High Prevalence of Oncogenic MYD88 and CD79B Mutations in Intravascular Large B-Cell Lymphoma: Implication for Therapy with Bruton's Kinase Inhibitors?

Introduction

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL). This systemic variant of DLBCL presents in small blood vessels and can affect every organ, with skin and central nervous system as preferential sites. Immuno-chemotherapy with R-CHOP is the standard therapy for IVLBCL. Unfortunately, IVLBCL patients have a poor prognosis with low response rates and frequent relapses.

Recently, activating mutations in MYD88 and CD79B have been identified as important molecular drivers of DLBCL, activating the toll-like receptor and the B-cell receptor pathways, respectively. In particular, a high prevalence of MYD88 mutations was observed and associated with poor prognosis in DLBCL presenting at immune-privileged sites, such as the brain and testis ( Vermaat et al . EHA 2017 abstract #P567). As IVLBCL often occurs in the central nervous system, we anticipated to identify a high prevalence of MYD88 and/or CD79B activating mutations in this DLBCL subgroup.

Aim

To investigate the frequency of MYD88 and CD79B mutations in IVLBCL.

Methods

For this retrospective study, we analyzed a unique set of 9 patients who were consecutively diagnosed with IVLBCL in participating academic and affiliated non-academic hospitals between 1999 and 2017. Clinical characteristics and treatment and survival data were collected. For most patients the status of Epstein Barr Virus (EBV) and MYC translocation was assessed (N=6) by EBER in situ hybridization and FISH, respectively. Allel-specific PCRs or next generation sequencing was used to determine the mutational status of MYD88 and CD79B as described previously ( Kraan et al., BCJ 2013 and Van Eijk et al., Exp Mol Pathol. 2013).

Results

Patient characteristics are summarized in table 1. The majority of patients (N=7) were diagnosed with IVLBCL localized in several organs; 2 cases showed skin manifestation only. Most patients underwent (immuno)-chemotherapy. In 7 cases a MYD88 mutation (L265P) was identified. In 3 patients harboring a MYD88 mutation, we found a coexisting CD79B (T197P or T197A) mutation. MYC translocations and EBV were not found in patients analyzed (N=6). In one patient mutations in MYD88 and CD79B were demonstrated both at primary diagnosis and at relapse.

Conclusion

Our study demonstrates a high prevalence (78%) of MYD88 (L265P) mutations in patients with IVLBCL. Patients with MYD88 mutations display a high prevalence of coexisting CD79B mutations (43%). As MYC translocations and EBV were not found, these results may imply that MYD88, and to a lesser extent CD79B, are important oncogenic drivers in IVLBCL. Recent studies by Wilson et al. (Nature Medicine 2015 & Cancer Cell 2017) showed that patients with MYD88 and/or CD79B mutations might be more susceptible to treatment with Bruton's Kinase inhibitors. Our study highlights the importance of investigating the mutational status of MYD88 and CD79B in a larger cohort of IVLBCL patients with poor prognosis and to explore the efficacy of molecularly targeted agents (such as Bruton's Kinase inhibitors).

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