Primary CNS lymphoma (PCNSL)

Overview

• Non-Hodgkin lymphoma that involves the CNS without evidence of systemic disease.
• >95% are DLBCL of nongerminal center (ABC) B-cell subtype; ~2% to 3% of all brain tumors. M>F, median age ~67 years.
• Most are ABC subtype with recurrent CD79B, PIM1, MYD88, and PD-L1 alterations.
• Can involve the parenchyma, cranial nerves, eye, spinal cord, and meninges; frequently presents as a single periventricular irregularly shaped lesion.
• Majority are immunocompetent; however, the immunocompromised are at markedly ↑ ↑ risk (solid organ transplantation, congenital immunodeficiency, HIV). EBV is associated with PCNSL in the immunocompromised.

Diagnosis & Staging

• Avoid corticosteroids before biopsy. Steroids may cause complete disappearance of the contrast-enhancing lesion ("ghost tumor"), making diagnosis difficult. Avoid them if CNS lymphoma is on the differential unless mass effect is causing serious and immediate complications.
• Biopsy is mandatory for diagnosis, even when radiographic findings are suggestive: stereotactic biopsy or CSF sampling. Surgery is only for obtaining tissue, not resection.
• Staging evaluation:
  • Slit-lamp / funduscopic examination of the eyes (rule out ocular/vitreoretinal lymphoma, ~15 to 25% of pts; concurrent disease managed with the systemic HD-MTX regimen, but persistent or isolated vitreoretinal disease may need intravitreal MTX/rituximab or ocular RT (WBRT fields may include the eyes)); considered standard of care by the International PCNSL Collaborative Group and EANO.
  • MRI of the spine (for spinal symptoms or positive CSF, not routine in asymptomatic pts).
  • PET/CT or CT of the chest/abdomen/pelvis to rule out systemic lymphoma.
  • LP for CSF cytology/flow, if safe.
  • HIV testing.
  • Testicular exam/ultrasound in men.
  • Primary CNS lymphomas typically do not involve the bone marrow; the role of BM biopsy at diagnosis is controversial.

Treatment: Induction

• High-dose MTX-based regimens, typical doses of 3.5 to 8 g/m², up to 8 cycles. A dose of at least 3 g/m² is needed for adequate CNS/CSF penetration.
  • MTR (MTX 8 g/m2, temozolomide, rituximab), Alliance 50202 trial: ORR 77%, CR 66%, 2-yr PFS 57%.
  • R-MPV (rituximab, MTX 3.5 g/m2, procarbazine, vincristine) (Grade 2C): ORR ~80%.
  • MATRix (MTX 3.5 g/m2, cytarabine 2 g/m2 q12h x4, thiotepa 30 mg/m2, rituximab): ORR 87%, CR 49%, 7-yr OS 56% (IELSG32).
  • MTX with high-dose cytarabine (HDAC), or HD-MTX with rituximab.
• ORR 35% to 95%; durable CR achievable in ~30%; late relapses (≥ 10 yrs) can occur, most notably after AutoSCT.
• Follow up with contrast MRI every 2 cycles during HD-MTX. If in CR, proceed to consolidation; if in PR, can give HIDAC x1 and proceed to consolidation if stable disease.
• Not a candidate for HD-MTX: TMZ ± rituximab, WBRT, or corticosteroids (conventional-dose MTX is not an effective CNS substitute).
• IT MTX adds no proven benefit when adequate systemic HD-MTX (≥3 g/m2) is delivered; may be considered only if adequate systemic MTX cannot be given or for persistent meningeal disease. IV MTX at >3 g/m² consistently achieves good CSF concentrations, and an Ommaya reservoir carries infection and other risks. Maintenance MTX has no proven benefit.

Treatment: Consolidation

• Induction-responsive patients have three consolidation options: high-dose chemotherapy with autologous stem-cell transplant (HDC-AutoSCT), non-myeloablative chemotherapy, or whole-brain radiation therapy (WBRT). HDC-ASCT is superior to non-myeloablative consolidation (IELSG43: 3-yr PFS 78% vs 51%, OS also improved); ASCT and WBRT have similar efficacy, but WBRT carries more neurotoxicity.
• HDC-AutoSCT (thiotepa-based) is the best option for young and fit patients. Patients with complete or ongoing partial response to a HD-MTX-based regimen benefit from thiotepa-based HDC with stem-cell rescue.
  • CALGB-51101: consolidative HDC-ASCT vs EA (etoposide/cytarabine) in PCNSL ≤75 yrs; all received induction MTR-A (MTR followed by one cycle of cytarabine). 2-yr PFS significantly better with myeloablative ASCT vs EA on the primary ITT analysis (73% vs 51%, P=.02); consolidation-landmark analysis in completers was NS (86% vs 71%, P=.21), with more induction failures in the EA arm (28% vs 11%); 3-yr OS 83% (HDC-ASCT) vs 72% (EA).
  • Hematologic toxicity with EA is substantial; patients not felt to be candidates for HDC-ASCT are also at high risk for EA toxicity, so cytarabine alone is preferred in that group (2 g/m2 q12h x4, or 3 g/m2 q24h x2).
• Non-myeloablative chemo: EA (etoposide 5 mg/kg q12h for 8 doses and cytarabine 2 g/m2 q12h for 8 doses).
• WBRT: effective but limited by delayed neurotoxicity/neurocognitive decline, especially in older patients.

R/R PCNSL

• Reinduction with HD-MTX if relapse >12 mo, or salvage AutoSCT.
• Other options: ibrutinib, lenalidomide, TMZ, pemetrexed, possibly PD-1 inhibitors, rituximab, and WBRT (with marked ↑ ↑ neurotoxicity).
• Ibrutinib monotherapy (R/R PCNSL / secondary CNS lymphoma) (Grommes C et al, Cancer Discov 2017 PMID 28619981; iLOC/Soussain Eur J Cancer 2019 PMID 31279304): ORR ~52 to 77%. BTK inhibitors cross the blood-brain barrier: ibrutinib, zanubrutinib, and tirabrutinib are all active. Tirabrutinib approved in Japan Mar 2020 for R/R PCNSL; not FDA-approved in the US as of 2026.
• Lenalidomide + rituximab (R2) (Ghesquieres H et al, Ann Oncol 2019 / REVRI): ORR ~35 to 40% in R/R PCNSL; an option for patients unable to tolerate HD-MTX re-induction.
• TEDDi-R (temozolomide, etoposide, pegylated liposomal doxorubicin, dexamethasone, ibrutinib, rituximab) (Lionakis MS et al, Cancer Cell 2017 PMID 28552327): CR 86% of evaluable pts (n=18 DA-TEDDi-R study; mixed newly dx and previously treated, not an exclusively R/R ITT rate); proof-of-concept for an ibrutinib-containing, MTX-free combination (DA-TEDDi-R has no MTX); ibrutinib with HD-MTX and rituximab is supported by Grommes phase 1b (Blood 2019).

Secondary CNS Lymphoma (contrast)

• Lymphoma both within and outside the CNS at diagnosis, or CNS relapse of systemic lymphoma. Rare, aggressive, poor prognosis.
• Standard R-CHOP has limited efficacy in CNS disease; the most effective drugs are MTX and cytarabine (Ara-C).
• For systemic DLBCL with concurrent parenchymal CNS disease: systemic MTX ≥3 g/m2 on day 15 of a 21-day R-CHOP cycle (supported with growth factors).
• For leptomeningeal disease: IT MTX/cytarabine (often via Ommaya), or systemic MTX 3 to 3.5 g/m2 with or after R-CHOP plus IT chemo.

High-Yield Pearls

• Avoid steroids before biopsy: they can dissolve the lesion and defeat diagnosis.
• Biopsy is mandatory; check the vitreous (slit-lamp) and CSF; PCNSL usually spares the marrow.
• HD-MTX ≥3 to 3.5 g/m2 is the backbone; MATRix is a leading induction regimen.
• Consolidation: thiotepa-based HDC-AutoSCT preferred if young/fit (better PFS than non-myeloablative chemo such as EA: IELSG43, CALGB 51101; similar efficacy to WBRT); WBRT limited by neurotoxicity.
• BTK inhibitors (ibrutinib), lenalidomide, and rituximab are active in R/R disease; IT chemo and maintenance MTX have no proven role.