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gies that do not adequately address the clinical problem. Although retrospective series are effective at generating hypotheses or identifying specific issues that warrant fur- ther study, it is nearly impossible to control for all the per- mutations of approaches to CNS prophylaxis as there is truly no standard approach. The best available data sug- gest that the most common approach to CNS prophylaxis involves repeated intrathecal injections of methotrexate or cytarabine during frontline therapy, while only a sig- nificant minority of patients receive high-dose methotrexate at a median dose of 3.5 g/m2 either during
P=0.003).16 In this study, the majority of other DLBCL cases with CNS spread were either HGBCL-DH/TH or associated with TP53 mutations. Another recent study investigated the genomic predictors of CNS relapse in 82 cases of primary testicular DLBCL which has a strong predilection for CNS spread.17 The authors identified BCL6 and/or PDL1 or PDL2 rearrangements as the most common genetic aberrations associated with CNS relapse after treatment for primary testicular DLBCL. Although the precise mechanisms by which various genetic aberra- tions cooperate to promote CNS spread remain undeter- mined, these results suggest that a more nuanced under- standing of the molecular biology of DLBCL involving the CNS may lead to novel therapeutic targets.
In order to improve clinical outcomes, however, novel therapies with demonstrable efficacy within genetically defined subtypes will be necessary. Multiple clinical stud- ies have reported impressive clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and ibru- tinib-based regimens in DLBCL involving the CNS, including patients who are refractory to chemothera- py.18,19 Even though a randomized phase III study did not show an overall benefit from adding ibrutinib to R-CHOP as part of frontline therapy for non-GCB DLBCL, certain subsets appeared to have improved outcomes.20 Further studies of BTK inhibitors with R-CHOP are currently ongoing and should provide additional data regarding rates of CNS relapse. In addition, the immunomodulatory agent lenalidomide has demonstrated good clinical activ- ity and favorable safety in DLBCL involving the CNS.21 Lenalidomide has also been added to R-CHOP as part of frontline therapy for DLBCL which may benefit certain subsets of DLBCL.22 The currently available data do not support the use of either ibrutinib or lenalidomide as part of frontline therapy to prevent CNS spread of DLBCL, but all clinical trials testing novel agents should report CNS-specific outcomes within genetically defined sub- types.
In summary, chemotherapy as CNS prophylaxis is not universally effective no matter what the delivery method, and the prevention and treatment of CNS relapse remain unmet clinical needs in the management of DLBCL. Penetration of the blood-brain barrier is an important consideration, but improved therapies will be required to overcome intrinsic chemotherapy resistance. A nuanced mechanistic understanding of targetable pathways under- pinning DLBCL involving the CNS has led to novel tar- geted agents and immunotherapy approaches that demonstrate promising clinical activity and good CNS penetrance. Novel agents that target oncogenic drivers based on the underlying biology of DLBCL subtypes may ultimately prove to be the most effective way to prevent and/or treat CNS recurrence.
Disclosures
No conflicts of interest to disclose.
References
1. Puckrin R, El Darsa H, Ghosh S, Peters A, Stewart DA. Lack of effec- tiveness of intravenous high-dose methotrexate for prevention of CNS relapse in patients with high-risk DLBCL: a retrospective analy-
frontline therapy or
patients who receive
receive concomitant
blurs this arbitrary
datasets demonstrate
ered high-risk receive
observation highlights that patient-related factors, such as age and perceived ability to tolerate treatment-related toxicity, greatly influence treatment decisions beyond prognostic scores and/or involvement of extranodal sites. Since all forms of CNS prophylaxis have clinically mean- ingful toxicities, this underscores the fact that an impor- tant limitation of all available datasets is selection bias. Finally, no form of CNS prophylaxis is universally effec- tive and the rate of CNS relapse in patients who receive prophylaxis is typically about 5% after 2 to 3 years of fol- low-up. In recognition that CNS relapses may be late events, the actual risk reduction of any form of CNS pro- phylaxis with chemotherapy is likely modest at best and currently employed strategies may simply delay the tim- ing of CNS recurrence.14
The risk of CNS involvement is not equally distributed across all subsets of DLBCL, however, which may allow for precision medicine strategies. In fact, DLBCL is not a single disease but comprises a spectrum of aggressive lymphomas with striking underlying genetic diversity. The current classification system recognizes both activat- ed B-cell (ABC) DLBCL and germinal center B-cell (GCB) DLBCL as distinct molecular subtypes and introduced a new entity, high-grade B-cell lymphoma, defined by the presence of MYC and BCL2 and/or BCL6 rearrangements (HGBCL-DH/TH).15 Indeed, patients with ABC (non- GCB) DLBCL subtype have an overall higher risk of CNS relapse.10 Furthermore, recent multiplatform genomic profiling studies have identified genetic subtypes of DLBCL with shared genetic features.6,7 One genetic sub- type, MCD, is characterized by frequent co-occurrence of MYD88L265P and CD79B mutations, prominent immune- editing features, and PIM1 mutations.6 These tumors occur almost exclusively within ABC DLBCL and fre- quently involve extranodal sites including the testes, breast and CNS.6 It is noteworthy that a separate multi- platform genomic profiling study described a very similar subtype termed Cluster 5 (C5) tumors which were char- acterized by MYD88L265P and CD79B mutations, gain of 18q, and PIM1 mutations and also exhibited a propensity for extranodal sites, including the CNS and testes.7 Furthermore, a recently reported series of 26 cases of sec- ondary DLBCL of the CNS confirmed a higher prevalence of MCD subtype than that observed in a reference cohort of relapsed DLBCL without CNS spread (38% vs. 8%,
immediately following. Notably, high-dose methotrexate may also intrathecal chemotherapy which
distinction. Furthermore, most that nearly half of patients consid- no form of CNS prophylaxis. This
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