Page 198 - 2020_02-Haematologica-web

J.S. Vermaat et al.
Supplementry Table S1). As such, the prognostic impact of the MYD88 mutational status on mortality was not supe- rior to the anatomical lymphoma location.
Next, we explored whether mutated MYD88 could improve the prognostic performance of the currently used IPI risk model (Table 4). The inclusion of the IPI as a con- tinuous variable (0-5 points) and the MYD88 status in the multivariable analysis demonstrated an independent and similar impact of mutated MYD88 (HR 1.83, 95%-CI 1.19- 2.80) and IPI (HR 1.77, 95%-CI 1.47-2.13) on OS. Similar effects were observed for cause-specific survival (Table 4). For the models, OS and relapse/progression, an increase in CVC-index was observed from 0.57 to 0.61 and 0.53 to 0.57, respectively. Altogether, these multivariable survival analyses demonstrated the significant prognostic impor- tance of mutated MYD88, next to (genetic) aberrations and clinical/biochemical variables, and the improvement of adding mutated MYD88 to the prognostic performance of the IPI.
To evaluate possible confounding of the impact of mutated MYD88 and with the outcomes by anatomical lymphoma location, we performed a sensitivity analysis for OS on the cohort stratified by the anatomical lym- phoma location, including CNS involvement. For patients with CNS involvement (N=35), MYD88 had an unadjust- ed HR of 1.94 (95%-CI 0.77-4.90) in the univariable analy- sis. For patients without CNS involvement (N=215), MYD88 did not have a significant impact on OS with an adjusted HR of 1.81 (95%-CI 0.96-3.42), when applying the multivariable analysis as described for model 3 (Table 3B). Although not statistically significant, the adjusted HR for this subgroup was similar to the original HR for the entire cohort.
Discussion
To the best of our knowledge, this is the first study eval- uating the clinical significance of mutated MYD88 and CD79B in DLBCL, in addition to the oncogenic drivers that are currently included in the WHO classification 2016 (EBV status and MYC, BCL2, and BCL6 rearrangements), the IPI risk factors, and well-defined anatomical locations.
The strength of this study is the large number of patients with good clinical annotation and complete molecular analysis (N=198). In addition, our study shows that the incorporation of the mutational status of MYD88 into a clinical/biochemical risk score as the IPI is feasible. An increase in the predictive performance of the IPI risk model as is illustrated by an increase in the CVC-index, suggests that this model can be improved by the introduc- tion of molecular aberrations. However, while interpreting the results, we have encountered several limitations. MYD88-mutated DLBCL more often had extranodal loca- tion, older age (and thus a high IPI), and non-GCB sub- type. Therefore, these patients were more frequently sub- jected to palliative care. Possibly the interaction between treatment and mutated MYD88 has not been tested as more data is needed. We present an average effect over different treatment modalities. Since the reported frequen- cies and survival outcomes are similar to previous reports in the literature, our cohort appears to be representative for the target population.3,7-9,13 To investigate the prognos- tic significance of mutated MYD88 adjusted for the IPI for the entire cohort, we considered PCNSL as advanced dis-
ease stage, although it is not common practice to apply the IPI in PCNSL patients. Additionally, our cohort is enriched for IP locations. Therefore, a sensitivity analysis was per- formed excluding PCNSL patients, demonstrating that the adjusted HR of MYD88 for OS was similar to the entire cohort. This indicates that our results are not affected by confounding by CNS localisation. Hence, we believe that our data corroborate the clinical relevance of mutant MYD88 for the diagnostic classification and prognostica- tion of DLBCL and support implementation of MYD88 mutational analysis in routine diagnostics. The simplicity and accessibility to examine MYD88 mutations and asso- ciated low costs permit an efficient timely implementa- tion. In addition, CD79B mutations were prognostic in the univariate analysis, but when adjusted for other aberra- tions in the multivariable analysis the prognostic impor- tance disappeared. This finding may be explained by the prominent overlap between MYD88 and CD79B muta- tions, as 78.2% of mutated CD79B had co-occurring MYD88 mutations.
An important result of our study is the recognition of the prominent mutual exclusivity between the presence of mutations in MYD88 and/or CD79B, MYC, BCL2, and BCL6 rearrangements, and EBV infection, indicating that MYD88 and/or CD79B-mutated tumors present a distinct DLBCL subcategory. In accordance with a large meta- analysis and two other studies,30,40,41 MYD88 L265P muta- tions were preferentially found in specific anatomical sites (e.g. testis and CNS) and were significantly associated with non-GCB subtypes, older age, and poor OS. However, the published literature has studied neither explicitly analysed IP sites, nor evaluated the interaction of MYD88 mutations with EBV status or oncogenic rearrangements in multivariable analysis. Other NGS studies have recently demonstrated high frequencies of mutated MYD88 (15-18%) in large cohorts of DLBCL.1,2,15,42-44 Besides a certain association of mutated MYD88 with poor OS (e.g. in non-GCB DLBCL), cluster analysis of multiple genes indicated distinct DLBCL subentities, including mutated MYD88 as an important classifier for NF-κB pathway activation. Again, these NGS studies did not take into account specific anatomical sites or investigated the interaction and prognostic significance of mutated MYD88 in correlation with the EBV status or MYC, BCL2, and BCL6 rearrangements.
In this context, our study adds important new knowl- edge by demonstrating MYD88 mutations as an adverse prognostic factor for OS and relapse/progression in a mul- tivariate analysis that takes all major known clinical and WHO classification-defined risk factors into account. This insight does not only show that the incorporation of the mutational status of MYD88 into a clinical/biochemical risk score as the IPI is feasible, but also highlights the importance of assessing MYD88 at the time of diagnosis for an optimal classification and patient counselling. An increase in the predictive performance of the IPI risk model, as is illustrated by an increase in the CVC-index, formally suggests that this model can be improved by the introduction of molecular aberrations. However, the prog- nostic impact of the MYD88 mutational status on the pre- sented multivariable models was not superior to anatom- ical lymphoma location. Whether the MYD88 mutational status outperforms the predictive performance of anatom- ical lymphoma location in the described prognostic mod- els needs further validation in an external cohort. Of note,
432
haematologica | 2020; 105(2)