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Editorials
Figure 1. Prevalence of mutations in genes involved in various functional pathways in diffuse large B-cell lymphoma (DLBCL). Most frequently mutated genes as identified by Bolen et al.5 in a cohort of 482 DLBCL patients arranged according to the affected pathways. NF-κB: nuclear factor kappa B; TLR: Toll-like receptor; BCR: B-cell receptor.
comprising tumors characterized by a high prevalence and co-occurrence of MYD88 and CD79B mutations that are almost exclusively classified as ABC DLBCL and have an unfavorable prognosis.15 Intriguingly, this genetic sub- group is linked to primary extranodal lymphomas, includ- ing lymphomas arising in the central nervous system (CNS), ocular vitreo-retina and testis, all considered ‘immune-privileged’ sites as they tolerate allografts and permit only selective entrance of immune cells.16-19 Importantly, Wilson et al. established that ABC DLBCL harboring mutations in CD79B, particularly those with concurrent MYD88 mutations, were highly responsive to treatment with ibrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor.20 These observations suggest that (extranodal) lymphomas belonging to the MCD subtype could also be targeted by inhibition of BCR signaling. Indeed, a phase Ib study in a panel of 18 primary central nervous system lymhpomas (PCNSL) demonstrated that ibrutinib monotherapy reduced tumor mass in 94% of patients.21 Additionally, a second phase I clinical trial
showed clinical responses to ibrutinib in 10 out of 13 PCNSL patients, including five complete responses.22 Collectively, these suggest that patients with other pri- mary extranodal lymphomas belonging to the MCD sub- type, such as primary testicular or vitreoretinal lym- phoma, might also benefit from treatment with BCR pathway inhibitors.
In conclusion, the study by Bolen et al.5 fully confirms the previously described genetic heterogeneity and com- plexity of DLBCL. As a consequence of this complexity, well-established prognostic classifiers, such as COO and IPI, can only partially account for the differential respons- es to R-CHOP (and related) immunochemotherapy. The identification of alterations of the BCL2 gene as the only genetic abnormalities significantly associated with reduced PFS points towards targeting BCL2 as a rational addition to standard immunochemotherapy. Although not of (independent) prognostic value in the context of standard immunochemotherapy, genetic abnormalities defining potentially druggable targets/pathways were
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