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Hospital  >  Care Programs  >  Odette Cancer Program  >  Hematology cancer care  >  About hematology cancer care  >  Treatment policies  >  Primary central nervous system lymphoma (PCNSL)

Primary central nervous system lymphoma (PCNSL)

Lead: Jiajia Liu/Matthew Cheung
Date of policy: May 21, 2020
Date of last revision: July 6st 2020

Terms of use

These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

  1. Diagnosis and pathologic classification:

    Primary central nervous system lymphoma (PCNSL) arises within the brain, spinal cord, leptomeninges, or eye (vitroretineal lymphoma) without involvement outside the CNS. 90% are diffuse large B cell lymphoma by histology, with rare cases consisting of low-grade B cell lymphomas, Burkitt lymphoma, or PTCL (1). It accounts for <1% of all non-Hodgkin lymphoma and 3% of all brain tumors with peak incidence in the 7th decade of life. Most are non-GCB by Hans algorithm (2).

    This policy concerns primary diffuse large B cell lymphoma of the CNS. Of note, diffuse large B cell lymphoma of the dura, intravascular large B cell lymphoma and immunodeficiency-associated CNS lymphomas are excluded from the WHO definition of primary CNS diffuse large-B cell lymphoma. These rare entities and primary CNS lymphoma of non-DLBCL histology should be discussed in MCC.

  2. Baseline testing:

    1. Full history and physical with attention to:
      • testicular exam in all males
      • Full neurological exam
      • Baseline cognitive assessment (such as MMSE, miniCOG, or MOCA)
      • ECOG performance status (3).
    2. Consultations: Ophthalmology for fundoscopy + slit lamp examination (20% have ocular involvement)
    3. Bloodwork:
      • CBC, Albumin, LDH, LFTs (Bilirubin, ALT, ALP), creatinine, Uric acid
      • Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody and HIV serology
      • Covid19 swab
    4. Imaging (4):
      • Gadolinium-enhanced MRI brain and spine
      • CT head, neck, chest abdomen & pelvis
      • FDG-PET/CT
      • Testicular ultrasound in men
      • MUGA scan or 2D echo (Age >60 or with cardiovascular risk factors)
    5. Pathological diagnosis
      • Avoid corticosteroids prior to biopsy. Discontinue if already started. If lesion disappeared, follow-up clinically and repeat imaging within a few weeks or if symptoms recur with an urgent biopsy if lesion regrows.
      • Stereotactic biopsy with intraoperative frozen section ideal; avoid unnecessary surgical resection
      • Pathology review if not reported at Sunnybrook or UHN
      • If biopsy not possible, need to show large clonal B cells in CSF or vitreous fluid by flow cytometry +/- IGHV PCR clonality
    6. Procedures
      • Lumbar Puncture with cell count, cytology, protein
      • Tb skin test, COVID-19 swab, and strongyloides serology for all patients
      • Bone marrow biopsy not needed if no systemic disease on FDG-PET/CT and normal CBC; consider if PET scan not done (5, 6).

  3. Prognostic index of the IELSG (International Extranodal Lymphoma Study Group) (7)

    General Index Parameter Remarks
    1 Age > 60y None
    1 PS 2-4 ECOG Performance Score
    1 Serum LDH elevated above upper normal
    1 Cerebrospinal fluid protein elevated above upper normal
    1 Deep structures involved basal ganglia, corpus callosum, brain stem, or cerebellum
    5 Maximum Score *This score was not validated for HIV+ PCNSL.
    # of Risk Factors - General index Risk Group
    0-1 1 = low
    2-3 2 = intermediate
    4-5 3 = high

  4. Treatment:

    *consider a clinical trial first at all stages of treatment if available*

    First line:

    Methotrexate (MTX) based (curative intent) treatment

    • Fit (physiologic age <70 years, CrCl >50ml/min and EF >45% (4))
      • MATRIX x 2 cycles à MRI at least PR (or close to) à MATRIX 3rd cycle (omit thiotepa) with stem cell mobilization of the chemotherapy cycle à complete MATRIX 4th cycle à ASCT (BCNU and thiotepa conditioning) (7)
        • ASCT is the preferred consolidation modality with similar OS and PFS to whole brain radiation therapy (WBRT) and less neurotoxicity (8, 9).
        • In select patients who are not eligible for ASCT (insufficient stem cell collection, prolonged side effects), WBRT for consolidation can be considered for patients <60 year old, and for patients >=60 year old only if they are not in CR Risks and benefits should be discussed at MCC.
        • Omission of consolidation can be considered in select cases.
      • Less fit (ECOG >/=2, comorbid conditions, age >60 years)
        • MATRIx with 25% dose reduction for cytarabine and thiotepa
        • HD-MVP-R (10)
        • HD-MTX+rituximab alone
        • Consider consolidation with ASCT
          • In select patients who are not eligible for ASCT (insufficient stem cell collection, prolonged side effects), WBRT for consolidation can be considered for patients <60 year old, and for patients >=60 year old only if they are not in CR Risks and benefits should be discussed at MCC.
          • Omission of consolidation can be considered in select cases.
        • No role for concurrent intrathecal chemotherapy and HD-MTX based regimen, if cytology negative; to consider if cytology positive, until cytology clears.

    Non-MTX based (palliative) treatment

    • See non-intensive options with evidence for relapsed/refractory disease below and consider obtention on a compassionate basis for first-line treatment if available.
    • Palliative WBRT (short course, low dose)
    • Temozolomide
    • Dexamethasone
    • Consider intrathecal chemotherapy if leptomeningeal disease and unfit for systemic chemotherapy

    Supportive/Ancillary treatment:

    • Supportive medications on MATRix:
      • Allopurinol 300 mg daily x 7 days starting D-1 for cycle 1 only
      • Filgrastim daily x 10 days
      • Valacyclovir 500mg daily
      • Septra DS MWF (to hold during admission for HD-MTX)
      • HBV prophylaxis if HbSAg+ and consider if HBcAb+
    • Febrile neutropenia should be managed following Febrile neutropenia guideline
    • Fertility preservation should be offered to all patients if age appropriate 

    Response assessment:
    MRI after 2 and 4 cycles of MTX-based regimen

    Second line:

    • Refractory disease after induction chemo
      • Very Fit: ICE X 2cycles then ASCT if PR or better.
    • Refractory disease after ASCT, or not fit for ICE:
      • WBRT +/- ocular rads if ocular involvement
    • Relapse:
      • Repeat biopsy if atypical MRI appearance or new brain lesion >2y after initial therapy
      • Repeat staging
      • If eligible for intensive treatment:
        • Eligible for intensive therapy
          • Re-induction:
            • If prolonged response (>24months) to initial MTX-containing regimen, consider repeating MTX-based regimen
            • If <24 months: R-ICE
          • Consolidation:
            • If previous ASCT: WBRT if age <60 or age >60 and not in CR can be considered vs. omission of consolidation in select patients who are not in CR after discussion of risks and benefits at MCC.
            • If previous WBRT: ASCT
            • Omission of consolidation can be considered in select cases.
          • If not a candidate intensive therapy, consider:
            • Ibrutinib (11)
            • Lenalidomide + rituximab (12)
            • Nivolumab
            • Palliative options above (temozolomide, WBRT, steroids, palliative care)

  5. Follow up: 

    • Follow visits every 3 months x 2 years, every 6 months x 3 years. Follow up will be transferred back to primary care physician between years 3 and 5
    • At each visit: history and physical exam, CBC, LDH every 6 months, cognitive assessment q6months (MMSE/MOCA/mini-COG).
    • If in remission, follow-up imaging with MRI q3 months x 1 year, q6 months for 1 year, and then at clinician’s discretion. Low threshold to repeat imaging if any new neurological symptoms arise.
    • Counselling on physical and psychosocial issues, smoking cessation, age-appropriate cancer screening, immunizations

  6. Special considerations

    Primary vitroretineal lymphoma:

    • If fit for intensive therapy: treat as PCSNL with MATRix x 4 + consolidative ASCT. Consider additional intravitreal MTX and/or ocular XRT.
    • If not eligible for intensive PCNSL treatment – consider intraocular treatment alone with intravitreal MTX and/or ocular XRT.


    HIV+ and other immunodeficiency-associated PCNSL

    • Majority are EBV positive
    • Multifocal lesions are more common, in up to 80% of patients, and there is often basal ganglia and corpus callosum involvement; a ringlike enhancement of lesions can be found in 75% of patients; spontaneous hemorrhage is also more frequent (4).
    • Recent trials in PCNSL have excluded HIV+ patients. Best evidence is for HD-MTX and HAART with long-term remissions (13).
    • Use of rituximab and HD-MTX combined with other chemotherapeutic agents (MATRix, etc.) is unclear as there are no trials involving HIV+ patients/ only a case report (14) ; there is a concern re: additive immunosuppression in patients with CD4 counts <50 on rituximab. Patients with higher CD4 counts and good performance status may be treated similarly to other PCNSL. Consider on a case-by-case basis with discussion in MCC.
    • No evidence for or against consolidation therapy in PCNSL. Consider if patient is able to tolerate.


    Primary leptomeningeal lymphoma

    • Rare entity, very atypical of PCSNL as initial presentation: systemic aggressive lymphoma must be carefully investigated and ruled out; flow very important - 19% are T-cell aggressive lymphomas (15).
    • Most (68%) patients treated with high-dose methotrexate in largest review of the literature (15). 66% received intrathecal chemotherapy.
    • If B large cell lymphoma, consider treating as primary CNS diffuse large-B cell lymphoma as above.


    Primary dural lymphoma

    • Rare entity; in published series, high prevalence of MZL and DLBCL histologies (16)
    • If DLBCL: treatment with R-CHOP without consolidative ASCT or WBRT has yielded good outcomes in a review of case series (17). The dural blood supply is not affected by the blood-brain barrier. Consideration of CNS prophylaxis with HD-MTX or IT-MTX is reasonable given proximity to CNS but not well studied.

  7. Key references:

    1. Grommes C, DeAngelis LM. Primary CNS Lymphoma. J Clin Oncol. 2017;35(21):2410-8.
    2. Swerdlow SH CE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition: International Agency for Research on Cancer (IARC); 2017.
    3. Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23(22):5034-43.
    4. Haldorsen IS, Espeland A, Larsson EM. Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR Am J Neuroradiol. 2011;32(6):984-92.
    5. Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA. A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol. 2013;70(3):311-9.
    6. Fox CP, Phillips EH, Smith J, Linton K, Gallop-Evans E, Hemmaway C, et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. Br J Haematol. 2019;184(3):348-63.
    7. Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, 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. 2016;3(5):e217-27.
    8. Houillier C, Taillandier L, Dureau S, Lamy T, Laadhari M, Chinot O, et al. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study. J Clin Oncol. 2019;37(10):823-33.
    9. Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosee P, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017;4(11):e510-e23.
    10. Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, 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. 2013;31(31):3971-9.
    11. Soussain C, Choquet S, Blonski M, Leclercq D, Houillier C, Rezai K, et al. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. Eur J Cancer. 2019;117:121-30.
    12. Ghesquieres H, Chevrier M, Laadhari M, Chinot O, Choquet S, Molucon-Chabrot C, 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)dagger. Ann Oncol. 2019;30(4):621-8.
    13. Moulignier A, Lamirel C, Picard H, Lebrette MG, Amiel C, Hamidi M, et al. Long-term AIDS-related PCNSL outcomes with HD-MTX and combined antiretroviral therapy. Neurology. 2017;89(8):796-804.
    14. Wolf T, Kiderlen T, Atta J, Stephan C, Kann G, Brodt HR, et al. Successful treatment of AIDS-associated, primary CNS lymphoma with rituximab- and methotrexate-based chemotherapy and autologous stem cell transplantation. Infection. 2014;42(2):445-7.
    15. Taylor JW, Flanagan EP, O'Neill BP, Siegal T, Omuro A, Deangelis L, et al. Primary leptomeningeal lymphoma: International Primary CNS Lymphoma Collaborative Group report. Neurology. 2013;81(19):1690-6.
    16. Karschnia P, Batchelor TT, Jordan JT, Shaw B, Winter SF, Barbiero FJ, et al. Primary dural lymphomas: Clinical presentation, management, and outcome. Cancer. 2020;126(12):2811-20.
    17. Quinn ZL, Zakharia K, Schmid JL, Schmieg JJ, Safah H, Saba NS. Primary Dural Diffuse Large B-cell Lymphoma: A Comprehensive Review of Survival and Treatment Outcomes. Clin Lymphoma Myeloma Leuk. 2020;20(2):e105-e12.
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