How we treat primary central nervous system lymphoma

Abstract

•HD-MTX based induction and consolidation with HDC/ASCT is our standard of care in young and fit patients (<70 y).•HD-MTX based combinations are the first line treatment in PCNSL candidate to chemotherapy irrespective of age.•Oral maintenance represents an alternative in responding patients not eligible for HDC/ASCT because of age/comorbidities.•Targeted drugs such as BTKi and IMiDs are promising especially in the elderly.•MYD88 and IL10 are optimal biomarkers and might improve suspicion and anticipate PCNSL diagnosis.•A multidisciplinary approach should be applied to reach the best outcomes. Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood–brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients. Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood–brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients. Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is a rare and aggressive lymphoproliferative disease that was recently recognized as a distinct entity by the 2017 World Health Organization classification of hematopoietic and lymphoid tumors.1Kluin P.M. Deckert M. Ferry J.A. Primary diffuse large B-cell lymphoma of the CNS.in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research in Cancer, Lyon, France2017: 300-302Google Scholar PCNSL accounts for 4% of primary CNS neoplasms and 4%-6% of extranodal lymphomas. New cases are generally diagnosed in the fifth or sixth decade of life, and with a slightly higher frequency among males.2Shiels M.S. Pfeiffer R.M. Besson C. et al.Trends in primary central nervous system lymphoma incidence and survival in the U.S.Br J Haematol. 2016; 174: 417-424Crossref PubMed Scopus (117) Google Scholar Except for immunosuppression status, no other risk factors predisposing the development of PCNSL are known. Management of patients with newly diagnosed PCNSL is complex and requires a multidisciplinary approach (Table 1). Clinical presentation of PCNSL is heterogeneous and depends on the involved CNS structures that could include brain, leptomeninges, eyes, cranial nerves, and spinal cord. Symptoms are mainly focal neurological deficits, personality changes, and increased intracranial pressure, and usually require immediate evaluation by neurologists and/or neurosurgeons, with a subsequent neuroimaging examination. Contrast-enhanced brain magnetic resonance imaging (MRI) (bMRI) is the best modality option for assessing PCNSL patients. Lesions are often isointense/hypointense on T2-weighted MRI, with surrounding edema and a homogeneous and strong pattern of enhancement. PCNSL presents as a solitary lesion in 60%-70% of cases, mostly located in the hemispheres, basal ganglia, corpus callosum, and periventricular regions. It tends to infiltrate the subependymal tissues and disseminates through the cerebrospinal fluid (CSF) to the meninges, which is often asymptomatic and detectable by cytology/immunophenotypic analysis on CSF in 16% of cases. Some patients (10%-20%) experience visual complaints (i.e. floaters, blurred vision, visual field defects, and decrease in vision) as initial and often exclusive symptoms. This ‘alternative’ presentation needs to be taken into account in the differential diagnosis of the ‘masquerade syndromes’ from an expert ophthalmologist who will confirm the presence of intraocular disease. An accurate staging disease aims both to define the extension of disease in different CNS structures and to rule out concomitant systemic lymphoma. Conventional staging with [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography (18FDG-PET), bone marrow biopsy/aspiration and testicular ultrasound, detects extra-CNS disease in 4%-12% of patients with presumptive diagnosis of PCNSL. Although it is used as a fast and sensitive procedure to exclude systemic disease during staging, 18FDG-PET plays a limited role to assess PCNSL lesions and response to treatment, mostly due to physiologic tracer accumulation in the brain. Recently, the novel PET tracer [68Ga]Ga-PentixaFor, used for the visualization of C-X-C chemokine receptor 4 (CXCR4)-positive malignancies, showed interesting applicability in both visualization and treatment response assessment of CNS lymphoma.3Herhaus P. Lipkova J. Lammer F. et al.CXCR4-targeted PET imaging of central nervous system B-cell lymphoma.J Nucl Med. 2020; 61: 1765-1771Crossref PubMed Scopus (16) Google Scholar Prospective assessment of this new theranostic agent in PCNSL is warranted.Table 1Diagnostic and staging work up in PCNSLTestAimsDiagnostic approaches Radiology assessment:Brain MRI; spinal MRI (only in symptomatic cases or with CSF positivity)To assess CNS involvement and prognostic factors (such as deep lesions) Stereotactic brain lesion biopsy (more rarely open brain biopsy):Morphology; IHC; molecular/cytogenetic analysisTo carry out histopathological diagnosis on the primary CNS lesion Vitrectomy and/or vitreous and/or humor aspirate (in cases of suspected ocular involvement):Morphology; immunophenotype/IHCTo carry out cytological diagnosis on primary vitreoretinal lesion CSF analysis:CytologyImmunophenotypeMolecular assessment: MYD88 mutational status and IL-10 levels in CSFTo assess leptomeningeal disseminationTo confirm the PCNSL suspicion in cases of CNS lesions not suitable for biopsyStaging approaches Radiometabolic assessment:18FDG-PET/CT total body and testis ultrasoundTo exclude extra-CNS disease: 18FDG-PET and testicular ultrasound demonstrate the presence of extraneural disease in 4%-12% of patients with presumptive diagnosis of PCNSL Bone marrow biopsy and aspirate:Morphology; immunophenotype/IHCTo assess bone marrow reserveTo exclude bone marrow involvement CSF analysis:Physico-chemical examCytologyImmunophenotypeTo assess leptomeningeal involvement: CSF sampling should be carried out in every patient with suspected or confirmed PCNSL. Increases in the leucocytes cell count and protein concentrations are often present, while glucose concentration is usually normal. Concurrent meningeal involvement, often asymptomatic, is detected by conventional CSF cytology in 16% of cases Ophthalmologic evaluation:Fundoscopy and slit lamp examination, fluorescein angiographyTo assess ocular lymphomatous infiltration: asymptomatic ocular involvement is detected in 5% of casesFitness work-up Blood test:Full blood count; liver and renal function index; serology for HIV, HCV, HBV; pregnancy testTo evaluate the bone marrow reserveTo exclude liver and renal damageTo evaluate supportive antiviral therapy Cardiac assessment:Echocardiography, electrocardiogramBasal pro-BNP protein and troponin serum levelTo assess baseline cardiac function Pulmonary assessment (only for patients with known lung disease):Thorax CT scanPulmonary function test (spirometry test and diffuse capability of CO2)PS according to ECOG or Karnofsky scaleTo diagnose chronic obstruction pulmonary disease or other pulmonary comorbiditiesTo define with standard tool the patient’s fitness and to consider the social and professional life before disease onset as well as comorbidities and eventual organ impairment secondary to them, in order to better define the choice of treatment18FDG-PET/CT, [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computerized tomography; CNS, central nervous system; CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency viruses; IHC, immunohistochemistry; IL-10, interleukin 10; MRI, magnetic resonance imaging; PCNSL, primary central nervous system lymphoma; pro-BNP, pro hormone B-type natriuretic peptide; PS, performance status. Open table in a new tab 18FDG-PET/CT, [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computerized tomography; CNS, central nervous system; CSF, cerebrospinal fluid; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency viruses; IHC, immunohistochemistry; IL-10, interleukin 10; MRI, magnetic resonance imaging; PCNSL, primary central nervous system lymphoma; pro-BNP, pro hormone B-type natriuretic peptide; PS, performance status. At presentation, most PCNSL patients receive immediate steroid therapy with fast symptomatic improvement and radiographic regression in ∼40% of patients. Mass shrinking can interfere with histopathological diagnosis; for this reason the use of steroids should be limited to cases of osmotherapy inefficacy and, if started, should be withheld at least 7-10 days before diagnostic biopsy. Importantly, a presumptive diagnosis of PCNSL should induce expert neurosurgeons to carry out stereotactic-guided biopsy of the mass to confirm diagnosis. Whereas stereotactic biopsy is a fast and safe procedure, wide tumor resection can induce permanent neurological deficits and treatment delay, without any survival benefits. In selected patients who require a timely control of neurological deterioration due to brain herniation or ventricle dilation, however, indication to tumor resection should be considered. At our institution, MYD88 mutational status and interleukin-10 level are assessed on CSF in patients with low PCNSL suspicion or with unsuitable lesions for biopsy, because the combined analysis is able to distinguish PCNSL from other CNS entities with a sensitivity and specificity of 94% and 98%, respectively.4Ferreri A.J.M. Calimeri T. Lopedote P. et al.MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.Br J Haematol. 2021; 193: 497-505Crossref PubMed Scopus (9) Google Scholar At consultation, our attention is focused on the general conditions of the patient, which implies a careful collection of information and clinical evaluation in order to assess the need of additional health facilities and services to improve the initial assistance. It is also important to identify the caregiver before to share the therapeutic choice with the interlocutors. The multidisciplinary team devoted to the management of PCNSL patients at our institution has extensive experience in clinical research, leading several clinical studies in this field. Accordingly, when faced with a patient with a new diagnosis of PCNSL, our first thought is to enroll him/her in a prospective trial. The following concepts regard our therapeutic choices for PCNSL patients managed outside prospective trials (Figure 1). Age and performance status (PS) are important prognostic factors; however, several other details, like comorbidity, organ function, frailty, and risk of neurotoxicity, should be considered in the choice of the better treatment. In prospective trials, age cut-off used to define young patients varied between 60 and 75 years. In routine practice, patients aged between 60 and 75 years often receive personalized treatment because of large variability in comorbidity and neurological conditions. Thus, in this population, we consider suitability to receive high dose chemotherapy plus autologous stem cell transplantation (HDC/ASCT) as the main parameter to distinguish ‘young-fit’ and ‘elderly-frail’ patients. The modern treatment of PCNSL includes two phases: induction and consolidation. Thus, based on the results of the IELSG32 trial,5Ferreri A.J.M. Cwynarski K. Pulczynski E. et al.Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial.Lancet Haematol. 2017; 4: e510-e523Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar polychemotherapy with four cycles of the MATRix regimen [methotrexate (MTX), cytarabine, thiotepa, rituximab] followed by HDC/ASCT is the preferred treatment option for young patients without severe comorbidities. Peripheral autologous hematopoietic stem cells (HSC) are usually collected after the second cycle. Patients with responsive disease according to International Primary CNS Lymphoma Collaborative Group criteria6Abrey L.E. Batchelor T.T. Ferreri A.J. et al.Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma.J Clin Oncol. 2005; 23: 5034-5043Crossref PubMed Scopus (516) Google Scholar are consolidated with ASCT using a conditioning regimen with carmustine and thiotepa.5Ferreri A.J.M. Cwynarski K. Pulczynski E. et al.Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial.Lancet Haematol. 2017; 4: e510-e523Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Our standard choice of MTX dose and administration schedule, that is 3.5 g/m2 in a 3-h infusion, is based on well-documented higher response rate and CSF levels. In the case of dose reductions due to toxicity, we try to deliver a dose of 3 g/m2 (85%) to not compromise CNS levels in the brain and MATRix includes the role of which in PCNSL treatment is a of At the to the IELSG32 the results of the randomized not The was focused on the role of rituximab in PCNSL patients aged a significant in patients 60 K. et in patients with primary CNS lymphoma a phase 3 Oncol. Full Text Full Text PDF PubMed Scopus Google Scholar an in patients 60 years was not because patients not receive consolidation with disappointing survival which a from this the results of the IELSG32 a of that demonstrate a better survival and overall survival in patients with A.J.M. Cwynarski K. Pulczynski E. et induction followed by autologous stem cell or whole-brain irradiation in Primary CNS results of the IELSG32 randomized trial. Oncol. 2021; Google Scholar and the that this drug not M. et and in primary CNS lymphoma results from the Oncol. 2021; PubMed Scopus Google Scholar to confirm our choice to rituximab as of the MATRix evaluation with is carried out after the second and of MATRix as well as after from and CSF are carried out at the in case of ocular and/or meningeal involvement at are at the of the treatment or in case of clinical In case of disease in the at the of systemic indication to treatment with rituximab and MTX is with the is an in PCNSL patients with a modern Accordingly, and in line with recently and international trials, we not use chemotherapy as of treatment. brain radiotherapy is an alternative to ASCT in case of or during is not our first choice as consolidation therapy due to the increased risk of impairment of in the A.J.M. Calimeri T. Lopedote P. et al.MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.Br J Haematol. 2021; 193: 497-505Crossref PubMed Scopus (9) Google Scholar and the C. et or autologous stem-cell transplantation for primary CNS lymphoma in patients 60 years of age and results of the randomized phase Clin Oncol. PubMed Scopus Google Scholar The is an important for the of it is from the of the induction are usually carried out at diagnosis and at the of and used as baseline to any during patients 70 years are not eligible for and should be according to the suitability to receive chemotherapy (Figure 1). Patients with renal function, bone marrow and cardiac function no disease or are for this treatment. combined treatment with an alkylating agent (i.e. and rituximab is et and and cytarabine for primary CNS lymphoma in an elderly an phase 2 trial.Lancet Haematol. Full Text Full Text PDF PubMed Scopus Google K. E. et methotrexate-based for elderly primary CNS lymphoma patients 2017; PubMed Scopus Google Scholar In responding J. et and followed by consolidation whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: results and Clin Oncol. PubMed Scopus Google Scholar or maintenance with oral alkylating M. et of treatment in elderly patients with primary central nervous system lymphoma by induction and results from a phase by the Lymphoma PubMed Scopus Google Scholar should be considered. to E. K. et chemotherapy with autologous stem cell in elderly patients with primary central nervous system lymphoma: a 2017; PubMed Scopus Google Scholar selected patients 70 years with and suitable organ function be for we consider MATRix at dose as induction before ASCT (Figure 1). Primary is an option for patients not eligible for with a of for some concomitant and maintenance this an patients are to exclusive care and, in this indication to brain biopsy should be with standard of care for patients with or PCNSL to be Clinical trials should be the preferred treatment option because this is the best to identify new drugs and strategies that could be investigated as of a prospective is not therapeutic choice should be based on phase trials. 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M. et for or primary CNS lymphoma and primary vitreoretinal lymphoma: analysis of the phase by the Lymphoma and the lymphoma J Full Text Full Text PDF PubMed Scopus Google Scholar CSF concentration with a safe however, an increased incidence of has been to of a timely or of steroid therapy might this severe drugs and have been investigated in patients with or PCNSL or primary vitreoretinal lymphoma an response in of the the response was usually et of plus of maintenance in CNS PubMed Scopus Google et of and for primary CNS or vitreoretinal PubMed Scopus Google Scholar used as agent at low dose as maintenance therapy and in with to be further investigated in this At the we not use cell protein because results of phase trials are receptor cells recently for the treatment of DLBCL, with promising results in other B-cell lymphomas. This approach to be in patients with or PCNSL results in patients with secondary CNS J. 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