Genomic Alterations and MYD88 Variant Mapping in Patients with Diffuse Large B-Cell Lymphoma and Response to Ibrutinib.

BACKGROUND

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy. Following front-line immunochemotherapy, 30-40% of DLBCL patients develop relapsed or refractory (r/r) disease, which can be treated with ibrutinib. It has been previously reported that MYD88 affects the response to ibrutinib in patients with r/r DLBCL.

OBJECTIVE

Here, we aimed to gather understanding of MYD88 in r/r DLBCL patients and to evaluate its influence on response to ibrutinib.

PATIENTS AND METHODS

In this study, tissue samples from DLBCL patients (n = 212) were retrospectively collected and sequenced by target-capturing panels of either 413 or 112 genes that are frequently mutated in non-Hodgkin's lymphoma. Sixty patients with MYD88 mutations and available clinical information were included for further analysis.

RESULTS

Seven MYD88 variants were identified, L265P (65.0%, n = 39), S219C (13.3%, n = 8), S243N (8.3%, n = 5), P258L (6.7%, n = 4), F283V (1.7%, n = 1), P141R (1.7%, n = 1), and V217F (1.7%, n = 1). One patient had MYD88 amplification. In addition, mutations in PIM1 (67%, n = 40), IGH fusion (48%, n = 29), CD79B (43%, n = 26), KMT2D (30%, n = 18), and TP53 (27%, n = 17) were identified. For patients with L265P, IRF4 (p = 0.011) was frequently mutated. Otherwise, TET2 (p = 0.016), NOTCH2 (p = 0.044), MET (p = 0.037), SOCS1 (p = 0.011), TNFRSF14 (p = 0.011), EZH2 (p = 0.037), and BCL6 (p < 0.001) mutations were associated with MYD88 non-L265P variants. The incidence rate of MYD88 L265P was significantly higher with central nervous system involvement (p = 0.034). Four out of nine MYD88 patients responded to ibrutinib containing treatment, and this included those with MYD88/CD79B.

CONCLUSIONS

This study adds clinical observations with MYD88 patients, further helping to understand the genetic features and possible correlation of MYD88 with response to ibrutinib.