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

Recommendations

• 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 recommendedV, A
• PCNSL diagnosis must be confirmed by histopathological examination of tumour biopsyIII, A
• 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 corticosteroidsIV, A
• Tissue samples should be collected by stereotactic biopsy in patients with brain lesionsIV, A
• 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 biopsyIV, D
• 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 difficultV, A
• 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 PCNSLIV, B
• 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 lymphomaIII, A
• Spinal cord imaging should be carried out in symptomatic patients or in case of CSF positivityV, B
• Unless lumbar puncture is clinically contraindicated, physical–chemical features of CSF as well as conventional cytology and flow cytometry should be assessed in all patientsIV, B
• 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 advisableIV, C
• All patients should undergo systemic imaging to exclude extra‐CNS disease using FDG–PET, preferably combined with contrast‐enhanced CT scanV, B
• If FDG–PET–CT is not feasible, contrast‐enhanced total‐body CT scan, bone marrow aspiration and biopsy and testicular US should be carried outV, B
• Enrolment in suitable prospective clinical trials should be offered to every patient with PCNSLI, A
• 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 infusionI, A
• 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
• 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 carersII, B
• Judicious reduction of MTX dose according to renal function and comorbidities is recommendedIII, A
• 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 treatmentIII, D
• Intravitreal ChT is not recommended in routine practice, except for patients with persistent intraocular lymphoma at the end of first‐line treatmentIII, D
• HDC–ASCT is recommended as consolidation in fit patients with responsive or stable disease after suitable induction ChTI, A
• Fitness for HDC–ASCT should be evaluated dynamically during treatment, especially in older patients who may gain or lose ‘HDC–ASCT fitness’ during induction ChTIII, B
• 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 comorbiditiesIII, A
• 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 choiceI, A
• 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 impairmentI, D
• 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 patientsIII, B
• 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 basisIV, C
• 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 immunomodulatorsV, C
• Assessment of response to treatment should follow modalities and timing proposed by the IPCG criteriaIII, B
• Fit patients with PVRL should be treated with HD‐MTX‐based induction ChT, using the same combinations proposed for other patients with PCNSL [IV, C]. Intravitreal MTX injections can be added if a rapid regression of intraocular disease is neededIV, C
• Patients with a CR or partial response to HD‐MTX‐based induction ChT can be eligible for consolidation with low‐dose bilateral ocular RT [IV, C]. The risks and benefits of consolidation with ASCT can be discussed with selected patientsV, C
• Therapeutic response should be assessed by slit lamp and fundus examination during and at the end of induction as well as after consolidation; however, precise response definition based on clinical evaluation is difficult. If available, assessment of MYD88 L265P and IL‐10 levels in aqueous humour may be useful to monitor intraocular response. Angiography and optical coherence tomography could improve response definitionV, C
• Oral alkylating agents [i.e. temozolomide (not EMA approved, not FDA approved)] and local therapies (ocular RT or intravitreal MTX injection) are acceptable options as first‐line treatment for unfit patients or patients with contraindications to ChTIV, B
• Fit patients with r/r PVRL should be treated with second‐line ChT and consolidative HDC–ASCTIII, B
• Local treatments, as well as ibrutinib, lenalidomide or temozolomide, are alternative options for patients with r/r PRVL in poor general conditionIII, B; not EMA approved, not FDA approved
• Patients with r/r PCNSL should be registered in a prospective clinical trial assessing novel drugs or strategiesIII, A
• 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 treatmentIII, B
• 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 temozolomideIII, B; not EMA approved, not FDA approved
• 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 responseIV, B
• The increased risk of neurotoxicity associated with WBRT should be considered in patients aged >60 years with r/r PCNSLIV, C
• Follow‐up imaging with cranial MRI should be carried out, particularly in patients eligible for intensive salvage therapies, at 3‐month intervals in the first 2 years from the end of treatment, every 6 months for another 3 years and subsequently on an annual basisIV, B
• Ophthalmological examination should be carried out annually if not involved initially, and more often if involved initially or in the case of visual deteriorationIV, B
• CSF assessment should only be carried out in the case of suspected or confirmed relapseIV, B
• Neurocognitive function and QoL should be assessed on an annual basis at least within clinical trialsI, B