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J.S. Vermaat et al.
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Figure 2. Molecular characterization discriminates distinct DLBCL subgroups with prognostic impact. (A) Venn diagram demonstrating the overlap of aberrations for 198 fully analysed DLBCL. (B) DLBCL without detected aberrations showed a superior overall survival compared to DLBCL with ≥1 affected aberrations (for cases with complete aberration analysis), identifying a novel good-risk group. (C) PFS of the novel identified risk group (for cases with complete driver analysis). (D) Cumulative incidences of novel identified risk group (for cases with complete driver analysis). CRS: competing risk; PFS: progression free survival.
Cooperative Oncology Group Performance Status (ECOG-PS), or patients’ refusal of treatment, 34 patients received palliative care only, mainly with steroids or (local) radiotherapy. The median follow up time was 6.6 years (range 0.1-15.7).36
Molecular characterization: mutated MYD88 discriminates a distinct DLBCL subgroup
According to the Hans’ algorithm, DLBCL were classi- fied as GCB (N=100, 40.0%), non-GCB (N=130, 52.0%), or unclassifiable (N=20, 8.0%), with no statistical differ- ence between nodal, extranodal, and IP locations (P=0.228)(Table 2).33
In 198 patients (79.2%), molecular analysis for MYD88 and CD79B mutations, MYC, BCL2, and BCL6 rearrange- ments, and EBV infection was complete, whereas in 52 patients, partial data sets were available (Figure 1; Table 2). MYD88 mutations were identified in 74 cases (29.6%), of whom 67 harbored the hotspot L265P mutation. The other MYD88 variants were S219C (N=5) and S243N (N=2). In line with a published meta-analysis,30 mutated MYD88 was significantly correlated with older age (≥65 years), anatomical lymphoma location, and non-GCB sub- type (P=0.006; P<0.001; P=0.042, respectively). CD79B mutations were detected in 29 patients (12.3%), including the hotspot Y196 mutation (N=28) and the L188 mutation (N=2, one patient had both mutations). MYC, BCL2, and BCL6 were rearranged in 23 (10.6%), 30 (13.6%), and 44 (20.3%) DLBCL, respectively, with a total of nine HGBL patients (4.1%).
As suggested by previous reports and other studies, MYD88 and CD79B mutations were significantly more common in IP-DLBCL (67.2% resp. 25.8%) compared to nodal (17.3% resp. 4.1%) and other extranodal sites (14.8% resp. 9.3%)(P<0.001 and P<0.001).26,29,39 In con- trast, BCL2 rearrangements were more prevalent in nodal and extranodal DBLCL (P=0.001), whereas MYC and BCL6 rearrangements were evenly distributed across the anatomical sites. EBV was positive in 28 patients (11.7%) and was not associated with an anatomical location (P=0.091).
In the 198 cases with complete molecular analysis, hard- ly any overlap between the presence of oncogenic rearrangements, EBV positivity, or MYD88 and/or CD79B mutations was observed (Figure 2A), suggesting that they represent distinct DLBCL subgroups with different drivers of lymphomagenesis. CD79B mutations co-occurred with MYD88 mutations in 18 of 23 cases (78.2%). In contrast, MYD88 mutations co-occurred with any rearrangement in only 7 of 60 patients (11.7%) and with EBV positivity in only one case (1.7%). EBV infection was detected in only 3 of 71 cases (4.2%) with a rearrangement. In 51 patients (25,8%) with full molecular characterization, no aberrancy was detected.
Mutated MYD88 predicts inferior survival
All outcomes are reported at the 5-year survival. For the
entire cohort, the OS was 61.0% (95%-CI 55.1-67.5) and the PFS was 52.6% (95%-CI 46.6-59.3). Cumulative inci- dences of relapse/progression and non-relapse mortality
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