Page 19 - 2021_02-Haematologica-web

Editorials
Figure 1. A subset of patients with diffuse large B-cell lymphoma (DLBCL) are at high risk of disease spread to the central nervous system (CNS) and are often treated with chemotherapy prophylaxis. A critical barrier to effective CNS prophylaxis is the blood brain barrier (1) which limits the entry of the chemotherapy agents most effective for systemic DLBCL (2). Current therapeutic options for chemotherapy CNS prophylaxis are systemic chemotherapy (3) or intrathecal chemotherapy (4) which are both limited in efficacy and increase toxicity. Novel small molecule inhibitors are being tested in DLBCL involving the CNS that effectively penetrate the blood brain barrier and may improve treatment options.
and/or BCL6 rearrangements (HGBCL-DH/TH).13 Indeed, Bobillo et al. observed that patients with ABC (non-GCB) DLBCL subtype had an overall higher risk of CNS relapse in their series.1 Furthermore, recent multiplatform genom- ic profiling studies have identified genetic subtypes of DLBCL with shared genetic features.3,4 One genetic sub- type MCD is characterized by frequent co-occurrence of MYD88L265P and CD79B mutations, prominent immune- editing features, and PIM1 mutations.3 These tumors occur almost exclusively within ABC DLBCL and fre- quently involve extranodal sites including the testes, breast and CNS.3 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 testis.4 Moreover, a recently reported series of 26 cases of sec- ondary DLBCL of the CNS confirmed a higher prevalence of MCD subtype than observed in a reference cohort of relapsed DLBCL without CNS spread (38% vs. 8%; P=0.003).14 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.15 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 co-operate to promote CNS spread remains unde- termined, these results suggest that a more nuanced understanding of the molecular biology of DLBCL involv- ing 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 ibrutinib- based regimens in DLBCL involving the CNS, including patients refractory to chemotherapy.16,17 Even though a randomized phase III study did not show an overall bene- fit from adding ibrutinib to R-CHOP as part of front-line therapy for non-GCB DLBCL, certain subsets appeared to have improved outcomes.18 Further studies of BTK inhibitors with R-CHOP are currently ongoing that should provide additional data regarding rates of CNS relapse. In addition, the immunomodulatory agent lenalidomide has demonstrated good clinical activity and favorable safety in DLBCL involving the CNS.19 Lenalidomide has also been added to R-CHOP as part of front-line therapy for DLBCL that may benefit certain subsets of DLBCL.20 The currently available data do not support the use of either ibrutinib or lenalidomide as part of front-line therapy to prevent CNS spread of DLBCL, but all clinical trials testing novel agents should report CNS-specific outcomes within genetically defined subtypes.
In summary, chemotherapy as CNS prophylaxis is not universally effective no matter what the delivery method,
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