Primary CNS Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Primary CNS Lymphoma

Primary central nervous system (CNS) lymphoma is defined as lymphoma limited to the cranial-spinal axis, including the brain, spinal cord, cerebrospinal fluid, and vitreoretinal space, without systemic disease.[11] This disease has increasingly been seen among patients with HIV and other immunocompromised people. Immunosuppression-related primary CNS lymphomas are almost always associated with Epstein-Barr virus. Unlike patients with other primary CNS lymphomas, patients with immunosuppression-related disease almost never have an activated B-cell cell-of-origin phenotype.[22] Computed tomography (CT) scans may show ring enhancement in 50% of patients with AIDS, while patients without AIDS almost always show only homogeneous enhancement.[33] Median overall survival in published trials generally ranges from 2 to 5 years.[44,55] Older age (>65 years) and HIV positivity are the most clinically relevant poor prognostic factors, but the prognosis for HIV-associated primary CNS lymphoma has improved with the use of combination antiretroviral therapy.[66] Such patients are then treated according to a protocol for patients who do not have HIV or immunosuppression.

Prognostic Factors

Poor prognostic factors for primary CNS lymphoma include the following:[77]

• Age older than 60 years.
• Elevated serum level of lactate dehydrogenase.
• Elevated cerebrospinal fluid protein concentration.
• Involvement of nonhemispheric areas of the brain (periventricular, basal ganglia, brainstem, and cerebellum).
• Intraocular disease and concomitant brain involvement.[88]

Diagnostics

When tumor progression occurs, it is usually confined to the CNS and/or the eye.[11] Occult systemic disease can be excluded by positron emission tomography-CT scans of the chest, abdomen, and pelvis, and sometimes with bone marrow biopsy.[99,1010]

In one prospective case series of 282 patients, 17% were found to have meningeal dissemination by cytomorphology, polymerase chain reaction of rearranged immunoglobulin heavy-chain genes, or meningeal enhancement on magnetic resonance imaging.[1111]

Pathogenesis

Although more than 95% of patients with primary CNS lymphoma have lymphoma of B-cell origin, 45 patients with CNS lymphoma of T-cell origin showed no difference in presentation or outcome in a retrospective series with data collected from 12 cancer centers.[1212] Almost all primary CNS lymphomas are diffuse large B-cell lymphomas of the activated B-cell nongerminal center subtype.[11]

Primary CNS lymphoma closely resembles the activated B-cell subtype of large B-cell lymphoma, with additional mutations in the B-cell receptor signaling pathway. 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.[1313][Level of evidence C3] Anecdotal cases of primary CNS Hodgkin lymphoma have also been reported.[1414]

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. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993.
4. Grommes C, DeAngelis LM: Primary CNS Lymphoma. J Clin Oncol 35 (21): 2410-2418, 2017.
5. 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.
6. 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.
7. 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.
8. 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.
9. O'Neill BP, Dinapoli RP, Kurtin PJ, et al.: Occult systemic non-Hodgkin's lymphoma (NHL) in patients initially diagnosed as primary central nervous system lymphoma (PCNSL): how much staging is enough? J Neurooncol 25 (1): 67-71, 1995.
10. Abrey LE, Batchelor TT, Ferreri AJ, et al.: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23 (22): 5034-43, 2005.
11. 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.
12. 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.
13. 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.
14. Gerstner ER, Abrey LE, Schiff D, et al.: CNS Hodgkin lymphoma. Blood 112 (5): 1658-61, 2008.

Treatment Option Overview for Primary CNS Lymphoma

Radiation Therapy

Because of the diffuse nature of central nervous system (CNS) lymphomas, aggressive surgical decompression with partial or gross total removal of the tumor is of no benefit to the patient. Median survival with surgery alone ranges from only 1 to 5 months. Until the mid-1990s, radiation therapy was the standard treatment, with doses of up to 45 Gy using standard fractionation. A prospective trial by the Radiation Therapy Oncology Group (RTOG-8315) used 40 Gy whole-brain radiation therapy (WBRT) and a 20-Gy boost to the tumor. The results were no better than those previously reported, with a median survival of 1 year and 28% of the patients surviving 2 years.[11,22] Disease recurs in the brain in 92% of patients despite high doses of radiation. The addition of spinal-axis radiation does not affect survival because it does not prevent cerebral relapse.

Combined Chemotherapy and Radiation Therapy

Two multicenter prospective trials (including RTOG-8806) used preirradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by WBRT.[33,44] Median survival times were no better than for radiation therapy alone. The failure of these and other combined-modality trials has been attributed to poor penetration of standard drugs through the blood-brain barrier and to increased neurological toxic effects. Retrospective reviews suggested improved results with the use of high-dose methotrexate or cytarabine with radiation therapy rather than with other combination regimens.[55,66] While combinations of high-dose methotrexate with WBRT improved progression-free survival (PFS) and overall survival (OS) anecdotally in patients participating in phase II trials, there was unacceptable neurological toxicity.[77,88,99]

Chemotherapy Alone

Trials using chemotherapy alone were justified because of the unsatisfactory results of using WBRT alone, and the neurological toxic effects seen using chemotherapy combined with WBRT. 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.[55,66,1010,1111,1212,1313]
• High-dose cytarabine.[1212,1313,1414]
• Rituximab.[1414,1515,1616]
• Thiotepa.[1616,1717]
• Ibrutinib.[1818,1919]
• Lenalidomide.[2020]
• Lenalidomide + rituximab.[2121]
• Pomalidomide.[2222]
• Nivolumab.[2323]

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.[2424,2525]

The International Extranodal Lymphoma Study Group investigated three different induction combinations in 227 patients with newly-diagnosed HIV-negative primary CNS lymphoma who were randomly assigned to one of three groups:[1616]

• High-dose methotrexate + high-dose cytarabine.
• High-dose methotrexate + high-dose cytarabine + rituximab.
• High-dose methotrexate + high-dose cytarabine + rituximab + thiotepa (the MATRix regimen).

With a median follow-up of 30 months, patients who received the four-drug combination had a complete remission rate of 49% (95% confidence interval [CI], 38%‒60%) compared with 23% (interquartile range [IQR], 14%‒31%) for patients who received the two-drug combination (hazard ratio [HR], 0.46; 95% CI, 0.28‒0.74) and 30% (IQR, 21%‒42%) for patients who received the three-drug combination (HR, 0.61; 95% CI, 0.40‒0.94).[1616][Level of evidence B3]

In a randomized, nonblinded, multicenter trial, 79 patients were randomly assigned to receive either high-dose methotrexate or high-dose methotrexate plus cytarabine.[2626] While the 3-year PFS was better for patients who received the two-drug regimen (HR, 0.54; 95% CI, 0.31–0.92; P = .01), there was no 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).[2626][Level of evidence B1]

In a randomized, prospective, multicenter trial, 200 patients were randomly assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab.[2727] With a median follow-up of 32.9 months, there was no difference in the 1-year event-free survival rate: 52% (95% CI, 42%−61%) with rituximab and 49% (95% CI, 39%−58%) without rituximab (HR, 1.00; 95% CI, 0.70−1.43; P = .99).[2727][Level of evidence B1]

The DA-TEDDI-R regimen incorporates temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab.[2828][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). This approach requires access to intravenous antifungal agents not available outside of a clinical trial.

In a phase II study of patients with relapsed or refractory primary CNS lymphoma, treatment with rituximab plus lenalidomide resulted in a 36% overall response rate.[2121][Level of evidence C3]

Additional randomized trials are needed to establish the optimal chemotherapy combination for induction therapy. The optimal length of induction therapy, the use of maintenance therapy, and the use of consolidation therapy are all areas of controversy that await further trial results.[2929]

Consolidation After Induction Chemotherapy

Several phase II studies have investigated consolidation with intensive chemotherapy supported by autologous stem cell transplantation (SCT).[1717,3030,3131,3232,3333,3434,3535] This approach is most applicable for younger patients with few comorbidities and good performance status, who also respond well to induction therapy.

Several prospective randomized trials are comparing or have compared the value of WBRT and the value of autologous SCT as consolidation after high-dose methotrexate induction therapy: International Extranodal Lymphoma Study Group 32 (IELSC32 [NCT01011920]), Pragmatic–Explanatory Continuum Indicator Summary (PRECIS [NCT00863460]) (a phase II randomized trial of 97 patients),[3636]Cancer and Lymphoma Group B/Alliance (CALGB 51101 [NCT01511562]), and International Extranodal Lymphoma Study Group 43 (IELSG43 [NCT02531841]).[3232]

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.[3737] After the completion of chemotherapy, responders were randomly assigned to receive either WBRT (45 Gy) or no treatment for complete-response patients and cytarabine for partial-response patients. There was no statistical difference in median OS, with 32.4 months for patients who received radiation therapy versus 37.1 months for those who did not receive radiation therapy (HR, 1.06; 95% CI, 0.80–1.40; P = .71).[3737][Level of evidence A1] Treatment-related neurotoxic effects were significantly worse on the radiation therapy arm. Such toxicity must be weighed against the possibility that the survival from chemotherapy alone may be marginally inferior to the survival when radiation is added.

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. 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), but no difference in OS, at 32.4 months versus 36.1 months (HR, 0.98; 95% CI, 0.79–1.26; P = .98). However, the study lacked the power to exclude a benefit or harm from the WBRT.[3838][Level of evidence B1] In this study, 19 patients were diagnosed with intraocular involvement at diagnosis; intraocular lymphoma was an independent negative prognostic indicator.[3939]

Current Clinical Trials

Use our advanced clinical trial searchadvanced 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 informationGeneral information about clinical trials is also available.

References:

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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. O'Neill BP, O'Fallon JR, Earle JD, et al.: Primary central nervous system non-Hodgkin's lymphoma: survival advantages with combined initial therapy? Int J Radiat Oncol Biol Phys 33 (3): 663-73, 1995.
4. Schultz C, Scott C, Sherman W, et al.: Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 14 (2): 556-64, 1996.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
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. 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.
15. 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.
16. 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.
17. 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.
18. Illerhaus G, Schorb E, Kasenda B: Novel agents for primary central nervous system lymphoma: evidence and perspectives. Blood 132 (7): 681-688, 2018.
19. 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.
20. Houillier C, Choquet S, Touitou V, et al.: Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology 84 (3): 325-6, 2015.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
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33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.