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

Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS), termed primary CNS lymphoma (PCNSL), is an aggressive neoplasm presenting with disease limited to the CNS. PCNSL was recognised as a distinct entity by the 2017 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues.¹ In the 2022 edition of the WHO classification,² this neoplasm is classified in the ‘Large B-cell lymphomas of immune-privileged sites' group, whereas it is considered a specific entity in the International Consensus Classification of Mature Lymphoid Neoplasms.³ This entity is also recognised by the WHO classification of CNS tumours.⁴ PCNSL can arise in both immunocompetent individuals and in those who are immunosuppressed (e.g. individuals living with human immunodeficiency virus and patients receiving immunosuppressive therapies following organ transplant). While no clear predisposing factors have been recognised in immunocompetent individuals, the nature, intensity and duration of immune suppression can influence the risk of PCNSL in those who are immunocompromised.⁵

This European Hematology Association (EHA)–European Society for Medical Oncology (ESMO) Clinical Practice Guideline (CPG) includes recommendations for the management of immunocompetent patients with PCNSL. In this population, PCNSL accounts for 2% of all primary CNS tumours and 4%-6% of extranodal lymphomas, with an incidence of 0.47/100 000 person-years.⁶ PCNSL is typically diagnosed in the sixth or seventh decade of life, with a median age at diagnosis of 68 years and a slightly higher frequency in males.⁷ Notably, the recent increase in incidence is limited to patients of >60 years. The incidence of PCNSL in African-American males of <50 years is more than twofold higher than that in Caucasian males of the same age.⁶ Among elderly patients, however, incidence in Caucasian males is twofold higher than that in African-American males. Similar patterns, but with a lesser magnitude, are evident among females.⁶

A comprehensive assessment of the extent of lymphoma involvement (see Supplementary Table S5, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010) is mandatory to determine both the compartments involved within the CNS and the presence of concomitant systemic disease, as recommended by the IPCG guidelines.¹³ Full neurological and oncohaematological evaluation is crucial before treatment planning. Gadolinium-enhanced MRI is the most relevant tool to define an extension of disease in the brain and spinal cord. Brain MRI should be repeated after biopsy and ideally within 14 days before starting treatment¹²; this is supported by extremely high proliferative activity, often with >90% of tumour cells expressing the Ki-67 antigen, which could potentially affect therapeutic response definition.¹ The involvement of spinal cord parenchyma is rare and specific MRI should be carried out only in patients with symptoms suggestive of spinal cord injury. Meningeal dissemination is often asymptomatic; thus, CSF analysis is advised in every patient with suspected or confirmed PCNSL, unless clinically contraindicated. Physical–chemical features in the CSF (i.e. normal glucose concentration, increased leukocyte count, high protein concentration) are not specific for PCNSL but may suggest meningeal dissemination and blood–CSF barrier disruption. Conventional cytology examination underestimates CSF involvement and should be coupled with flow cytometry to improve diagnostic sensitivity.¹⁵

Accurate ophthalmological examination should be carried out in every patient with PCNSL. Vitrectomy, however, is not mandatory in patients with histopathological diagnosis of PCNSL carried out on brain biopsies. Assessment of IL-10 level, MYD88 L265P and monoclonal IgVH rearrangement on vitreous and aqueous humours offers diagnostic potential as a conservative procedure to confirm intraocular disease during staging, but its precise role in routine practice remains to be defined.

Assessment for extra-CNS disease is relevant as patients with PCNSL and secondary CNS lymphoma (SCNSL) exhibit different prognoses and require different treatment protocols.¹⁶ Conventional staging with [¹⁸F]2-fluoro-2-deoxy-d-glucose–positron emission tomography (FDG–PET), preferably combined with contrast-enhanced CT scan, can identify systemic disease in 4%-12% of patients with a presumptive diagnosis of PCNSL.¹⁶ When FDG–PET is not available, bone marrow biopsy and aspiration and testicular ultrasound (US) are recommended to accompany CT imaging.

To predict outcomes and better stratify patients in clinical trials, two scoring systems have been proposed: the International Extranodal Lymphoma Study Group (IELSG) score¹⁷ and the Memorial Sloan Kettering Cancer Center prognostic score.¹⁸ Validation of other proposed scores is pending.

Before starting treatment, bone marrow status and cardiac, liver and renal functions should be assessed (see Supplementary Table S5, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010). A battery of cognitive functions and quality of life (QoL) measures has been proposed by the IPCG.¹⁹ Its use outside clinical trials remains to be defined.

A proposed algorithm for the treatment of newly diagnosed PCNSL is shown in Figure 2.

The therapeutic challenges in PVRL are twofold: to limit visual consequences and to prevent CNS dissemination. Fifty-six percent to 90% of patients with PVRL develop CNS dissemination within 30 months; this is the main cause of death in patients with PVRL.⁶³ Median survival appears to be longer when the patient is treated at the time of PVRL diagnosis rather than at CNS relapse.⁷¹ Data on heterogeneous treatments are mainly retrospective, with evident bias related to the involved medical specialists (i.e. haematologists or ophthalmologists). Thus, debate persists on the best treatment for PVRL, both at presentation and for relapsed or refractory (r/r) disease. Treatment options include local therapies (intravitreal drug injection or ocular RT), systemic (immuno)ChT or both. A proposed algorithm for the treatment of PVRL is shown in Figure 3.

Antitumour drugs (usually MTX or rituximab) can be injected in the vitreous under local anaesthesia, with varied duration and number of injections.⁹ This approach is used in first-line treatment or at relapse, either alone (usually in unilateral disease) in patients not eligible for systemic ChT,⁶⁶ or in addition to systemic treatment when rapid antitumour activity is needed. External beam ocular RT is rarely used alone as first-line treatment in patients with bilateral ocular involvement or as salvage treatment for elderly patients. The recommended technique to irradiate the eyes is summarised in Supplementary Table S8, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010. Overall, local treatments seem to be effective in controlling intraocular disease, but they fail to prevent CNS relapses and ocular relapses remain frequent.⁹ Encouraging results were recently reported in patients treated with a combination of bilateral ocular RT and HD-MTX-based ChT.^{9, 72} However, it is not yet clear whether CNS-directed polyChT should be given upfront to prevent CNS dissemination.⁶³ Systemic treatments for PVRL remain empirical. HD-MTX-based polyChT has been frequently used either alone or combined with a local therapy to treat PVRL at presentation⁹; however, control of intraocular disease is poor.⁷³ In a recent retrospective study of 59 patients with PVRL receiving HD-MTX-based ChT, median survival without brain relapse was prolonged (73 months) and none of the eight patients who received an additional local treatment experienced intraocular relapse after a median follow-up of 5 years.⁷³

Intensive thiotepa-based ChT followed by ASCT is feasible and effective in fit patients with r/r PVRL.^{9, 74} Temozolomide and targeted therapies, such as lenalidomide (alone or in combination with rituximab) or ibrutinib, have demonstrated some activity in r/r PVRL.⁷⁵

Despite therapeutic progress, 16%-26% of patients aged ≤70 years with PCNSL are primary refractory to HD-MTX-based ChT,^{7, 35} and a further 25% experience relapse after initial response.⁷⁶ Relapse rates are remarkably higher among older patients. Relapses occur predominantly in the CNS, often in sites distant from the primary lesion.⁷⁷ Most relapses are associated with rapid disease progression and corresponding neurological symptoms; only 20% of relapses are diagnosed on surveillance MRI.^{78, 79} The prognosis of patients with r/r PCNSL is very poor, and benefits from salvage therapies are often marginal. Notably, patients who experience relapse after the first 3 years of follow-up demonstrate a significantly better 2-year survival rate after relapse (70%) than patients with refractory disease (11%) and those who experience a relapse during the second or third years of follow-up (12%).²⁶

A proposed algorithm for the treatment of r/r PCNSL is shown in Figure 4. HD-AraC- or HD-ifosfamide-based ChT followed by consolidative HDC–ASCT is an option for fit patients.^{79, 80} HD-MTX rechallenge can result in a second durable remission in patients who experience long-lasting regression after a previous HD-MTX-based combination.⁸¹ Patients with contraindications to ChT can be treated with salvage WBRT, with a reported median OS of 11 months.⁸² Less than 5% of relapses occur outside the CNS⁷; these patients may achieve remission with rituximab–cyclophosphamide–doxorubicin–vincristine–prednisone (R–CHOP) immunoChT.⁸

Given the extended survival of many patients with PCNSL following the widespread use of modern approaches, there is a growing interest in follow-up and long-term treatment implications. Notably, combined CRT is associated with disabling neurotoxicity with a cumulative 5-year incidence rate of 25%-35%. Prospective data on the optimal follow-up strategy for patients with PCNSL are lacking. The IPCG guidelines recommend a follow-up every 3 months for 2 years in patients enrolled in clinical trials, then every 6 months for an additional 3 years and thereafter annually for at least 5 years, for a total of 10 years of follow-up.¹³ Details on follow-up strategy and long-term treatment sequelae are reported in Supplementary Table S10, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010.

This CPG was developed in accordance with the ESMO standard operating procedures for CPG development (http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology). The relevant literature has been selected by the expert authors. The FDA/EMA or other regulatory body approval status of new therapies/indications is reported at the time of writing this CPG. Levels of evidence and grades of recommendation have been applied using the system shown in Supplementary Table S11, available at https://doi.org/10.1016/10.1016/j.annonc.2023.11.010. Statements without grading were considered justified standard clinical practice by the authors. For future updates to this CPG, including eUpdates and Living Guidelines, please see the ESMO Guidelines website: https://www.esmo.org/guidelines/guidelines-by-topic/esmo-clinical-practice-guidelines-haematological-malignancies/primary-central-nervous-system-lymphomas.

All authors conceptualized, wrote, and approved the final version.

AJMF reports personal financial interests for advisory board membership for AbbVie, AstraZeneca, Bristol Myers Squibb (BMS), Genmab, Gilead, Incyte, Juno, Novartis, PletixaPharm and Roche; institutional financial interests as local Principal Investigator (PI) for ADC Therapeutics, Amgen, BeiGene, BMS, Genmab, Gilead, Hutchison Medipharma, Incyte, Janssen, Novartis, Pfizer, Pharmacyclics and Takeda; institution research grants from BTG Therapeutics; institutional funding from Roche; non-financial interests as a member of the Global Outreach Committee of the EHA and as a member of the Board of Directors (President) of Fondazione Italiana Linfomi. GI reports personal financial interests as an advisory board member for Gilead, Incyte, Roche and as an invited speaker for Riemser; non-financial interests as a member of Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO) and a leadership role for the German Lymphoma Alliance (Mitglied des Vorstandes). JKD reports personal financial interests as an advisory board member for Eli Lilly. DPA reports non-financial interests as a member of an academic subcommittee for the British Society of Neuroradiologists. JECB reports personal financial interests as an advisory board member for Gilead and lecture honorarium from Novartis; institutional financial interests for funding of educational symposia from Roche and TEVA. TC reports personal financial interests for advisory board membership and consultancy for Janssen-Cilag S.p.A; speaking honoraria from Takeda; participation in the Hema for the Future project for Sandoz. KC reports personal financial interests as an advisory board member for AbbVie, Atara, Celgene, Incyte, Janssen, Kite, Roche and Takeda; personal financial interests as an invited speaker for Incyte, Kite, Roche and Takeda; non-financial interests as a member of the American Society of Clinical Oncology (ASCO) and the EHA, and leadership roles with the National Cancer Research Institute (NCRI; chair of UK NCRI T-cell lymphoma study group). CPF reports personal financial interests as an advisory board member for AbbVie, AstraZeneca, Atarabio, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, MorphoSys, Ono, Roche, SERB and Sobi; personal financial interests as an invited speaker for AbbVie, Gilead/Kite, Incyte, Janssen, Roche and Takeda; institutional financial interests as coordinating PI for BeiGene and Roche; institutional financial interests as a steering committee member for Genmab and MorphoSys; non-financial interests for an advisory role for Blood Cancer UK (clinical trials funding committee member) and Lymphoma Action (medical advisory panel member); non-financial interests for leadership roles with Cure Leukaemia (clinical trials steering committee member) and the NCRI (chair of UK NCRI aggressive lymphoma study group). KHX reports personal financial interests as an invited speaker for BTG. MP reports personal financial interests as an invited speaker for BeiGene and Novartis; personal financial interests for expert testimony for Ventana Roche. ES reports personal financial interests as an invited speaker for Riemser Pharma; personal financial interests for a writing engagement for Riemser Pharma; personal financial interests as an advisory board member for SERB Pharmaceuticals; institutional financial interests as a coordinating PI for Riemser Pharma and as a local PI for AbbVie, Riemser Pharma and Roche; non-financial interests as a PI for AbbVie and Roche; non-financial interests as a member of the DGHO and German Lymphoma Alliance. CS reports institutional funding from AstraZeneca. LS reports personal financial interests as an advisory board member for Kyowa Kirin and Takeda; personal financial interests as author royalties from Munksgaard Publishing and Springer Verlag; institutional financial interests as a steering committee member for Varian and ViewRay; non-financial interests for leadership roles with the International Lymphoma Radiation Oncology Group (Vice Chair) and the Danish Lymphoma Radiation Oncology Group (Chair); non-financial interests as a PI for the European Organisation for Research and Treatment of Cancer (EORTC); non-financial interests as a member of ASCO, American Society for Therapeutic Radiology and Oncology (ASTRO) and European Society for Therapeutic Radiology and Oncology (ESTRO). EZ reports personal financial interests as an advisory board member for AbbVie, BeiGene, BMS, Curis, Eli Lilly, Incyte, Ipsen, Janssen, Merck, Miltenyi Biomedicine and Roche; institutional financial interests for travel grants from BeiGene, Gilead, Janssen and Roche; institutional financial interests for trial sponsorship from AstraZeneca, BeiGene, Celgene/BMS, Incyte, Janssen and Roche. CB reports personal financial interests as an invited speaker for AbbVie, Pfizer and Sobi; personal financial interests as an advisory board member for BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, MorphoSys, Novartis, Regeneron and Roche; institutional funding from AbbVie, Amgen, Celltrion, Janssen, MSD, Pfizer and Roche. MJ reports personal financial interests as an advisory board member for BMS, Genmab, Gilead, Janssen and Novartis; personal financial interests as an invited speaker for Incyte; institutional financial interests as an invited speaker for Roche; institutional funding from AbbVie, AstraZeneca, Celgene, Gilead, Janssen and Roche; institutional financial interests as coordinating PI for BioInvent. MD reports personal financial interests as an invited speaker for AstraZeneca, Gilead/Kite, Janssen, Novartis and Roche; personal financial interests as an advisory board member for AstraZeneca, BeiGene, BMS/Celgene, Genmab, Gilead, Janssen, Lilly/Loxo, Novartis and Roche; institutional research grants from AbbVie, Bayer, Celgene, Janssen and Roche; institutional funding from Gilead/Kite; non-financial interests as a member of ASCO, American Society of Hematology (ASH; subcommittee member), DGHO (prior Board member), EHA (Executive Board member), ESMO (Faculty member) and Lymphoma Research Foundation [LRF; Mantle Cell Lymphoma (MCL) Consortium member]. DM has declared no conflicts of interest.

No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO (for Annals of Oncology) and EHA (for HemaSphere) central funds.