General Information About Primary Central Nervous System (CNS) Lymphoma

Primary CNS lymphoma is defined as lymphoma limited to the cranial-spinal axis, including the brain, spinal cord, cerebrospinal fluid (leptomeningeal space), and vitreoretinal space (ocular space), without systemic disease (stage IE).[1] This disease has increasingly been seen among immunocompromised patients, such as those with HIV. Immunosuppression-related primary CNS lymphomas are almost always associated with the Epstein-Barr virus.

Histology

Almost all primary CNS lymphomas are diffuse large B-cell lymphomas of the activated B-cell nongerminal center subtype with additional mutations in the B-cell receptor signaling pathway, especially MYD88 and CD79B mutations.[1] However, patients with immunosuppression-related disease almost never have an activated B-cell phenotype.[2]

More than 95% of patients with primary CNS lymphoma have B-cell phenoptype. However, in a retrospective series with data collected from 12 cancer centers, the 45 patients with CNS lymphoma of T-cell phenotype showed no difference in presentation or outcome.[3]

Anecdotal cases of primary CNS Hodgkin lymphoma have also been reported.[4]

Diagnostic Evaluation

Computed tomography (CT) scans are used to diagnose primary CNS lymphoma. This scan may show ring enhancement in 50% of patients with HIV, while homogenous enhancement is almost always seen in patients without HIV.[5]

Positron emission tomography (PET)–CT scans are used to exclude occult systemic disease of the chest, abdomen, and pelvis. A bone marrow biopsy may be excluded with a clear PET-CT scan.[6] All compartments of the CNS should be evaluated, even if asymptomatic, including the vitreoretinal compartment and the cerebrospinal fluid (CSF) when feasible.

In one prospective case series of 282 patients with primary CNS lymphoma, 17% of patients were found to have meningeal dissemination by cytomorphology, polymerase chain reaction of rearranged immunoglobulin heavy-chain genes, or meningeal enhancement on magnetic resonance imaging.[7]

Prognosis and Prognostic Factors

Median overall survival in published trials generally ranges from 2 to 5 years,[8,9] although a retrospective case series of 40 patients with low-grade primary CNS lymphoma derived from 18 cancer centers in five countries reported a better long-term outcome (median survival, 7 years) than is associated with the usually aggressive CNS lymphoma.[10][Level of evidence C3]

Poor prognostic factors for primary CNS lymphoma include the following:[11]

• Age older than 60 years.
• HIV positivity.
• Elevated serum level of lactate dehydrogenase.
• Elevated CSF protein concentration.
• Involvement of nonhemispheric areas of the brain (periventricular, basal ganglia, brainstem, and cerebellum).
• Intraocular disease and concomitant brain involvement.[12] When tumor progression occurs, it is usually confined to the CNS and/or the eye.[1]

Older age and HIV positivity are the most clinically relevant poor prognostic factors. However, the prognosis for patients with HIV-associated primary CNS lymphoma has improved with the use of highly active antiretroviral therapy.[13] These patients are treated with the same paradigm as patients who do not have HIV or immunosuppression.

References:

1. Schaff LR, Grommes C: Primary central nervous system lymphoma. Blood 140 (9): 971-979, 2022.
2. Gandhi MK, Hoang T, Law SC, et al.: EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity. Blood 137 (11): 1468-1477, 2021.
3. Shenkier TN, Blay JY, O'Neill BP, et al.: Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol 23 (10): 2233-9, 2005.
4. Gerstner ER, Abrey LE, Schiff D, et al.: CNS Hodgkin lymphoma. Blood 112 (5): 1658-61, 2008.
5. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993.
6. Jelicic J, Hansen DL, Carlsen SS, et al.: Is it possible to omit bone marrow biopsy in diagnostic workup in patients with newly diagnosed primary CNS lymphoma? A retrospective analysis in the PET/CT era. [Abstract] Blood 140 (Suppl 1): A-627, 1334-5, 2022.
7. Fischer L, Martus P, Weller M, et al.: Meningeal dissemination in primary CNS lymphoma: prospective evaluation of 282 patients. Neurology 71 (14): 1102-8, 2008.
8. Grommes C, DeAngelis LM: Primary CNS Lymphoma. J Clin Oncol 35 (21): 2410-2418, 2017.
9. Fox CP, Phillips EH, Smith J, et al.: Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. Br J Haematol 184 (3): 348-363, 2019.
10. Jahnke K, Korfel A, O'Neill BP, et al.: International study on low-grade primary central nervous system lymphoma. Ann Neurol 59 (5): 755-62, 2006.
11. Lukas RV, Stupp R, Gondi V, et al.: Primary Central Nervous System Lymphoma-PART 1: Epidemiology, Diagnosis, Staging, and Prognosis. Oncology (Williston Park) 32 (1): 17-22, 2018.
12. Kreher S, Strehlow F, Martus P, et al.: Prognostic impact of intraocular involvement in primary CNS lymphoma: experience from the G-PCNSL-SG1 trial. Ann Hematol 94 (3): 409-14, 2015.
13. Gupta NK, Nolan A, Omuro A, et al.: Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro Oncol 19 (1): 99-108, 2017.

Treatment of Primary CNS Lymphoma

Treatment Options for Primary CNS Lymphoma

Treatment options for primary CNS lymphoma include the following:

1. Induction therapy.
2. Consolidation after induction therapy.

Induction therapy

Trials using chemotherapy alone were justified because of the unsatisfactory results of using whole-brain radiation therapy (WBRT) alone [1,2] and significant neurological toxicity using high-dose methotrexate or other chemotherapeutic agents that cross the blood-brain barrier in combination with WBRT.[3,4,5]

Severe, delayed, neurological toxic effects were rarely seen in chemotherapy-only trials in the absence of subsequent radiation therapy. However, salvage radiation can be given for relapsed or refractory disease, sometimes at reduced dosage.[6,7]

Numerous phase I and phase II studies over two decades established the following active drugs for induction therapy or for treatment of relapsing disease. The following drugs have been used as single agents and in combinations:

• High-dose methotrexate.[8,9,10,11,12,13] Outside of clinical trials, high-dose methotrexate is the most frequently used standard induction therapy.[14] However, it is given to inpatients, and it is too toxic for patients with a creatinine clearance under 35 cc/min or for most patients older than 75 years.
• Lenalidomide with rituximab.[15] When high-dose chemotherapy is not feasible, this is the most frequently used combination. Lenalidomide can be initiated at low doses (e.g., 5 mg daily, 21 out of 28 days) in the setting of renal insufficiency.
• High-dose cytarabine.[12,13,16]
• Rituximab.[16,17,18]
• Thiotepa.[18,19]
• Temozolamide.[20]
• Ibrutinib.[21,22]
• Procarbazine.[23]
• Vincristine.[23]
• Pomalidomide.[24]
• Nivolumab.[25]

Evidence (chemotherapy with or without other therapy):

1. The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3). With a median follow-up of 88 months, the overall survival (OS) rate was:[26][Level of evidence A1]
   • 21% for group 1.
   • 37% for group 2.
   • 56% for group 3.

   The groups were compared as follows:

   • Group 1 versus group 2: hazard ratio (HR), 0.64; 95% confidence interval [CI], 0.41–0.99; P = .04.
   • Group 1 versus group 3: HR, 0.42; 95% CI, 0.24–0.64; P = .00005.
   • Group 2 versus group 3: HR, 0.66; 95% CI, 0.44–0.98; P = .04.

   The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

   • The 113 patients who attained a complete response (CR), partial response, or stable disease were randomly assigned to 36 Gy whole-brain radiation therapy versus autologous stem cell transplant (ASCT) after thiotepa + bic-chloroethylnitrosourea + carmustine (BCNU) conditioning. No significant differences were seen in 7-year PFS or OS in regard to consolidation in this phase II trial.[26][Level of evidence B1]
   • The thiotepa + BCNU conditioning regimen was well tolerated by patients aged 60 to 70 years. It had improved tolerability compared with prior reports using the more intensive thiotepa + bulsulfan regimen.[26][Level of evidence D]
   • Patients who received the two-drug combination had a complete remission rate of 23% (interquartile range [IQR], 14%‒31%; HR, 0.46; 95% CI, 0.28‒0.74). Patients who received the three-drug combination had a complete remission rate of 30% (IQR, 21%‒42%; HR, 0.61; 95% CI, 0.40‒0.94). Patients who received the four-drug MATRix combination had a complete remission rate of 49% (95% CI, 38%‒60%).
   • The addition of rituximab and thiotepa to high-dose methotrexate plus cytarabine resulted in a significant improvement in CR, PFS, and OS.[26][Level of evidence A1]
2. In a randomized, nonblinded multicenter trial, 79 patients were assigned to receive high-dose methotrexate with or without cytarabine.[27][Level of evidence B1]
   • The 3-year PFS rate was better for patients who received the two-drug regimen (HR, 0.54; 95% CI, 0.31–0.92; P = .01).
   • There was no statistical difference in the 3-year OS rate (46% for the two-drug regimen vs. 32% for the one-drug regimen; HR, 0.65; 95% CI, 0.38–1.13; P = .07).
   • This trial was the basis for setting the combination of high-dose methotrexate and high-dose cytarabine as the control arm in the MATRix trial.
3. In a randomized, prospective, multicenter trial, 200 patients were assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab.[28][Level of evidence B1]
   • With a median follow-up of 32.9 months, there was no difference in the 1-year event-free survival (EFS) rate: 52% with rituximab (95% CI, 42%−61%) and 49% without rituximab (95% CI, 39%−58%; HR, 1.00; 95% CI, 0.70−1.43; P = .99).
4. Several other combination induction regimens were created empirically and presented as phase II trials.[29][Level of evidence C3]
   • Rituximab + high-dose methotrexate + procarbazine + vincristine (R-MPV) (objective response rate [ORR], 97%; CR, 66%)[23].
   • High-dose methotrexate + rituximab + temozolamide (HD MTX + R + TEM) (ORR, 80%; CR, 66%).[20]
   • High-dose methotrexate ± rituximab (HD MTX ± R) + other chemotherapy (retrospective analysis of 885 patients) (ORR, 59%; CR, 50%).[29]

Summary

High-dose methotrexate regimens delivered with rituximab and other chemotherapeutic agents is used for induction therapy. The MATRix regimen described above has become one such standard based on randomized OS benefit with a four-drug regimen versus a two-drug or a three-drug regimen.[26][Level of evidence 1A] The MATRix regimen has never been compared with some of the other combination therapies mentioned above. A meta-analysis of rituximab randomized trials found improved PFS with the addition of rituximab (HR, 0.65; 95% CI, 0.45–0.95) but no difference in OS.[30][Level of evidence B2]

Consolidation after induction chemotherapy

Consolidation therapy with or without WBRT

Evidence (consolidation therapy with or without WBRT):

1. In a prospective, randomized, phase II trial, 87 patients (median age, 59–66 years) had induction therapy with high-dose methotrexate + high-dose cytarabine + rituximab + procarbazine + vincristine. Afterward, 37 patients had consolidation therapy with low-dose WBRT at 23.4 Gy.[31]
   • With a median follow-up of 55 months, the 2-year intention-to-treat PFS was 78% with low-dose WBRT versus 54% without low-dose WBRT (HR, 0.51; P = .015).[31][Level of evidence B1]
   • Investigator-assessed neurotoxicity was less than 15% in each arm and not significantly different. Another small phase II trial that examined low-dose WBRT at 23.4 Gy also found no increased problems seen on neuropsychological testing.[32,33]
2. In a prospective, randomized, phase II trial of 97 newly diagnosed patients who received high-dose methotrexate combination therapy for induction, patients were randomly assigned to receive WBRT at 40 Gy versus ASCT.[34]
   • With a median follow-up of 8 years, deterioration of balance was significantly greater for patients who received WBRT versus patients who received ASCT (52% vs. 10%, P ≤ .001). Worsening neurocognition was also greater for patients who received WBRT (64% vs. 13%, P < .001).
   • The 8-year EFS rate was 67% for patients who received ASCT versus 39% for patients who received WBRT (HR, 0.13; P < .001). There was no significant difference in OS (69% for ASCT vs. 54% for WBRT).[34][Level of evidence B1]
   • The authors concluded that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and inferior efficacy.
3. In a prospective, randomized trial of 551 immunocompetent patients with newly diagnosed primary CNS lymphoma, all patients received induction chemotherapy with six cycles of high-dose methotrexate (4 g/m²) with or without ifosfamide. After chemotherapy was completed, responders were randomly assigned to receive either WBRT (45 Gy) or no treatment for complete-response patients and cytarabine for partial-response patients.[35]
   • There was no statistical difference in median OS at 32.4 months for patients who received WBRT versus at 37.1 months for those who did not receive WBRT (HR, 1.06; 95% CI, 0.80–1.40; P = .71).[35][Level of evidence A1]
   • Treatment-related neurotoxic effects were significantly worse in the WBRT arm.
4. In a prospective, randomized trial, 410 immunocompetent patients with newly diagnosed primary CNS lymphoma were scheduled to receive high-dose methotrexate. Patients were randomly assigned to receive either WBRT or no radiation therapy.[36]
   • In the intent-to-treat population, WBRT was associated with longer PFS at 15.4 months versus 9.9 months (HR, 0.79; 95% CI, 0.64–0.98; P = .034). There was no difference in OS at 32.4 months versus 36.1 months (HR, 0.98; 95% CI, 0.79–1.26; P = .98).[36][Level of evidence B1]
   • Long-term treatment-related neurotoxic effects were not reported, and the induction chemotherapy would now be considered substandard.

Summary

The significant neurotoxicity of standard dose WBRT [37] has reduced its role to short-duration disease control at relapse, when the expected survival is short enough that the benefit outweighs the longer-term neurological consequences. For patients unable to undergo consolidation with ASCT due to age, performance status, or comorbidities, low-dose WBRT (23.4 Gy) would be a consolidation option.

Consolidation therapy with or without ASCT

Evidence (consolidation therapy with or without ASCT):

1. In a prospective, randomized trial published in abstract form, 346 patients with newly diagnosed primary CNS lymphoma (patients aged 65 years and younger and patients aged 66–70 years with a performance status of 2 or lower) underwent induction therapy with 4 cycles of rituximab, high-dose methotrexate, high-dose cytarabine, and thiotepa (IELSG43 [NCT02531841]). Eighty-six patients discontinued treatment due to toxicity or progression. Of the 260 patients who completed induction therapy, 229 patients were randomly assigned to receive either chemotherapy consolidation with rituximab, dexamethasone, etoposide, ifosfamide, and carboplatin (n = 115) or ASCT using BCNU and thiotepa (n = 114).[38][Level of evidence A1]
   • With a median follow-up of 44 months, the 3-year OS rate was 86% (78%–91%) for ASCT versus 71% (61%–78%) for chemotherapy alone (HR, 0.47; P = .01).[38][Level of evidence A1]
   • The 3-year PFS was 79% (71%–86%) for ASCT versus 53% (43%–62%) for chemotherapy alone.
   • There was no negative effect on neurocognitive function in either arm in the absence of progression.
   • This was the first randomized trial establishing a survival advantage for newly diagnosed patients receiving ASCT who are young enough and healthy enough to endure this aggressive approach.
2. In a prospective, randomized, phase II trial, 97 newly diagnosed patients receiving high-dose methotrexate combination therapy for induction were randomly assigned to receive WBRT at 40 Gy or ASCT.[34]
   • With a median follow-up of 8 years, deterioration of balance was significantly greater for patients who received WBRT than for patients who received ASCT (52% vs. 10%, P ≤ .001). Worsening neurocognition was also greater for patients who received WBRT (64% vs. 13%, P < .001).
   • The 8-year EFS rate was 67% for patients who received ASCT versus 39% for patients who received WBRT (HR, 0.13; P < .001). There was no difference in OS (69% for ASCT vs. 65% for WBRT).[34][Level of evidence B1]
   • The authors concluded that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and inferior efficacy.
3. A prospective, randomized, phase II trial in newly diagnosed patients aged 75 years and younger received intensive induction therapy with high-dose methotrexate at 8 g/m² every 2 weeks, temozolamide, rituximab, and high-dose cytarabine. Patients were randomly assigned at the start of therapy to consolidation with thiotepa + BCNU conditioning with ASCT or nonmyeloablative therapy with high-dose cytarabine with a 46-hour infusion of etoposide (EA).[39]
   • With a median follow-up of 3.8 years, the median PFS was 6 years (95% CI, 3.9-NR) for ASCT versus 2.4 years (95% CI, 0.6-NR) for EA (P = .02).[39][Level of evidence B1]
   • PFS from time of consolidation was not statistically different (HR, 0.58; 95% CI, 0.25–1.36; P = .21).
   • There was no difference in the 3-year OS rate: 83% (69%–91%) for ASCT and 72% (57%–82%) for EA.
   • This trial showed the limitations of induction therapy, which affected the impact of consolidation.
4. Several phase II studies evaluated consolidation with intensive chemotherapy supported by ASCT.[19,20,23,40,41,42,43] This approach is appropriate for patients aged 80 years and under with few comorbidities, good performance status, and an adequate response to induction therapy.

Summary

Consolidation therapy with ASCT results in an OS advantage for newly diagnosed patients with good performance status, few comorbidities, and an adequate response to induction therapy (in this case, the MATRix regimen: high-dose methotrexate, high-dose cytarabine, rituximab, and temozolamide).[39] For patients unable to proceed to ASCT, consolidation with low-dose WBRT (32.4 Gy) or non-myeloablative therapy might be considered.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Pollack IF, Lunsford LD, Flickinger JC, et al.: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63 (5): 939-47, 1989.
2. Nelson DF, Martz KL, Bonner H, et al.: Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23 (1): 9-17, 1992.
3. Fisher B, Seiferheld W, Schultz C, et al.: Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma. J Neurooncol 74 (2): 201-5, 2005.
4. Ekenel M, Iwamoto FM, Ben-Porat LS, et al.: Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer 113 (5): 1025-31, 2008.
5. van der Meulen M, Dirven L, Habets EJJ, et al.: Cognitive functioning and health-related quality of life in patients with newly diagnosed primary CNS lymphoma: a systematic review. Lancet Oncol 19 (8): e407-e418, 2018.
6. Khimani NB, Ng AK, Chen YH, et al.: Salvage radiotherapy in patients with recurrent or refractory primary or secondary central nervous system lymphoma after methotrexate-based chemotherapy. Ann Oncol 22 (4): 979-84, 2011.
7. Shah GD, Yahalom J, Correa DD, et al.: Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25 (30): 4730-5, 2007.
8. Gavrilovic IT, Hormigo A, Yahalom J, et al.: Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 24 (28): 4570-4, 2006.
9. Blay JY, Conroy T, Chevreau C, et al.: High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 16 (3): 864-71, 1998.
10. 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 21 (6): 1044-9, 2003.
11. Hoang-Xuan K, Taillandier L, Chinot O, et al.: Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 21 (14): 2726-31, 2003.
12. Pels H, Schmidt-Wolf IG, Glasmacher A, et al.: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21 (24): 4489-95, 2003.
13. Juergens A, Pels H, Rogowski S, et al.: Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 67 (2): 182-9, 2010.
14. Schaff LR, Grommes C: Primary central nervous system lymphoma. Blood 140 (9): 971-979, 2022.
15. Ghesquieres H, Chevrier M, Laadhari M, et al.: Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol 30 (4): 621-628, 2019.
16. Chen YB, Batchelor T, Li S, et al.: Phase 2 trial of high-dose rituximab with high-dose cytarabine mobilization therapy and high-dose thiotepa, busulfan, and cyclophosphamide autologous stem cell transplantation in patients with central nervous system involvement by non-Hodgkin lymphoma. Cancer 121 (2): 226-33, 2015.
17. Mocikova H, Pytlik R, Sykorova A, et al.: Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry. Leuk Lymphoma 57 (12): 2777-2783, 2016.
18. Ferreri AJ, Cwynarski K, Pulczynski E, et al.: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 3 (5): e217-27, 2016.
19. Schorb E, Fox CP, Fritsch K, et al.: High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study. Bone Marrow Transplant 52 (8): 1113-1119, 2017.
20. Rubenstein JL, Hsi ED, Johnson JL, et al.: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31 (25): 3061-8, 2013.
21. Illerhaus G, Schorb E, Kasenda B: Novel agents for primary central nervous system lymphoma: evidence and perspectives. Blood 132 (7): 681-688, 2018.
22. Grommes C, Tang SS, Wolfe J, et al.: Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood 133 (5): 436-445, 2019.
23. Omuro A, Correa DD, DeAngelis LM, et al.: R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 125 (9): 1403-10, 2015.
24. Tun HW, Johnston PB, DeAngelis LM, et al.: Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma. Blood 132 (21): 2240-2248, 2018.
25. Nayak L, Iwamoto FM, LaCasce A, et al.: PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129 (23): 3071-3073, 2017.
26. Ferreri AJM, Cwynarski K, Pulczynski E, et al.: Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. Leukemia 36 (7): 1870-1878, 2022.
27. Ferreri AJ, Reni M, Foppoli M, et al.: High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374 (9700): 1512-20, 2009.
28. Bromberg JEC, Issa S, Bakunina K, et al.: Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 20 (2): 216-228, 2019.
29. Houillier C, Soussain C, Ghesquières H, et al.: Management and outcome of primary CNS lymphoma in the modern era: An LOC network study. Neurology 94 (10): e1027-e1039, 2020.
30. Schmitt AM, Herbrand AK, Fox CP, et al.: Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis. Hematol Oncol 37 (5): 548-557, 2019.
31. Omuro AM, DeAngelis LM, Karrison T, et al.: Randomized phase II study of rituximab, methotrexate (MTX), procarbazine, vincristine, and cytarabine (R-MPV-A) with and without low-dose whole-brain radiotherapy (LD-WBRT) for newly diagnosed primary CNS lymphoma (PCNSL). [Abstract] J Clin Oncol 38 (Suppl 15): A-2501, 2020.
32. Morris PG, Correa DD, Yahalom J, et al.: Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 31 (31): 3971-9, 2013.
33. Lesueur P, Damaj G, Hoang-Xuan K, et al.: Reduced-dose WBRT as consolidation treatment for patients with primary CNS lymphoma: an LOC network study. Blood Adv 6 (16): 4807-4815, 2022.
34. Houillier C, Dureau S, Taillandier L, et al.: Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study. J Clin Oncol 40 (32): 3692-3698, 2022.
35. Thiel E, Korfel A, Martus P, et al.: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11 (11): 1036-47, 2010.
36. Korfel A, Thiel E, Martus P, et al.: Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology 84 (12): 1242-8, 2015.
37. Correa DD: Neurocognitive functions in primary CNS lymphoma. Neuro Oncol 23 (8): 1220-1221, 2021.
38. Illerhaus G, Ferreri AJ, Binder M, et al.: Effects on Survival of Non-Myeloablative Chemoimmunotherapy Compared to High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation (HDC-ASCT) As Consolidation Therapy in Patients with Primary CNS Lymphoma - Results of an International Randomized Phase III Trial (MATRix/IELSG43). [Abstract] Blood 140 (Suppl 2): A-LBA-3, 2022.
39. Batchelor T, Giri S, Ruppert A, et al.: Myeloablative versus non-myeloablative consolidative chemotherapy for newly diagnosed primary central nervous system lymphoma: Results of CALGB 51101 (Alliance). [Abstract] J Clin Oncol 39 (Suppl 15): A-7506, 2021.
40. Illerhaus G, Kasenda B, Ihorst G, et al.: High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol 3 (8): e388-97, 2016.
41. Kasenda B, Schorb E, Fritsch K, et al.: Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol 23 (10): 2670-5, 2012.
42. Ferreri AJ, Illerhaus G: The role of autologous stem cell transplantation in primary central nervous system lymphoma. Blood 127 (13): 1642-9, 2016.
43. DeFilipp Z, Li S, El-Jawahri A, et al.: High-dose chemotherapy with thiotepa, busulfan, and cyclophosphamide and autologous stem cell transplantation for patients with primary central nervous system lymphoma in first complete remission. Cancer 123 (16): 3073-3079, 2017.

Treatment of Recurrent Primary CNS Lymphoma

Treatment Options for Recurrent Primary CNS Lymphoma

The prognosis for patients with recurrent CNS lymphoma is poor, with a median survival of 6 to 12 months, but up to 43 to 50 months if autologous stem cell transplant (ASCT) consolidation is performed (if not applied previously).[1] This finding implies that deferred ASCT until first relapse may still result in longer-term survival. The prognosis is worse for patients 60 years and older, who account for more than 50% of cases.[2]

Treatment options for recurrent primary CNS lymphoma include the following:

1. Reinduction therapy followed by stem cell transplant.

Reinduction therapy followed by stem cell transplant

Patients with recurrence after high-dose methotrexate-based combination chemotherapy may try autologous stem cell consolidation after reinduction of remission with single-agent or combination therapy from the following options:[3]

1. Rituximab + lenalidomide.[4]
2. Rituximab + lenalidomide + ibrutinib.[5]
3. Rituximab.[6]
4. Ibrutinib.[7]
5. Temozolomide.
6. Chimeric antigen receptor (CAR) T cells.
7. DA-TEDDI-R: temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab (under clinical evaluation).

Patients deemed ineligible for transplant can receive palliative care with these agents.

Evidence (reinduction therapy):

1. A phase I/II clinical trial evaluated CD19-directed CAR T-cell therapy using tisagenlecleucel in patients with relapsed primary CNS lymphoma.[8][Level of evidence C3]
   • One-half of the patients (6 of 12) had a complete response.
   • Three patients maintained a complete response at 9 months, 12 months, and 23 months at the time of data cutoff.
   • Five patients had low-grade immune cell–assisted neurotoxicity.
   • One patient had grade 3 neurotoxicity.

   CAR T-cell therapy provides an option for patients with relapsed primary CNS lymphoma.[8]

2. The DA-TEDDI-R regimen incorporates temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab.[7][Level of evidence C3]
   • Among 18 patients who received this regimen (five previously untreated), the complete remission rate was 86%, but high rates (39%) of invasive aspergillosis were reported.

   Further studies of this regimen are under way (NCT03964090 and NCT02203526). Dexamethasone should be avoided with ibrutinib single agent or combination therapy due to the risk of serious fungal infections. This approach requires access to intravenous antifungal agents not available outside of a clinical trial. By eliminating dexamethasone and ibrutinib, the other drugs may be used together with less risk of fungal infections.

3. In a phase II study, patients with relapsed or refractory primary CNS lymphoma were treated with rituximab plus lenalidomide.[4][Level of evidence C3]
   • An overall response rate of 36% was reported.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Schenone L, Houillier C, Tanguy ML, et al.: Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network. Bone Marrow Transplant 57 (6): 966-974, 2022.
2. Jahnke K, Thiel E, Martus P, et al.: Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neurooncol 80 (2): 159-65, 2006.
3. Han CH, Batchelor TT: Diagnosis and management of primary central nervous system lymphoma. Cancer 123 (22): 4314-4324, 2017.
4. Ghesquieres H, Chevrier M, Laadhari M, et al.: Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol 30 (4): 621-628, 2019.
5. Houillier C, Chabrot CM, Moles-Moreau MP, et al.: Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. Neurology 97 (13): 628-631, 2021.
6. Schmitt AM, Herbrand AK, Fox CP, et al.: Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis. Hematol Oncol 37 (5): 548-557, 2019.
7. Lionakis MS, Dunleavy K, Roschewski M, et al.: Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell 31 (6): 833-843.e5, 2017.
8. Frigault MJ, Dietrich J, Gallagher K, et al.: Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial. Blood 139 (15): 2306-2315, 2022.

Treatment of Intraocular Lymphoma

Retrospective reviews of selected patients with primary intraocular lymphoma and no evidence of disseminated central nervous system (CNS) disease showed that localized therapy with intraocular methotrexate or ocular radiation therapy or systemic therapy with rituximab were effective in clearing lymphoma cells from the eye. However, most patients had subsequent CNS relapse.[1,2][Level of evidence C3] Anecdotal series reported lower relapse rates when high-dose methotrexate was added, but prospective multicenter trials with even retrospective controls do not exist.[1,2][Level of evidence D]

Relapsing disease in the rest of the CNS is treated with the same options listed for primary CNS lymphoma in the brain. In a phase III randomized study of whole-brain radiation therapy, patients with intraocular disease and concomitant brain involvement had a worse prognosis than those with brain involvement alone (19 patients with both, 391 patients with brain involvement only).[3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Grimm SA, Pulido JS, Jahnke K, et al.: Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol 18 (11): 1851-5, 2007.
2. Soussain C, Malaise D, Cassoux N: Primary vitreoretinal lymphoma: a diagnostic and management challenge. Blood 138 (17): 1519-1534, 2021.
3. Korfel A, Thiel E, Martus P, et al.: Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology 84 (12): 1242-8, 2015.

Key References for Primary CNS Lymphoma Treatment

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of primary CNS lymphoma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for primary CNS lymphoma. Listed after each reference are the sections within this summary where the reference is cited.

• Ferreri AJ, Illerhaus G: The role of autologous stem cell transplantation in primary central nervous system lymphoma. Blood 127 (13): 1642-9, 2016.[PUBMED Abstract]

  Cited in:

  • Treatment of Primary CNS Lymphoma.
• Korfel A, Thiel E, Martus P, et al.: Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology 84 (12): 1242-8, 2015.[PUBMED Abstract]

  Cited in:

  • Treatment of Primary CNS Lymphoma.
  • Treatment of Intraocular Lymphoma.
• Thiel E, Korfel A, Martus P, et al.: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11 (11): 1036-47, 2010.[PUBMED Abstract]

  Cited in:

  • Treatment of Primary CNS Lymphoma.

Latest Updates to This Summary (09 / 13 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was reformatted.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of primary CNS lymphoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Primary Central Nervous System Lymphoma Treatment is:

• Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Primary Central Nervous System Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389331]

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Last Revised: 2024-09-13