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D. Qualls et al.
ciated with CNS relapse risk, as well as mortality.11-15 Few data are available to inform the optimnal intensity of ther- apy required to eradicate occult CNS disease, but our prac- tice is to treat occult CNS involvement by lymphoma in the same way as we treat active secondary CNS lymphoma.
The rate and patterns of CNS involvement with DLBCL have evolved with the introduction of rituximab-containing therapy. Most studies have found a slight decrease in the incidence of CNS relapse with rituximab use, with modern rates of 2-4%.7,16-19 This decrease is likely due to superior control of systemic disease, as well as a benefit from mini- mal penetration of the rituximab antibody in the CSF.7,9,20 Accordingly, localization of CNS relapse in the modern era has shifted to the brain parenchyma in the majority of cases, whereas relapse in the leptomeningeal compartment predominated prior to the introduction of rituximab.7,20-21 Relapses within the CNS generally occur early in the treat- ment course, often presenting prior to completion of initial therapy or shortly thereafter.16,19
A significant proportion (14-48%) of patients with CNS relapse also have systemic relapse at the time of diagno- sis.11,12,22,23 While isolated CNS relapse may be prevented with effective CNS prophylaxis, concomitant systemic and CNS relapse likely represents a failure of systemic treat- ment,7,16 and patients with concurrent CNS and systemic relapse appear to have a worse prognosis than those with CNS relapse alone.24 Current studies do not reliably differ- entiate between isolated and concomitant systemic/CNS relapse when exploring the efficacy of CNS prophylaxis, so this remains an important area for future investigation.
CNS-directed prophylactic therapy has been widely uti- lized in DLBCL. This practice is based largely on the estab- lished benefit in other high-grade lymphomas with a high risk of CNS involvement, particularly Burkitt lymphoma and acute lymphoblastic leukemia.25,26 Data demonstrating a benefit of prophylactic strategies in DLBCL, however, have been limited and occasionally conflicting. This is largely due to the low overall risk of CNS events, as well as reliance on retrospective analyses and underpowered subset analy- ses of prospective studies, which suffer from small sample sizes and significant heterogeneity in indications and meth- ods for prophylaxis. As a result, selection of appropriate patients for CNS prophylaxis, as well as the type and timing of prophylactic strategies, remain highly controversial.
In this review, we attempt to consolidate current infor- mation and examine the most recent advances regarding CNS risk assessment and approaches to CNS prophylaxis in patients with DLBCL.
Evaluating risk of central nervous system recurrence
Optimal CNS prophylaxis in DLBCL relies first upon accurately identifying the small proportion of high-risk patients who should be targeted for CNS evaluation and intervention. Modern risk stratification includes both tradi- tional clinical and laboratory assessments, as well as incor- poration of pathological and molecular characteristics of the patient’s disease.
Clinical risk models
The risk of CNS involvement in patients with DLBCL is concentrated in high-risk populations with certain patient- and disease-specific characteristics. Studies performed in
the early 2000s demonstrated that patients with high International Prognostic Index (IPI) scores were at greater risk of CNS involvement.10,27-29 The original IPI consisted of five risk factors: age >60 years, elevated lactate dehydro- genase, Eastern Cooperative Oncology Group (ECOG) Performance Status >1, advanced stage disease, and involvement of more than one extranodal site. More recently, the German High Grade NHL Study Group (DSHNHL) and British Columbia Cancer Agency (BCCA) developed and validated the CNS International Prognostic Index (CNS-IPI) as a risk stratification tool to predict risk of CNS recurrence.18 They examined an initial cohort con- sisting of 2164 patients enrolled in DSHNHL clinical trials and identified five risk factors for CNS disease based on multivariate analysis: these include four of the five original IPI risk factors (with the exception of >1 extranodal site), plus either kidney or adrenal involvement. The presence of multiple extranodal sites was likely not a significant risk factor in multivariable analysis because of the overlap with advanced stage, but it was nonetheless retained in the final six-factor model for ease of application. Patients are stratified as having low (0-1 points), intermediate (2-3 points), or high (4-6 points) risk disease, which predicted 2-year rates of CNS relapse of 0.8%, 3.9%, and 12%, respectively (Figure 1). The model was validated on 1597 patients in the BCCA database. Notably, additional risk factors for CNS recurrence were identified in the valida- tion cohort based on multivariable analysis, which likely reflect differences in the populations of patients between the two cohorts; additional risk factors included >1 extra- nodal sites, and involvement of the testis, pericardium, orbit, or bone marrow.
Subsequent studies have confirmed the utility of the CNS-IPI, particularly in validating risk associated with the highest risk cohort with four to six risk factors.17,19,30
High-risk extranodal sites
Certain extranodal sites have been implicated as dis- crete risk factors for subsequent CNS relapse, though few have been found to be independently predictive of CNS involvement on multivariable analyses. Testicular involve- ment in DLBCL is the most well-established, with studies demonstrating CNS relapse rates of 12-25%, even in stage I completely resected disease.31-34 Unlike other systemic DLBCL which typically recur early, primary testicular DLBCL can relapse in the CNS as late as 10 years after ini- tial diagnosis, and occurs most commonly within the brain parenchyma.31,32 There appears to be a pathophysio- logical relationship between primary testicular DLBCL and primary CNS DLBCL. Both diseases tend to be acti- vated B-cell (ABC)-like by transcriptional profiling, and share genetic features including oncogenic toll-like recep- tor signaling based on MYD88 mutations or NFKBIZ amplification, B-cell receptor pathway activation, and BCL-6 deregulation.35 Altered adhesion molecule expres- sion also likely contributes to the predilection of primary testicular DLBCL for immune privileged sites such as the testis and CNS, while the loss of HLA-DR and surface immunoglobulin and increased expression of PD-L1 and PD-L2 via 9p24.1 amplification contribute to immune escape.35,36
Additional sites of extranodal involvement have histori- cally been associated with greater risk of CNS relapse, although on multivariate analysis these have not been consistently predictive in the modern era. These sites
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haematologica | 2019; 104(1)