Primary CNS lymphoma

aka PCNSL

Primary CNS lymphoma is a lymphoma confined to the brain, eyes and spinal fluid. Unlike most brain tumours it is chemo-sensitive: high-dose methotrexate-based treatment cures a substantial minority, and consolidation with a stem-cell transplant has replaced whole-brain radiation for the fit.

PCNSL is almost always a diffuse large B-cell lymphoma of activated B-cell type, with near-universal MYD88 L265P and CD79B mutations and 9p24 (PD-L1) gains. It presents with focal deficits or cognitive change; diagnosis needs stereotactic biopsy before steroids, plus eye examination and CSF cytology/flow.

Induction is high-dose methotrexate (≥3 g/m²) combined with cytarabine, thiotepa and rituximab (MATRix, IELSG32) or with temozolomide/procarbazine (R-MPV). Consolidation with high-dose chemotherapy and autologous transplant matches or beats whole-brain radiotherapy with far less neurotoxicity (IELSG32, PRECIS), so radiation is reserved for the unfit or as salvage. Older patients receive methotrexate-based regimens with maintenance (temozolomide, lenalidomide or ibrutinib). Relapsed disease responds to ibrutinib, lenalidomide and PD-1 blockade transiently; CD19 CAR-T crosses into the CNS with responses in small series.

The open problems are neurotoxicity, the elderly majority who cannot receive intensive therapy, and the lack of a randomised standard beyond induction.

State of the art today

Cure is possible: about half of fit patients treated with MATRix and autologous transplant are alive and disease-free at seven years (IELSG32).
Transplant consolidation has largely replaced whole-brain radiotherapy, avoiding its dementing neurotoxicity.
CSF ctDNA (MYD88 L265P) enables less invasive diagnosis and response monitoring.
BTK inhibition and CD19 CAR-T show CNS penetration and activity, though durability is limited outside transplant.

Who it affects

Primary CNS lymphoma affects about 0.5 per 100,000 per year and is ~4% of primary brain tumours, rising in the elderly and in the immunosuppressed.

Group

central nervous system

Where the cases are

Cases by country · GLOBOCAN 2022

All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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Newly diagnosed, fit (<65-70)

Rituximab + high-dose methotrexate + cytarabine ± thiotepa (MATRix) ×4, then high-dose thiotepa-based chemotherapy with autologous transplant (IELSG32, IELSG43).

NCCN · Category 2A

MethotrexateRituximabAutologous stem cell transplant (high-dose therapy)

Newly diagnosed, older/unfit

High-dose methotrexate with temozolomide, procarbazine or rituximab (e.g. MT-R, R-MP), then maintenance (temozolomide, lenalidomide) or reduced-dose WBRT; ibrutinib-based induction in trials.

EANO/ESMO PCNSL guideline

MethotrexateTemozolomideRituximabLenalidomide

Relapsed/refractory

Re-induction with methotrexate if durable first remission; ibrutinib, lenalidomide-rituximab, high-dose chemotherapy/ASCT if not done, WBRT; CD19 CAR-T and PD-1 inhibitors in trials or off-label.

IbrutinibLenalidomideAxicabtagene ciloleucelNivolumab

Subtypes & biomarkers

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Subtypes

Immunocompetent PCNSL (DLBCL, ABC type)
AIDS-related / post-transplant PCNSL (EBV-driven)
Primary vitreoretinal lymphoma
Primary leptomeningeal lymphoma

Biomarkers clinicians test

MYD88 L265P and CD79B mutations (tissue and CSF ctDNA)
CSF cytology and flow cytometry
IL-10 in CSF/vitreous
MSKCC and IELSG prognostic scores (age, performance status)
Slit-lamp examination for ocular involvement

Target prevalence in this cancer

Target / alteration	Prevalence	Measure	Source
CD79b	50-70%	CD79B mutation

How common each drug target or alteration is in this cancer. Population-level and approximate; see the target page for detail. Full matrix.

History

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1980High-dose methotrexate shown active in PCNSL
Methotrexate
1992Methotrexate before radiotherapy doubles survival (DeAngelis)
Methotrexate
2010G-PCNSL-SG-1: omitting WBRT does not shorten survival
Sets the stage for radiation-free strategies.
2016IELSG32: MATRix induction
Adding rituximab and thiotepa to methotrexate-cytarabine improves response and survival.
RituximabMethotrexate
2017Autologous transplant equals WBRT with less neurotoxicity
IELSG32 second randomisation and PRECIS.
Autologous stem cell transplant (high-dose therapy)
2017Ibrutinib active in relapsed PCNSL
Ibrutinib
2022IELSG32 7-year update confirms cures
Autologous stem cell transplant (high-dose therapy)

Pipeline

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ApprovedSmall-molecule covalent BTK inhibitor (first generation)

Ibrutinib · Imbruvica

ApprovedCAR-T (CD19)

Axicabtagene ciloleucel · Yescarta

ApprovedImmunomodulatory drug (cereblon E3 ligase modulator)

Lenalidomide · Revlimid

Open problems

Most patients are over 65 and cannot tolerate curative-intent therapy.
Neurocognitive decline from disease and therapy.
No randomised evidence for maintenance strategies.
Vitreoretinal lymphoma relapse and CNS spread.

Trials

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Recruiting now (live from ClinicalTrials.gov)

Recruiting trials near you · live from ClinicalTrials.gov

Primary CNS lymphoma

condition: Primary CNS lymphoma

Open on ClinicalTrials.gov →

within

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Expert centres

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Where the expertise is

Centres linked to this cancer in OnCo

Advanced Centre for Treatment, Research and Education in CancerNavi Mumbai, IN
via Nivolumab
Dartmouth Cancer CenterLebanon, NH, USNCI comprehensive
via Nivolumab
German Hodgkin Study GroupCologne, DE
via Nivolumab
Istituto Nazionale Tumori IRCCS Fondazione G. PascaleNaples, IT
via Nivolumab
Kyoto University HospitalKyoto, JP
via Nivolumab
Laura and Isaac Perlmutter Cancer Center at NYU Langone HealthNew York, NY, USNCI comprehensive
via Nivolumab
LYSA – The Lymphoma Study AssociationPierre-Bénite (Lyon), FR
via Axicabtagene ciloleucel
National Cancer Center Hospital EastKashiwa, Chiba, JP
via Nivolumab
Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, IL, USNCI comprehensive
via Temozolomide
SWOG Cancer Research NetworkPortland, OR, US
via Nivolumab
The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research InstituteColumbus, OH, USNCI comprehensive
via Ibrutinib
West German Cancer Center (WTZ), University Hospital EssenEssen, DE
via Nivolumab

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about Primary CNS lymphoma

Generated from this cancer's standard of care, biomarkers, and pipeline · 15 questions

Newly diagnosed

What is my exact diagnosis, stage, and grade, and which tests established them?
Why: Everything else follows from an accurate stage and subtype.
Which biomarkers have been tested on my tumour (for example MYD88 L265P and CD79B mutations, CSF cytology and flow cytometry, IL-10 in CSF/vitreous, MSKCC and IELSG prognostic scores, Slit-lamp examination for ocular involvement), and what were the results?
Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
Which subtype is my cancer, and does that change the recommended treatment?
Why: Recognised subtypes for this cancer include Immunocompetent PCNSL, AIDS-related / post-transplant PCNSL, Primary vitreoretinal lymphoma.
Is germline (inherited) genetic testing recommended for me or my family?
Why: Inherited variants can change treatment and matter for relatives.

Newly diagnosed, fit (<65-70)

For my situation (newly diagnosed, fit (<65-70)), which of the standard options do you recommend and why?
Why: Guideline options include: Rituximab + high-dose methotrexate + cytarabine ± thiotepa (MATRix) ×4, then high-dose thiotepa-based chemotherapy with autologous transplant (IELSG32, IELSG43).
Am I a candidate for Methotrexate, Rituximab, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Newly diagnosed, older/unfit

For my situation (newly diagnosed, older/unfit), which of the standard options do you recommend and why?
Why: Guideline options include: High-dose methotrexate with temozolomide, procarbazine or rituximab (e.g. MT-R, R-MP), then maintenance (temozolomide, lenalidomide) or reduced-dose WBRT; ibrutinib-based induction in trials.
Am I a candidate for Methotrexate, Temozolomide, Rituximab or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Relapsed/refractory

For my situation (relapsed/refractory), which of the standard options do you recommend and why?
Why: Guideline options include: Re-induction with methotrexate if durable first remission; ibrutinib, lenalidomide-rituximab, high-dose chemotherapy/ASCT if not done, WBRT; CD19 CAR-T and PD-1 inhibitors in trials or off-label.
Am I a candidate for Ibrutinib, Lenalidomide, Axicabtagene ciloleucel or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Any stage

Are there clinical trials I could join, for example of Ibrutinib, Axicabtagene ciloleucel, Lenalidomide?
Why: Trials are how the next standard of care is set; asking early keeps options open.
Would a second opinion at a high-volume centre change anything, and can you help arrange it?
Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
Why: Supportive care improves quality of life and helps patients complete treatment.
I read that “Most patients are over 65 and cannot tolerate curative-intent therapy”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.
I read that “Neurocognitive decline from disease and therapy”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.