CNS lymphoma

See ((CNS lymphoma relapse))


Clinical presentation and diagnosis of secondary central nervous system lymphoma.



Systemic non-Hodgkin lymphoma (NHL) may involve the nervous system at every level, including peripheral nerve, spinal nerve root, spinal cord, meninges, and brain. 



Nervous system involvement may include direct invasion or compression of these structures, as well as paraneoplastic effects of NHL. 



In the more aggressive lymphomas, a high-grade such as Burkitt lymphoma and lymphoblastic lymphoma, the rate of CNS relapse can reach 30-50%. 



In diffuse large B cell lymphoma CNS involvement occurs in approximately 2-5% of patients.



Central nervous system (CNS) complicates a significant minority of NHL patients, but peripheral nervous system (PNS) involvement is rare. 



The most common manifestations of NHL involvement of the CNS include: leptomeningeal disease and parenchymal brain involvement.



Lymphoma cells are thought to enter the CNS by: hematogenous spread, direct extension from adjacent bone marrow infiltration, or growth along neurovascular bundles. 



Most CNS involvement by non-Hodgkin lymphoma (NHL) occurs in the setting of relapsed disease.



A considerable percentage of patients with non-Hodgkin’s lymphoma may have had subclinical CNS involvement at the time of diagnosis. 



There is a high rate of CNS involvement within six months of initial therapy in many patients with aggressive NHL.



Diffuse large B-cell lymphoma patients have a 5% overall risk of central nervous system events of relapse or progression.



CNS involvement accounts for high morbidity and frequently fatal outcomes,1 and shortened overall survival of <6 months.



Early diagnosis of CNS involvement is critical for successful treatment.



Meta-analysis identified a decrease in rates of CNS relapse in the post-rituximab era, probably due to improved control of systemic lymphoma.



There has been a change in the pattern of CNS relapse, with the dominance of parenchymal over leptomeningeal relapse, and delayed response.



Risk factors for CNS relapse: increased serum lactate dehydrogenase (LDH) levels and/or involvement of >1 extranodal site.



The International Prognostic Index (IPI) score  is as an independent predictor for CNS relapse.



Elevated LDH and a poor performance status are  identified as independent predictive factors for CNS relapse. 



Extranodal involvement have shown that testicular or breast involvement is associated with a higher rate of CNS relapse.



There is a higher CNS relapse rate among patients with renal involvement by lymphoma. 



To assess the risk of CNS disease in DLBCL includes the 5 IPI factors in addition to kidney/adrenal gland involvement, and it stratifies patients into 3 risk groups for CNS relapse: low risk (0–1 factors; 2-year risk of 0.6%), intermediate risk (2–3 factors; 2-year risk of 3.4%), and high risk (4–6 factors; 2-year risk of 10.2%).



Studies suggest a high percentage of CNS involvement in DLBCL cases with MYC rearrangement, particularly when associated with either additional BCL-2 or BCL-6 gene rearrangements: in these patients, the frequency of CNS disease ranges from 9% to 45%. 



Such patients should be screened  for CNS involvement by lumbar puncture and cerebrospinal fluid (CSF) analysis by conventional cytology.



Definitive diagnosis of central nervous system lymphoma (CNSL) relies on a positive CSF cytology.



As far as CNS lymphoma is concerned, 


the most informative is magnetic resonance imaging (MRI), including contrast-enhanced MRI, with a sensitivity of 71% vs. 36% for computerized tomography (CT).



Most CNSL lesions are associated with either diffuse or, more frequently, local enhancement, which often includes the leptomeninges, cranial nerves, or the periventricular region.



While histopathological and immunohistochemical analysis of stereotactic biopsy samples is considered a standard procedure for the diagnosis of PCNSL, it is not a routine procedure in patients who already have been diagnosed with DLBCL. 



CSF cytology is a highly specific diagnostic approach for CNSL.



CSF cytology is of limited sensitivity, and produces a significant percentage (20%–60%) of false-negative results.



The morphological features of inflammatory lymphocytes in CSF can mimic  those of lymphoid tumor cells, leading to false-positive results in some cases.



Studies of flow cytometry (FCM) analysis of CSF samples have demonstrated increased sensitivity between 3% and 20% of cases as compared with cytology.



Very few false-negative FCM results ranging from 0%–<1%.



The use of FCM in the diagnostic work-up of CNS involvement in DLBCL is mandatory.



CNS lymphoma is associated with Increases in protein and LDH levels, pleocytosis, and decreased glucose levels in CSF.



These parameters are nonspecific and therefore unreliable for routine diagnosis of CNS disease.



CSF levels of soluble (s)CD21, sCD22, sCD24, sCD38, sCD44, sCD72, and immunoglobulin (IG) heavy and light chain isotypes are of limited diagnostic utility.



CSF-positive cases (8%–13% vs. 11%–16%) have been obtained by polymerase chain reaction (PCR) analysis of IG gene sequences and cytomorphology, indicating the utility of PCR analysis of IG genes may be limited to selected cases in which CSF cytology and FCM are not informative.



Increased CSF levels of sCD19, sAnti-thrombin III (sATIII), sCD27, β2 microglobulin, IL-6, IL-10, CXCL13, neopterin, osteopontin, and several microRNAs (miRNA19b, miRNA21, and miRNA92a) are potentially useful biomarkers for CNS lymphoma.



The presence of occult CNSL in high-risk DLBCL may be considered an adverse prognostic factor, although its independent prognostic value has not been definitively established.



CNS relapse in DLBCL mainly occurs within less than one year after diagnosis, 


suggesting that affected patients probably harbor occult malignant cells in the CNS at diagnosis.



FCM improves the identification of CNS involvement by 4- to 10-fold as compared with cytology.



CNS prophylaxis therapy  is most commonly delivered via the intrathecal (IT) route



The administration of IT methotrexate (MTX) prophylaxis is recommended during each cycle of chemotherapy, with a total of 4 to 8 doses.



12 mg methotrxate dosing achieves therapeutic levels in the CSF (>1 μmol/L) for 24 to 48 hours.



There are data to suggest that IT rituximab is efficacious in the treatment of CNS relapse.



Triple  intrathecal therapy with methotrexate, cytarabine and hydrocortisone is the most commonly used schedule for CNS prophylaxis in hematological malignances.



There is no definitive evidence that CNS direct prophylaxis with IT administration improves CNS progression-free survival in patients with parenchymal CNS involvement. 



IV MTX doses ≥3 g/m2 can produce therapeutic levels in CSF and parenchyma. 



The  most effective and least toxic route of CNS prophylaxis delivery (IT, parenteral, or a combination thereof) remains largely unanswered.



Rates of CNS relapse were similar in patients who received prophylaxis (6%) and those who did not (5.9%).



In a retrospective analysis of patients with high-risk DLBCL, comparing three different strategies of CNS-directed therapy: IT MTX with R-CHOP (group 1); R-CHOP with IT MTX and two cycles of HD-MTX (group 2); and dose-intensive systemic chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX (group 3). 



A total of 23 CNS relapses occurred (24%, 8%, and 2.3% in groups 1, 2, and 3, respectively). 



The addition of HD-MTX and/or HD-cytarabine appears to be associated with lower incidence of CNS relapse as compared with IT chemotherapy alone.



Patients with primary testicular lymphoma should receive IT MTX during primary chemotherapy. 



Triple IT therapy (MTX 15 mg, cytarabine 40 mg, and hydrocortisone 20 mg) is an option for CNS prophylaxis. 



HD-MTX and/or IT chemotherapy should be considered for cases of CNS involvement at the time of DLBCL diagnosis.



In patients for whom HD-MTX is inadequate due to age or comorbidities, IT liposomal cytarabine should be considered. 



In the case of CNS relapse: salvage therapy HD-MTX-based induction followed by ASCT.



Thiotepa and BCNU are included in the conditioning regimen before ASCT. 



In the case of refractoriness or early relapse after HD-MTX, consider clinical trial or radiotherapy. 



IT MTX (12–15 mg once per cycle, 4–6 doses) or triple IT (MTX 15 mg, cytarabine 40 mg, hydrocortisone 20 mg) as CNS prophylaxis should be administered during primary therapy.



Secondary involvement of CNS in aggressive NHL can occur at presentation or early in the first year, usually associated with or anticipating systemic relapse.



Both CNS and systemic lymphoma should be considered for the treatment of CNS dissemination.



The usefulness of radiotherapy for the management of CNS lymphoma is limited by its toxicity, especially in older patients. 



Whole-brain radiotherapy has been used in combination with chemotherapy in PCNSL, but its true impact on outcome remains controversial.



Whole-brain radiation is generally reserved for salvage therapy in patients with MTX resistance.



Systemic chemotherapy agents that cross the blood-brain barrier (BBB) can avoid the need for IT chemotherapy administered via multiple lumbar punctures or ventricular reservoirs. 



IV MTX is active in primary and secondary CNSL.



Doses  of methotrexate ≥1 g/m2 achieve tumoricidal levels in brain parenchyma, doses of 8 g/m2 produce higher cytotoxic levels in serum and CSF than IT MTX, and doses of 3 g/m2 are sufficient to treat brain and leptomeningeal disease, without associated IT MTX.



There is a failure-free survival benefit in patients who received HD-MTX plus HD-cytarabine as induction therapy, followed by radiotherapy as consolidation, in primary CNS lymphoma.



Other anti-lymphoma agents that cross the blood brain barrier such as procarbazine or ifosfamide have been used in combination with HD-MTX, and have showed encouraging activity.



High-dose chemotherapy consolidation followed by autologous stem cell transplant (ASCT) rescue is a very promising option in patients with recurrent SCNSL, with better outcomes in patients who achieve CR before transplantation.



In a German  phase II study, HDMTX, ifosfamide, dexamethasone and IT LC followed by HD-cytarabine, thiotepa and IT LC, and, for responding patients, consolidation with BCNU, thiotepa, etoposide, and ASCT rescue, resulted in 50% CR, with a 2-year OS rate of 68% after transplantation.



In a recent Italian trial, HDMTX and cytarabine, followed by R-HDS (rituximab, cyclophosphamide, cytarabine, and etoposide) supported by ASCT was associated with 63% CR and 5-year OS of 68% for transplanted patients.



Current treatments are multifaceted approaches, such as multi-drug regimens with non-cross resistance and CNS activity, rituximab to improve systemic lymphoma control, IT therapy, and treatment intensification with ASCT.



IT MTX, cytarabine, and thiotepa can be administered into the spinal fluid, allowing the drug to reach the spinal cord and brain. 



These agents require  administration two or three times a week. 



Intraventricular or IT administration of rituximab may be of value in the treatment of patients with recurrent CD20-positive CNSL.


Intraventricular administration of rituximab (10–25 mg) is feasible, has shown encouraging anti-CNSL activity and clinical benefit, and when combined with intraventricular MTX results in improved responses.



Patients with synchronous CNS and systemic aggressive NHL at presentation should receive immunochemotherapy for the systemic disease and CNS-targeted chemotherapy for CNSL. 



High-dose chemotherapy followed by ASCT is feasible and effective for recurrent aggressive CNS lymphoma, and is probably the best currently available curative option.



In MTX-sensitive patients, HD-MTX administration to achieve maximum cytoreduction is advisable, followed by thiotepa or carmustine-based conditioning regimens and ASCT.



Patients with MTX-resistant lymphoma or those relapsing within 6 months after consolidation schemas may not be candidates for high-dose rescue strategies.



Patients with systemic DLBCL and synchronous CNS parenchymatous and/or leptomeningeal lymphoma at diagnosis should be treated with HD-MTX-containing regimens (recommendation 1, level of evidence B). 



In cases involving leptomeningeal lymphoma, associated ITtreatment can be administered.








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