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Figure 1. European multicenter evaluation of amplicon-based next generation sequencing assays.
Editorials
nostic impact independent of VAF, for example NFKBIE, while for others, for example NOTCH1, only high but not low VAF was associated with inferior survival.9 Independent of specific prognostic information of a given variant, the mere presence of low VAF mutations reflects clonal complexity that, in turn, has been associated with shorter time to first treatment,9 and in patients treated with ibrutinib, with the risk of clonal evolution and even- tual disease progression.10 Specific mutations in BTK or PLCG2 and BCL2 that are associated with disease progres- sion on BTK inhibitors or venetoclax, respectively, may be detected at low VAF many months before overt clinical progression.11-13 While the presence of these mutations does not immediately warrant changes in treatment, they can identify patients that could benefit from closer obser- vation.
This ERIC initiative takes an important step towards standardization of NGS based testing in clinic practice. A few considerations regarding widespread implementation may be in order. The common testing material consisted of DNA from 48 patients.1 Ideally, all mutations of inter- est, at variable VAF would be represented in the testing material which could present challenges to scale for wide- spread standardization. Bioinformatics was centralized. Using different bioinformatic pipelines could add addi-
tional variability. All test sites are academic ERIC member institutions that are experienced with standardization efforts that ERIC has been conducting over many years. Conceivably, adding less experienced centers could lower the concordance rate. In localities where different com- mercial entities may be doing the bulk of testing the approach may also have to be adapted. Overall, the cur- rent study highlights once more the extraordinary contri- butions ERIC makes to the standardization of key labora- tory data in CLL including IGHV sequencing, diagnostic flow cytometry, and the detection of minimal residual dis- ease.14-16
The performance of NGS assays reported here provides a solid basis for implementation in clinical testing. So the tools for precision medicine seem ready. Are we ready to use them? Given the expanding choices of therapies with distinct mechanisms of action, predictive markers that guide patients to the most promising therapy would be very valuable. However, to date, few predictive markers have been identified. IGHV unmutated status is predictive of benefit from targeted therapy with ibrutinib or veneto- clax based therapy over chemoimmunotherapy. Mutated NOTCH1 was found to predict lack of benefit of adding rituximab to fludarabine and cyclophosphamide, but that provides little actionable information for current treat-
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