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relapses has decreased and these relapses more common- ly involve the brain parenchyma where CSF evaluation provides a lower diagnostic yield.7,20,21 As such, routine evaluation of the CSF in patients without neurological symptoms in the modern era remains controversial. Our own practice is to evaluate the CSF at baseline in all patients with neurological symptoms, in patients with disease infiltrating neural foramina, and in most patients with double- or triple-hit lymphoma, as these patients are at particularly high risk and often relapse within the leptomeninges. For high-risk asymptomatic DLBCL patients without double- or triple-hit cytogenetics who we are treating with intrathecal methotrexate for CNS prophylaxis, we evaluate their baseline CSF at the time of their initial intrathecal injection. For high-risk patients receiving CNS prophylaxis with high-dose systemic methotrexate, we consider whether a finding of an occult positive CSF would alter the patient’s treatment plan as CNS-directed therapy is already planned. Patients with relative contraindications to CNS prophylaxis, or less clear indications for prophylaxis in whom the risk/benefit ratio is not as well defined, may benefit from CSF analysis to assist in clinical decision-making.
An alternative approach is to perform baseline CNS evaluation with CSF cytology and flow cytometry in all patients considered at high-risk of CNS relapse. Our practice has shifted away from this strategy in all high- risk patients as the rate of leptomeningeal relapse has declined in the rituximab era, decreasing the yield of broadly applied CSF testing. Furthermore, it remains unclear whether additional CNS-directed therapy for occult disease is needed if these patients are already receiving empiric systemic high-dose methotrexate as CNS prophylaxis. For patients receiving intrathecal rather than systemic CNS-directed chemotherapy, how- ever, the finding of occult lymphoma within the CSF should prompt intensification of the intrathecal treat- ment regimen beyond what would be administered for prophylaxis alone. Ultimately the decision of whether to perform baseline CSF evaluation should be personalized to the patient based on that person’s discrete CNS risk factors, symptomatology, medical comorbidities, and treatment plan.
One potential area for future research is the use of polymerase chain reaction to evaluate the presence of occult CNS disease. Recent studies in primary CNS lym- phoma have shown that assessments for micro-RNA (miRNA) and U2 small nuclear RNA fragments (RNU2- 1f) via polymerase chain reaction were able to detect pri- mary CNS DLBCL with high sensitivity and specifici- ty.59,60 Studies performed in other cancers with CNS involvement have also demonstrated the utility of next- generation sequencing of CSF cell-free DNA in detecting and characterizing CNS disease.61,62 While similar studies still need to be performed in secondary CNS lymphoma, it is possible that utilizing these techniques could further improve our ability to assess occult CNS involvement.
At initial diagnosis, a careful history and neurological examination should be performed in all patients. The presence of any neurological signs or symptoms war- rants magnetic resonance imaging evaluation of the brain and/or spine based on the relevant clinical finding. In the absence of neurological signs or symptoms of concern, there are insufficient data to recommend routine baseline neuroimaging.
Central nervous system prophylaxis
Despite the widespread use of CNS prophylaxis in patients determined to be at high risk of CNS recurrence, its efficacy remains controversial. There are no random- ized controlled trials designed specifically to determine whether prophylactic strategies reduce CNS events. Most relevant data, therefore, come from subset analyses of clinical trials which are not powered to determine the impact of CNS prophylaxis, and from retrospective analy- ses that are susceptible to selection and reporting biases.63 Interpretation of these data is further confounded by sig- nificantly varying protocols with different indications, timing, dosing, and chemotherapeutic agents employed for prophylaxis.
Indications for central nervous system prophylaxis
Ultimately the goal of CNS prophylaxis is to minimize the incidence of CNS relapse, while allocating such thera- py to those at highest risk and sparing those with low-risk disease unnecessary toxicity. As discussed above, there is a spectrum of risk associated with specific disease features and patients’ characteristics, and the threshold for use of prophylaxis varies from clinician to clinician.
Based on the aforementioned discussion of biological and clinical risk stratification, prophylactic CNS-directed therapy should be considered for nearly all patients with double- or triple-hit lymphoma, DLBCL patients with a high-risk CNS-IPI score (4-6 risk factors), and intermedi- ate-risk patients (2-3 risk factors) who are ABC-subtype with dual expression of MYC and BCL2. We also recom- mend CNS prophylaxis in patients with disease in select- ed high-risk anatomic locations, including primary testic- ular DLBCL, orbital disease involving the globe or posteri- or compartment, and disease directly infiltrating spinal neuroforamina. CNS prophylaxis in patients with multi- ple other discrete extranodal locations remains more con- troversial based on available data and should be personal- ized in the context of the overall clinical and biological risk factors for the patient.
Intrathecal therapy
Intrathecal chemotherapy, particularly methotrexate, has been the most widely employed method of prophy- laxis. Despite extensive data available, however, a protec- tive benefit favoring this approach for prevention of CNS relapse has never been established, either before or after the introduction of rituximab.
Three prospective studies in the rituximab era found no benefit from intrathecal methotrexate among patients defined as high risk. The RICOVER-60 trial conducted by the DSHNHL compared CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisolone at 14-day inter- vals) to R-CHOP-14 (CHOP-14 plus rituximab) in patients over 60 years of age and recommended CNS prophylaxis with intrathecal methotrexate in patients with involve- ment of the testes, head or upper neck. Among 1222 sub- jects, 273 received at least one cycle of intrathecal methotrexate. Notably, only 57% of patients on this trial who met criteria for CNS prophylaxis actually received it, perhaps reflecting a lack of enthusiasm for this approach by treating investigators. When comparing CNS recur- rence rates within this targeted population based on administration of prophylaxis, no significant preventive benefit could be identified.16 These findings were replicat-
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haematologica | 2019; 104(1)