MYD88 (L265P) mutation is associated with an unfavourable outcome of primary central nervous system lymphoma

Primary central nervous system lymphomas (PCNSL) are rare forms of diffuse large B cell lymphoma (DLBCL) that arise within the brain or the eyes. The current molecular classification of DLBCL distinguishes two main subtypes: activated B-cell-like (ABC)-lymphoma and germinal centre B-cell-like (GCB)-lymphoma (Zhang et al, 2013). PCNSL typically show an immunophenotype resembling that of ABC-DLBCL (Zhang et al, 2013). Somatic mutations in the myeloid differentiation primary response gene 88. (MYD88), CD79b molecule, immunoglobulin-associated beta (CD79B) and caspase recruitment domain family, member 11 (CARD11) genes were recently shown to control cell survival of ABC-DLBCL by promoting the nuclear factor (NF)jB signalling pathway (Zhang et al, 2013). The mutation frequencies of MYD88, CD79B and CARD11 are 15–30%, 17–23% and 8–18% in ABC-DLBCL (Zhang et al, 2013) and are reported to be 40–79%, 30~-44% and 11–30% in PCNSL, Indicating that they are strongly over-represented in PCNSL (Braggio et al, 2015; Yamada et al, 2015). In addition, several other gene mutations were more prevalent in PCNSL than in DLBCL, not otherwise specified; “pim-1 oncogene” (PIM1: 20–44%), “transducin (beta)-like 1 X-linked receptor 1” (TBL1XR1: 7–23%), “BTG family, member 2” (BTG2: 22– 30%), “PR domain containing 1, with ZNF domain” (PRDM1: 7–20%) and “tumor necrosis factor, alpha-induced protein 3” (TNFAIP3: 11–20%) (Braggio et al, 2015). Nonetheless, the clinical relevance of these mutations remains unclear, although several specific clinical parameters may predict the treatment outcome of PCNSL patients. These include altered mental activity and elevated creatinine clearance (CrCl) (Taoka et al, 2010); age >50 years and Karnofsky performance score <70 (Memorial Sloan-Kettering Cancer Center prognostic score; Abrey et al, 2006); age >75 years, increased serum lactate dehydrogenase level, cerebrospinal fluid protein concentration and lymphoma involvement of deep brain structures (International Extranodal Lymphoma Study Group prognostic scoring system; Abrey et al, 2006), were identified as prognostic factors. However, recent advances in genetic knowledge are not incorporated in any of these proposals. Hence, we conducted this study to elucidate the impact of gene mutations on clinical outcome of PCNSL. We analysed 42 human immunodeficiency virus (HIV)negative PCNSL patients who were treated with a modified version of the European Organization for Research and Treatment of Cancer protocol (Taoka et al, 2010) at the University of Tsukuba Hospital between March 2005 and May 2015. This protocol consisted of intermediate-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone and intrathecal chemotherapy with MTX and cytarabine (Table SI) (Taoka et al, 2010). All PCNSL patients in this study had DLBCL. GCB and ABC phenotypes were assessed by immunohistochemistory using anti-CD10, MUM1 and BCL6 antibodies. Targeted deep sequencing was performed by using Ion Ampliseq technology (Methods S1, Table SII). Clinical parameters were collected from the clinical record (Methods S1). Overall survival (OS) and progression-free survival (PFS) were estimated using the KaplanMeier method and compared by the Peto-Peto generalized Wilcoxon test. All data were analysed with EZR (http://www. jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html). Multivariate analysis was performed with Cox regression model. Significance was set at P ≤ 0 05. The major clinical characteristics of the 42 patients are summarized in Table SIII. At least one mutation was detected in 38 out of 42 cases (90 4%). Notably, we found recurrent mutations in MYD88 (67%), CD79B (43%), PIM1 (69%), TBL1XR1 (24%), BTG2 (29%), PRDM1 (24%) and TNFAIP3 (12%) (Table SIV, Fig. S1) at frequencies similar to those previously reported (Braggio et al, 2015; Yamada et al, 2015). For the entire cohort, the median follow-up time was 26 months (range, 1–105 months), with 3-years OS and PFS of 46% and 26%, respectively, comparable to the survival rate of our previous cohort treated with the same protocol (Taoka et al, 2010). Univariate analysis showed that age >75 years (P = 0 0105) and altered mental activity (P = 0 0202) (Table SV) were significantly associated with inferior OS. In addition, MYD88 L265P mutation (P = 0 127, Fig. 1A), CrCl >90 ml/min (P = 0 124) and deep brain involvement (P = 0 0649) showed a tendency to be associated with inferior OS, although statistically non-significant (Table SV). When adjusted in a multivariate Cox regression analysis, MYD88 L265P mutation remained as a significant risk factor for death (hazard ratio (HR), 2 903; 95% confidence interval (CI), 1 013–8 323, P = 0 0474), together with altered mental activity (HR, 4 729; 95% CI, 1 522–14 7, P = 0 0072) (Table I). Regarding PFS, CrCl >90 ml/min (P = 0 0286) and altered mental activity (P = 0 0473) were significant factors for inferior PFS (Table SV). MYD88 L265P mutation (P = 0 0872, Fig. 1B) was not significantly associated, but showed a tendency to be