomitant systemic lymphoma involvement did worse than patients with isolated CNS relapse.
Consolidation chemotherapy with autologous HCT — High-dose chemotherapy using CNS-penetrating agents (eg, thiotepa) with autologous HCT has emerged as an appropriate consolidative therapy after induction treatment for secondary CNS DLBCL in eligible patients. In retrospective and prospective studies, thiotepa-based HCT has encouraging durability of response in these high-risk patients, with three-year progression-free and overall survival as high as 75 to 80 percent [3,17,20,27,29-34].
Both retrospective and small prospective studies must be interpreted in the context of the favorable subset of patients who are considered candidates for HCT consolidation. Transplant candidates are sufficiently young and fit to tolerate high-dose chemotherapy and have had chemotherapy-sensitive disease demonstrated after induction therapy. That said, these studies importantly demonstrate that for patients who do meet these criteria, durable remission and survival can be achieved in a significant proportion of eligible patients.
Phase II trials incorporating HCT for secondary CNS DLBCL are summarized below:
●A German prospective multicenter study included 30 adults with relapsed systemic and CNS DLBCL (median age 58 years) . CNS disease involved brain parenchyma in over half of patients, leptomeninges in 23 percent, and both in 20 percent. Following sequential induction therapy that included methotrexate (4 g/m2), cytarabine, thiotepa, ifosfamide, dexamethasone, and IT liposomal cytarabine, 24 responding patients (80 percent) received high-dose chemotherapy (carmustine, thiotepa, and etoposide) and autologous HCT. Among patients who completed HCT, median progression-free survival was 24 months, and two-year overall survival was 68 percent.
●In the Italian phase II study discussed above of MAR induction, followed by sequential high-dose antimetabolite intensification, followed by high-dose chemotherapy with autologous HCT, 38 patients were enrolled and 20 (52 percent) underwent HCT consolidation with carmustine/thiotepa . The five-year event-free and overall survival rates for transplanted patients were 63 and 68 percent, respectively. (See 'Methotrexate-based induction regimens' above.)
●The MARIETTA study discussed above of MATRix-RICE followed by carmustine/thiotepa with autologous HCT in responding patients included 75 patients, 37 (49 percent) of whom ultimately proceeded to HCT . At two years, the progression-free and overall survival rates for transplanted patients were both 83 percent. (See 'Methotrexate-based induction regimens' above.)
Medically unfit or chemotherapy refractory — For patients unfit for intensive chemotherapy and those with relapsed/refractory disease, novel agent strategies can be used, depending on lymphoma subtype. Patients with CNS relapse of DLBCL as well as certain other histologies (eg, high-grade B cell lymphoma, transformed indolent non-Hodgkin lymphoma [NHL], and primary mediastinal B cell lymphoma) should be considered for anti-CD19 CAR-T cells if they have received at least two prior lines of lymphoma therapy.
Radiation therapy can also provide palliative benefit, particularly when disease is bulky and symptomatic. (See 'Radiation therapy' below.)
Ibrutinib — The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has modest efficacy in systemic DLBCL, particularly in the activated B cell-like (ABC) subtype, where responses have been observed in 37 percent of patients . Encouraging activity has also been observed in primary CNS DLBCL, which is enriched for the ABC subtype and mutations in MYD88 and CD79B, all of which appear to increase the likelihood of ibrutinib response.
A phase I study of ibrutinib in patients with relapsed primary or secondary CNS DLBCL evaluated doses of 420 to 840 mg orally daily . No dose-limiting toxicities were observed, and ibrutinib was confirmed to achieve therapeutic levels in the CNS. Among seven patients with secondary CNS lymphoma, there were five responses, including four complete remissions; median progression-free survival was 7.4 months . In a phase II clinical trial of ibrutinib 560 mg orally daily in 44 evaluable patients with relapsed/refractory primary CNS lymphoma, there were 10 complete and 17 partial responses, for an overall response rate of 61 percent .
Lenalidomide — Lenalidomide also has preferential activity within systemic DLBCL of the ABC subtype. A phase I trial evaluated lenalidomide orally once daily at doses of 10 to 20 mg, plus intravenous (IV) rituximab. Among six patients with relapsed/refractory secondary CNS DLBCL, there were two complete responses .
Checkpoint inhibitors — Patients with primary mediastinal B cell lymphoma may be uniquely sensitive to programmed cell death protein 1 (PD-1) inhibitor therapy, making the anti-PD-1 inhibitors pembrolizumab or nivolumab appealing options for these patients in the relapsed setting .
Beyond this subtype, additional data are required for immune checkpoint inhibitors in primary and secondary CNS DLBCL. In a case report, nivolumab produced a complete response in a patient with CNS relapse of primary testicular DLBCL .
Chimeric antigen receptor T cell therapy — CAR-T cells targeting CD19 are approved by the US Food and Drug Administration (FDA) for the treatment of relapsed/refractory DLBCL (de novo or transformed from indolent B cell NHL), high-grade B cell lymphoma, mantle cell lymphoma (MCL), and follicular lymphoma.
Among pivotal trials for the approved CAR-T cell products, the study of lisocabtagene maraleucel was the only one to enroll patients with CNS involvement, and efficacy in the CNS was demonstrated . The axicabtagene ciloleucel and tisagenlecleucel trials excluded patients with CNS lymphoma involvement [42,43]; however, both have been reported to be effective in retrospective analyses using commercial product [44-46]. These data validate that CAR-T cells traffic to the CNS, where they can induce durable responses in patients with secondary CNS lymphoma involvement.
Available data for specific products in patients with secondary CNS lymphoma include the following:
●Lisocabtagene maraleucel – In the TRANSCEND NHL trial of lisocabtagene maraleucel, three of six evaluable patients with heavily pretreated secondary CNS DLBCL achieved a complete response [41,47]. All patients also had concomitant systemic lymphoma involvement.
●Tisagenlecleucel – A retrospective single-center analysis of eight patients treated with tisagenlecleucel for secondary CNS DLBCL, high-grade B cell lymphoma, or primary mediastinal B cell lymphoma reported two complete and two partial responses . Responses were observed in patients who had isolated CNS lymphoma as well as those with concomitant systemic disease. Only one patient had grade 1 neurotoxicity.
●Axicabtagene ciloleucel – A retrospective multicenter study included five patients with active secondary CNS DLBCL treated with axicabtagene ciloleucel [45,46]. Among these, there were three responses, two of which were complete.
Use of CAR-T cell therapy in relapsed/refractory DLBCL is reviewed in more detail separately. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Chimeric antigen receptor T cell therapy'.)
Adjunctive and palliative therapies
●Patient selection – We generally reserve IT therapy for patients with leptomeningeal-predominant disease who fail or cannot receive adequate systemic doses of methotrexate . IT therapy may also be used adjunctively with systemic therapy in patients with symptomatic leptomeningeal disease with the goal of achieving rapid cytoreduction and symptomatic improvement. When using IT therapy adjunctively, we typically administer concurrent IT therapy until the cerebrospinal fluid (CSF) has demonstrated clearance of lymphoma cells, at which time we continue systemic therapy alone. Others may use IT therapy more routinely as part of intensive multidrug consolidation regimens discussed above. (See 'Methotrexate-based induction regimens' above.)
●Delivery methods – IT chemotherapy can be administered by lumbar puncture (LP) or through a ventricular reservoir (Ommaya). Although Ommaya reservoir insertion requires a neurosurgical procedure, it avoids the need for repeated LPs and improves the distribution of chemotherapy within the subarachnoid space. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Route of administration'.)
Of note, IT chemotherapy should not be administered in patients with hydrocephalus or other evidence of abnormal CSF flow, as complete or partial block increases the risk of toxicity. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Candidates for IT therapy'.)
●Specific agents – Cytarabine and methotrexate are the two most commonly used agents, either alone or as a three-drug combination with hydrocortisone . Both methotrexate and cytarabine have activity in NHL and can be administered alone or in combination with concomitant CNS-directed systemic therapy. Administration of IT chemotherapy is discussed in more detail elsewhere. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Intrathecal therapy'.)
Radiation therapy — Radiation therapy is effective for most types of NHL, but short- and long-term neurocognitive effects limit the use of brain radiation for disseminated CNS lymphoma. Craniospinal radiation therapy is also associated with significant bone marrow toxicity, particularly in patients with secondary CNS lymphoma who have received prior systemic therapy.
Focal radiation therapy can nonetheless be useful for palliation in patients with bulky foci of disease causing mass effect and edema. Glucocorticoids should always be administered concomitantly to treat severe edema. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Symptomatic treatment'.)
Radiation to an involved area of the spine can achieve effective short-term palliation in patients with refractory pain due to nerve root involvement. Whole brain radiation is a palliative option in patients with multiple cranial neuropathies who are not eligible for chemotherapy, or as a potential bridge therapy in patients with bulky parenchymal disease .
OTHER LYMPHOMA HISTOLOGIES — Data to guide CNS therapy in lymphomas other than diffuse large B cell lymphoma (DLBCL) and other high-grade B cell lymphomas are limited. In general, we recommend use of therapies that are proven to be effective in the systemic setting, as long as those therapies are known to cross the blood-brain barrier.
Most notably, this includes the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, which is approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM); the second-generation BTK inhibitor zanubrutinib is also approved for CLL, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and LPL/WM with case reports of activity in CNS disease; lenalidomide, which induces responses in secondary CNS DLBCL and is highly active in the treatment of systemic follicular lymphoma, MCL, MZL, and LPL/WM; and CAR-T cells, which induce responses in secondary CNS DLBCL and have also been approved for relapsed/refractory systemic follicular lymphoma and MCL.
Chronic lymphocytic leukemia — CNS involvement is rare in patients with CLL. When the CNS is involved, the distribution is usually leptomeningeal rather than parenchymal. Care must be taken to gauge true cerebrospinal fluid (CSF) involvement, however, as any peripheral blood contamination at the time of lumbar puncture (LP) can lead to detectable CLL by cytology and flow cytometry.
For patients with secondary CNS involvement by CLL who are ibrutinib naïve, we treat with ibrutinib with or without an anti-CD20 monoclonal antibody and continue ibrutinib until progression or intolerance. Ibrutinib crosses the blood-brain barrier and induces durable response in CNS CLL. As an example, among six patients treated with ibrutinib for active CLL within the CNS, there were three complete and three partial responses, including durable remissions . Responses were observed in the parenchymal as well as leptomeningeal compartments.
The B cell leukemia/lymphoma 2 (BCL2) inhibitor venetoclax has also been demonstrated to cross the blood-brain barrier, but with only anecdotal evidence of responses to date [51,52]; additional data are needed. Intrathecal (IT) cytarabine and/or rituximab can be considered as an adjunctive treatment to accelerate clearance of leptomeningeal CLL, if needed.
Mantle cell lymphoma — MCL rarely progresses in the CNS and may involve the leptomeningeal or parenchymal compartments. BTK inhibitors are also standard treatments for relapsed systemic MCL, and durable responses have been reported with ibrutinib for secondary CNS involvement by MCL . A case series of five patients treated with ibrutinib for CNS MCL reported responses in all five patients, one of whom was treated as monotherapy and the remainder in combination with additional agents (cytarabine, methotrexate, glucocorticoids) .
In patients who progress on a BTK inhibitor, the anti-CD19 chimeric antigen receptor T (CAR-T) cell brexucabtagene autoleucel has been approved for relapsed/refractory MCL with high rates of complete remission and should be considered for appropriate patients with CNS involvement by MCL not responding to a BTK inhibitor .
Lenalidomide and venetoclax each penetrate the CNS and have significant activity in relapsed systemic MCL, warranting further investigation in secondary CNS MCL. Methotrexate, cytarabine, and rituximab may have activity, both intravenous (IV) and IT, and can be considered in patients refractory to targeted therapies.
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia — LPL/WM may involve the leptomeninges, in which case it is known as Bing-Neel syndrome [56-59]. Ibrutinib is approved and available for the treatment of systemic LPL/WM and has been studied retrospectively in 28 patients with Bing-Neel syndrome . Ibrutinib monotherapy led to symptomatic improvement in 85 percent of patients, radiographic improvement in 83 percent, and complete CSF remission in 47 percent. Five-year overall survival was 82 percent.
Marginal zone lymphoma — MZL is a low-grade B cell lymphoma that rarely presents within the CNS and most commonly involves the dura, where it can mimic meningioma; parenchymal and intraocular presentations have also been reported [62-65]. These lesions may be focal and in this setting are optimally treated with complete surgical excision or involved field radiation therapy, with high rates of complete and durable remission.
Follicular lymphoma — Follicular lymphoma is the most common indolent B cell lymphoma but rarely involves the CNS. As with MZL, follicular lymphoma may present as a primary dural lymphoma . When localized, involved field radiation therapy is the preferred treatment, as follicular lymphoma has high rates of complete response to radiation, even when administered at low doses.
For systemic therapy, lenalidomide-rituximab may be considered for the rare patient with diffuse CNS involvement based on high rates of response, including durable complete remissions, in systemic follicular lymphoma. The anti-CD19 CAR-T cell therapies axicabtagene ciloleucel and tisagenlecleucel are approved for relapsed/refractory follicular lymphoma after at least two prior lines of therapy and should be considered in such patients with CNS involvement, given the proven ability of these products to cross the blood-brain barrier and induce lymphoma responses in the CNS [68,69]. Tisagenlecleucel has lower rates of CNS toxicity and so may be preferred.
Peripheral T/NK cell lymphomas — Peripheral T/NK cell lymphomas are a heterogeneous collection of uncommon lymphomas that rarely disseminate to the CNS. The most common T cell lymphoma subtypes reported with CNS relapses are peripheral T cell lymphoma not otherwise specified (PTCL NOS), anaplastic large cell lymphoma (ALCL), extranodal NK/T cell lymphoma (ENKTL), acute T cell leukemia/lymphoma (ATLL), angioimmunoblastic T cell lymphoma (AITL), and enteropathy-associated T cell lymphoma (EATL) [70-74].
Most PTCLs are aggressive diseases with inferior outcomes compared with DLBCL , and published series in CNS relapse of PTCL consistently report median overall survival of only one to two months [70,71,73,74]. ALCLs, particularly the anaplastic lymphoma kinase (ALK)-positive subtype of ALCL, appear to have higher chances for cure than other PTCLs in the CNS.
No standard approach to management exists. These tumors may be chemotherapy sensitive, and so for most cases induction therapy incorporating high-dose methotrexate and cytarabine followed by consolidative thiotepa-based autologous HCT in responding patients may offer the best opportunity for durable remission in sufficiently young, fit patients.
For ALK-positive ALCL not achieving complete response to chemotherapy, oral ALK inhibitors such as crizotinib and alectinib can cross the blood-brain barrier and induce responses, as they can in chemotherapy-refractory systemic ALK-positive ALCL [76,77]. ENKTL is an Epstein-Barr virus (EBV)-associated T cell lymphoma that commonly expresses programmed cell death ligand 1 (PD-L1), and preliminary efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab has been demonstrated, making this a rational strategy in relapsed ENKTL with CNS disease .
SUMMARY AND RECOMMENDATIONS
●Prognostic assessment – Secondary central nervous system (CNS) involvement by lymphoma, most commonly diffuse large B cell lymphoma (DLBCL), is generally associated with a poor prognosis and limited long-term survival. However, prolonged survival is possible, especially for younger patients with good performance status and either a synchronous presentation of CNS and systemic DLBCL or an isolated CNS recurrence. (See 'Prognosis' above.)
●Acute symptom management – Patients often have acute neurologic symptoms including altered mental status, cranial neuropathies, weakness, and seizures. Glucocorticoids and antiseizure medications should be administered symptomatically to maximize pretreatment performance status. (See 'Acute symptom management' above.)
●Treatment selection for DLBCL – When an aggressive approach is feasible, treatment consists of induction therapy with a methotrexate-based regimen followed by consideration of consolidative therapy with high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) in eligible patients.
Selection of an induction regimen is based on disease distribution (isolated CNS versus CNS plus systemic), stage (newly diagnosed versus relapsed), and prior therapies.
•For most patients with newly diagnosed DLBCL with synchronous CNS and systemic involvement, we suggest induction therapy with R-CHOP (table 3) plus high-dose methotrexate (Grade 2C). Reasonable alternatives include MATRix-RICE (table 4 and table 5), R-Hyper-CVAD/MA, and R-CODOX-M/IVAC (table 6). (See 'Curative-intent regimens' above.)
•For most patients with relapsed DLBCL with isolated CNS involvement, we suggest induction therapy with a high-dose methotrexate-based multidrug regimen, rather than methotrexate alone (Grade 2C). Examples of acceptable regimens include MAR (methotrexate, cytarabine, rituximab), MATRix (MAR plus thiotepa), and MTR (methotrexate, temozolomide, rituximab) (table 4). (See 'Methotrexate-based induction regimens' above.)
•For patients with relapsed DLBCL with concurrent CNS and systemic involvement, induction options to induce durable control of both CNS and systemic disease include MATRix-RICE (table 4 and table 5) and MAR (methotrexate, cytarabine, rituximab). (See 'Methotrexate-based induction regimens' above.)
Systemic options in such patients who cannot receive methotrexate include R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin), RICE (table 5), and either ibrutinib or lenalidomide in patients with activated B cell-like/non-germinal center B cell-like (ABC/non-GCB) DLBCL. (See 'Our approach' above.)
Eligible patients should proceed to consolidative high-dose chemotherapy with autologous HCT if they respond to induction chemotherapy. (See 'Consolidation chemotherapy with autologous HCT' above.)
Patients who are not chemotherapy candidates, or who relapse after induction and consolidative therapy, are considered for alternative therapies including additional chemotherapy, radiation, novel and targeted agents, and cellular immunotherapy. (See 'Palliative approaches' above and 'Medically unfit or chemotherapy refractory' above and 'Radiation therapy' above.)
●Lymphomas other than DLBCL – Management of secondary CNS involvement of other lymphoma histologies is individualized. We prioritize use of agents proven to be effective in the systemic setting, as long as those therapies cross the blood-brain barrier, such as ibrutinib and lenalidomide. (See 'Other lymphoma histologies' above.)
●Role of intrathecal (IT) therapy – We generally reserve IT therapy for patients who fail or cannot receive adequate systemic doses of methotrexate. It may also be used adjunctively with systemic therapy in patients with highly symptomatic leptomeningeal disease in order to achieve more rapid symptom control. (See 'Intrathecal therapy' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Andrew Norden, MD, Ephraim Hochberg, MD, Fred H Hochberg, MD, and Joachim M Baehring, MD, DSc, who contributed to earlier versions of this topic review.
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