Genomic risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma

TL;DR

This study identifies genomic risk factors that can predict central nervous system relapse in patients with diffuse large B-cell lymphoma, potentially improving treatment strategies.

Contribution

The study introduces a genomic classifier that outperforms existing clinical tools in predicting CNS relapse risk in DLBCL patients.

Findings

MYD88 L265P and CDKN2A loss, along with mutations in TET2, ARID1A, and INO80, are independently linked to CNS relapse risk.

The genomic classifier achieved an AUROC of 0.91, significantly better than the IPI (0.77) or IPI+COO (0.81).

Abstract

Central nervous system (CNS) relapse is associated with poor survival, and remains an unmet challenge in patients with diffuse large B-cell lymphoma (DLBCL). Identifying patients at high risk of CNS relapse and offering prophylactic treatment could improve patient prognosis.

Here, we studied 234 patients with DLBCL using open patient-level clinical and sequencing data to explore risk factors for CNS relapse. Patients were divided into Cohort A (CNS involvement at baseline), Cohort B (CNS recurrence), and Cohort C (patients without secondary CNS involvement and with a follow-up interval > 3 years). We investigated the risk factors for CNS relapse in Cohorts B + C.

Genetic alterations with statistical significance, determined by univariate analysis, and an incidence rate ≥ 5%, together with clinical factors, correlated with CNS relapse risk in a multivariate analysis. Multivariate logistic regression analysis revealed that concomitant MYD88 L265P and CDKN2A loss (p = 0.012), TET2 mutation (p = 0.037), ARID1A mutation (p = 0.010), and INO80 (p = 0.002) were independently correlated with a high risk of CNS relapse after adjusting for the IPI risk groups, B symptom and cell of origin (COO). The classifier that integrated genomic risk factors was superior in predicting CNS relapse (area under the receiver operating characteristic curve [AUROC]: 0.91) compared with the IPI (AUROC: 0.77, p < 0.001) or IPI in combination with COO classifiers (AUROC: 0.81, p = 0.013).

This study identified several genomic alterations as risk factors for CNS relapse.

The online version contains supplementary material available at 10.1007/s44313-025-00087-1.

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