The Impact of MYD88 and/or CD79B Gene Mutations on Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma

Background: Central nervous system (CNS) relapse is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The CNS-international prognostic index (IPI) is a validated predictive score for CNS relapse; however, its predictive accuracy can be improved. Recently, genetic subgroups of DLBCL have been identified; the MCD type, characterized by MYD88and CD79B mutations, is a distinct entity with a high prevalence of extranodal involvement and a poor clinical prognosis. While the MCD type is reported to be common among patients with DLBCL and CNS relapse, whether the MCD type is at risk for CNS relapse has not been fully investigated.

We have previously reported the significance of MYD88 and/or CD79B hotspot mutations in patients with untreated DLBCL (Fujii et al. Annals of Hematol, 2024). In that study, MYD88^L265P and CD79B^Y196 mutations in genomic DNA extracted from tumor samples, obtained at initial diagnosis, were evaluated using allele-specific PCR and a highly sensitive one-base extension assay with a SNaPshot Multiplex Kit. In the current study, we used the patient cohort from the reported study to evaluate the significance of MYD88 and/or CD79B mutations in CNS relapses in patients with DLBCL.

Patients and methods: From the previous patient cohort (n=302), patients who i) did not receive anthracycline-containing immunochemotherapy, ii) were lost to follow-up within one year of initial diagnosis, or iii) had poor PCR results were excluded. A total of 270 patients were included in this study.

Patients whose tumor samples had MYD88 ^L265P and/or CD79B ^Y196 mutations were categorized as MYD88/CD79B(+) and the others were categorized as MYD88/CD79B(-). The cumulative incidence of CNS relapse was estimated, accounting for competing risks of death, and described according to CNS-IPI risk and MYD88/CD79B status. In univariate analysis, the hazard ratio (HR) was estimated using the Fine–Gray model to assess the impact of clinical factors and MYD88/CD79B status on incidence of CNS relapse.

Results: Baseline characteristics of the 270 patients were as follows: median age 71 years (interquartile range [IQR] 63-78), an elevated lactate dehydrogenase level in 65% of patients, 25% with ≥ 2 extranodal sites, and 53% with Ann Arbor stage III/IV disease. A total of 55 patients (20%) were MYD88/CD79B(+). The median follow-up was 6.68 years (IQR, 4.29-9.77), during which 20 CNS relapses occurred. The median duration between initial diagnosis and CNS relapse was 11.5 months (IQR, 7.56-29.9).

Univariate analyses revealed that MYD88/CD79B(+) was significantly associated with CNS relapse (HR 4.99, 95% CI 2.08-11.99), along with clinical factors, such as ≥ 2 extranodal diseases, clinical stage III/IV, and presence of B symptoms. Specific extranodal lesions, such as muscle, ascites/peritoneum, adrenal gland/kidney, uterus, nasal/paranasal sinus, and skin were associated with CNS relapse.

Among the 55 MYD88/CD79B(+) patients, 11 (20%) developed CNS relapse, which continued to occur even 3 years after the initial diagnosis. The 3- and 8-year cumulative CNS relapse rates were 10.9% (95% CI 4.4-20.8) and 24.9% (95% CI 12.7-39.2), respectively. There were no apparent differences in the clinical features of the 55 patients, according to the presence or absence of CNS relapse.

According to the CNS-IPI, patients were categorized into low- (n=79, 29%), intermediate- (n=125, 46%), or high-risk (n=66, 25%) groups. The 3-year cumulative CNS relapse rates were 1.3%, 3.2%, and 15.2% in the low-, intermediate-, and high-risk groups, respectively. Among the CNS-IPI low- or intermediate-risk patients, 32 were MYD88/CD79B(+), with 6 (18.8%) developing CNS relapse. In contrast, only 2 of 182 (1.1%) MYD88/CD79B(-) patients in the same risk group developed CNS relapse. In the CNS-IPI high-risk patients, 5 of 23 (21.7%) MYD88/CD79B(+) patients and 7 of 43 (16.3%) MYD88/CD79B(-) patients developed CNS relapse.

Conclusions: This study demonstrates that MYD88/CD79B(+) status is a significant risk factor for CNS relapse and may be associated with a continuous relapse pattern. In addition, MYD88/CD79B(+) may identify patients at high risk for CNS relapse among those identified as low- or intermediate-risk by the CNS-IPI, although validation is required. Finally, this study suggests that heterogeneous mechanisms, not solely explained by genetic characteristics, may underlie CNS relapse.