Primary CNS lymphoma

 Reference: Annals of Oncology June 2024

ESMO guidelines

Diagnosis Recommendations

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Contrast-enhanced cranial MRI is the recommended imaging modality for patients with PCNSL [II, A]. The IPCG protocol based on 3T or 1.5T MRI is recommended [V, A].

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PCNSL diagnosis must be confirmed by histopathological examination of tumour biopsy [III, A].

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Corticosteroid therapy before tissue biopsy should be avoided whenever clinically possible [IV, D]. In case of clinical deterioration, urgent biopsy should be carried out before the start of corticosteroids [IV, A].

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Tissue samples should be collected by stereotactic biopsy in patients with brain lesions [IV, A].

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Tumour resection is not recommended, except in carefully selected patients with rapidly increasing intracranial pressure who may benefit from surgical debulking at the time of tumour biopsy [IV, D].

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Diagnosis is based on morphology and immunohistochemistry [minimum stain panel includes cluster of differentiation (CD)20, CD3, CD10, B-cell lymphoma (Bcl)-6, Bcl-2, multiple myeloma 1 (MUM1) and Ki-67 antibodies]. Molecular analysis of Ig heavy and light chain loci can be used in selected cases where diagnosis is difficult [V, A].

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When brain biopsy is contraindicated, CSF examination is a valid option. Flow cytometry, MYD88 L265P mutation analysis and IL-10 levels in CSF samples may support a diagnosis of PCNSL [IV, B].

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Suspicion of PVRL should be confirmed by conventional cytology examination of the vitreous humour and, when possible, by flow cytometry. Although not diagnostic, MYD88 L265P mutation and IL-10 levels may be assessed in the vitreous and aqueous humours as indicators of ocular lymphoma [III, A].

Staging

Recommendations

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Spinal cord imaging should be carried out in symptomatic patients or in case of CSF positivity [V, B].

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Unless lumbar puncture is clinically contraindicated, physical–chemical features of CSF as well as conventional cytology and flow cytometry should be assessed in all patients [IV, B].

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Ophthalmological assessment by slit lamp fundoscopy should be carried out in all patients to exclude intraocular involvement [IV, A]. When available, retinal angiography or tomography is advisable [IV, C].

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All patients should undergo systemic imaging to exclude extra-CNS disease using FDG–PET, preferably combined with contrast-enhanced CT scan [V, B].

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If FDG–PET–CT is not feasible, contrast-enhanced total-body CT scan, bone marrow aspiration and biopsy and testicular US should be carried out [V, B].

Treatment recommendations- Newly diagnosed

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Enrolment in suitable prospective clinical trials should be offered to every patient with PCNSL [I, A].

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When a prospective trial is not available, induction ChT including HD-MTX is recommended at a minimum dose of 3 g/m2 delivered in a 3-h infusion [I, A].

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Combinations of HD-MTX with other cytotoxic agents that cross the blood–brain barrier and have been tested in prospective (preferably randomised) trials are recommended (e.g. MATRix, R–MBVP, rituximab–HD-MTX–carmustine–etoposide–prednisone, R–MPV, R–MT) [I, A].

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The benefit of adding rituximab [not European Medicines Agency (EMA) approved, not Food and Drug Administration (FDA) approved] to induction HD-MTX-based polyChT remains unclear. The balance between tolerability and efficacy should be discussed with patients and their carers [II, B].

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Judicious reduction of MTX dose according to renal function and comorbidities is recommended [III, A].

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Intrathecal ChT is not recommended in routine practice, except for patients with CSF dissemination who are unable to receive ChT including MTX at ≥3 g/m2 or for patients with persistence of CSF or meningeal disease at the end of first-line treatment [III, D].

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Intravitreal ChT is not recommended in routine practice, except for patients with persistent intraocular lymphoma at the end of first-line treatment [III, D].

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HDC–ASCT is recommended as consolidation in fit patients with responsive or stable disease after suitable induction ChT [I, A].

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Fitness for HDC–ASCT should be evaluated dynamically during treatment, especially in older patients who may gain or lose ‘HDC–ASCT fitness’ during induction ChT [III, B].

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Thiotepa-based ASCT conditioning regimens should be used. The dose of thiotepa combined with either busulfan or carmustine should be based on established protocols and informed by patient fitness and comorbidities [III, A].

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Consolidation WBRT at a dose of 36-40 Gy/20 fractions is recommended in young patients who are not suitable candidates for ASCT. Safety profiles (haematological and cognitive toxicities) should be considered for individual therapeutic choice [I, A].

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Consolidation WBRT at a dose of 36-40 Gy/20-22 fractions should be avoided or deferred in elderly patients because of the high risk of disabling neurocognitive impairment [I, D].

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Reduced-dose WBRT (23.4 Gy) is an option for patients with responsive disease after suitable induction ChT, but the longer-term effects on cognitive function remain to be defined, especially in elderly patients [III, B].

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Watchful waiting can be considered in elderly patients in CR after induction with an established drug combination [II, B]. Maintenance with oral drugs, such as alkylating agents or immunomodulators such as lenalidomide (not EMA approved, not FDA approved) can be considered on an individual basis [IV, C].

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There is no established standard of care for patients unfit for HD-MTX-based ChT. Valid (but incompletely investigated) palliative options include upfront WBRT [III, B], corticosteroids, oral alkylating agents with or without rituximab (not EMA approved, not FDA approved), BTK inhibitors and immunomodulators [V, C].

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Assessment of response to treatment should follow modalities and timing proposed by the IPCG criteria.

Relapsed refractory PCNSL treatment recommendations

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Patients with r/r PCNSL should be registered in a prospective clinical trial assessing novel drugs or strategies [III, A].

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Fit patients with refractory or early relapsed PCNSL can be treated with, for example, HD-ifosfamide- or HD-AraC-based combinations, followed by ASCT or WBRT according to previous treatment [III, B].

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Patients with refractory or early relapsed PCNSL unfit for salvage polyChT could be treated with WBRT [V, C] or with a single drug such as ibrutinib, lenalidomide or temozolomide [III, B; not EMA approved, not FDA approved].

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Patients with late relapse of PCNSL could be re-treated with HD-MTX, employing the same or similar ChT regimen used in first-line treatment, and consolidated with ASCT or WBRT in the case of response [IV, B].

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The increased risk of neurotoxicity associated with WBRT should be considered in patients aged >60 years with r/r PCNSL [IV, C].

IPCG guidelines for response assessment

The International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) response criteria combine MRI findings, ophthalmologic examination, cerebrospinal fluid analysis, and corticosteroid use to assess treatment response in primary CNS lymphoma.^[1-2] These criteria were published in 2005 to standardize response assessment across clinical trials.^[2]

Response Categories

The IPCG criteria define the following response categories:^[3-4]

Complete Response (CR):

• Complete disappearance of all gadolinium enhancement on brain MRI
• No corticosteroid use
• Negative CSF cytology
• Normal ophthalmologic examination (if previously involved)

Unconfirmed Complete Response (CRu):

• Either no residual gadolinium enhancement but continued steroid use, OR
• Small residual gadolinium enhancement probably related to biopsy or hemorrhage

Partial Response (PR):

• ≥50% decrease in size of contrast-enhancing tumor on MRI
• Stable or reduced corticosteroid dose
• No new lesions

Progressive Disease (PD):

• ≥25% increase in tumor size on MRI, OR
• Appearance of any new tumor lesion

Stable Disease:

• Situations that do not meet criteria for CR, CRu, PR, or PD

Key Assessment Components

The IPCG criteria require evaluation of multiple disease sites:^[1-2]

• Brain MRI with gadolinium contrast to measure enhancing lesions
• Ophthalmologic examination including slit-lamp examination for vitreoretinal involvement
• CSF analysis with cytology when safely obtainable
• Corticosteroid dose documentation, as steroids can dramatically reduce enhancement independent of tumor response