Primary central nervous system lymphomas: EHA-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

Abstract

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

Figure 1

Diagnostic algorithm for PCNSL in immunocompetent patients. Purple: general categories or stratification; white: other aspects of management. ADC, apparent diffusion coefficient; CNS, central nervous system; CSF, cerebrospinal fluid; DLBCL, diffuse large B‐cell lymphoma; FDG–PET, [¹⁸F]2‐fluoro‐2‐deoxy‐d‐glucose–positron emission tomography; IgVH, immunoglobulin heavy chain variable; IL, interleukin; MRI, magnetic resonance imaging; NHL, non‐Hodgkin lymphoma; PCNSL, primary central nervous system lymphoma; PET, positron emission tomography; PVRL, primary vitreoretinal lymphoma; SCNSL, secondary central nervous system lymphoma. ^aThe most common neurological symptoms are focal deficits (70%; hemiparesis, ataxia), neuropsychiatric symptoms or personality changes (43%), high intracranial pressure (33%), seizures (14%), headache, confusion, cognitive dysfunction and lethargy; seizures occur rarely. ^bThe most common ocular symptoms are blurred vision and floaters. ^cSee Supplementary Table S1, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010. ^dSee Supplementary Table S5, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010. ^ePCNSL suspicion on MRI is usually based on site of disease and MRI features. The most common sites of disease are frontal lobe and other areas of the brain hemispheres (38%), thalamus or basal ganglia (16%), corpus callosum (14%), periventricular regions (12%), cerebellum (9%), meninges (16%), spinal cord (1%) and cranial and spinal nerves (<1%). MRI features are reported in Supplementary Table S2, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010. In particular, lesions are hypointense on T1, isointense to hypointense on T2, reduced ADC, with variable surrounding oedema, homogeneous and often strong enhancement. PET positivity can be indicative of disease outside the CNS. ^fConsider surgical or endoscopic biopsy of systemic disease and, if a diagnosis of NHL is made, consider treatment for SCNSL. ^gSuggested exams on vitrectomy samples include conventional cytology, flow cytometry, MYD88 mutational analysis, level of IL‐6 and IL‐10. Biomarkers can be assessed on anterior chamber samples. ^hCSF analyses include physical–chemical analysis, conventional cytology examination, flow cytometry, MYD88 L265P, IL‐10 level and IgVH clonality in selected cases. ⁱSee Supplementary Table S5, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010. ^jSee Figure 2. ^kSee Figure 3.

Figure 2

Treatment algorithm for newly diagnosed PCNSL. Purple: general categories or stratification; green: RT; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments; white: other aspects of management. ASCT, autologous stem cell transplantation; ChT, chemotherapy; CR, complete remission; EMA, European Medicines Agency; FDA, Food and Drug Administration; HD‐AraC, high‐dose cytarabine; HD‐MTX, high‐dose methotrexate; MATRix, high‐dose methotrexate–high‐dose cytarabine–rituximab–thiotepa; MBVP, methotrexate–carmustine–teniposide–methylprednisolone; MPV, methotrexate–procarbazine–vincristine; MT, methotrexate–temozolomide; MT–R, methotrexate–temozolomide–rituximab; PCNSL, primary central nervous system lymphoma; PD, progressive disease; PR, partial response; PS, performance status; R, rituximab; R–MP, rituximab–methotrexate–procarbazine; RT, radiotherapy; SD, stable disease; WBRT, whole‐brain radiotherapy. ^aSee text for drug options. ^bRituximab is not EMA or FDA approved in this setting; its use in induction combinations remains a matter of debate and the balance between tolerability and efficacy should be discussed with patients and their carers. ^cReduced‐dose WBRT.

Figure 3

Treatment algorithm for PVRL. Purple: general categories or stratification; green: RT; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments; white: other aspects of management. ChT, chemotherapy; CR, complete remission; EMA, European Medicines Agency; FDA, Food and Drug Administration; HDC–ASCT, high‐dose chemotherapy and autologous stem cell transplantation; HD‐MTX, high‐dose methotrexate; IL‐10, interleukin‐10; IPCG, International PCNSL Collaborative Group; MTX, methotrexate; PCNSL, primary central nervous system lymphoma; PD, progressive disease; PR, partial response; PVRL, primary vitreoretinal lymphoma; R, rituximab; R–DHAP, rituximab–dexamethasone–cytarabine–cisplatin; R–ICE, rituximab–ifosfamide–carboplatin–etoposide; RT, radiotherapy; SD, stable disease. ^aPatients with no major comorbidities and good clinical condition. ^bPatients with relevant comorbidities or poor clinical condition at the discretion of the clinician. ^cNot EMA approved, not FDA approved. ^dPR is defined according to the IPCG criteria but with an undetectable level of IL‐10 in aqueous humour.

Figure 4

Treatment algorithm for r/r PCNSL. Purple: general categories or stratification; green: RT; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments; white: other aspects of management. ASCT, autologous stem cell transplantation; BSC, best supportive care; ChT, chemotherapy; CR, complete remission; EMA, European Medicines Agency; FDA, Food and Drug Administration; HD, high dose; HD‐AraC, high‐dose cytarabine; HD‐MTX, high‐dose methotrexate; PCNSL, primary central nervous system lymphoma; PD, progressive disease; PR, partial response; r/r, relapsed or refractory; RT, radiotherapy; SD, stable disease; WBRT, whole‐brain radiotherapy. ^aDrugs and doses vary according to age, comorbidity and frailty. ^bNot EMA approved, not FDA approved. ^cChoice of consolidation therapy in fit patients aged <70 years should consider the consolidation strategy used in first‐line treatment; a different consolidation is preferred (i.e. salvage with WBRT if ASCT was used in first‐line treatment and vice versa). A second ASCT may be an option for selected patients, especially those with long‐lasting remission after the first ASCT.