Extranodal diffuse large B-cell lymphoma: Clinical and molecular insights with survival outcomes from the multicenter EXPECT study

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin's lymphoma with distinct clinical and molecular heterogeneity. DLBCL that arises in extranodal organs is particularly linked to poor prognosis. This study aimed to determine the clinical and molecular characteristics of extranodal involvement (ENI) in DLBCL and assess the actual survival status of the patients.

Methods: In this population-based cohort study, we investigated the clinical features of 5,023 patients newly diagnosed with DLBCL. Their clinical conditions, eligibility criteria, and sociodemographic details were recorded and analyzed. Gene panel sequencing was performed on 1,050 patients to discern molecular patterns according to ENI.

Results: The 2-year overall survival (OS) rate was 76.2% [95% confidence interval (CI), 74.0%-78.2%], and the 5-year OS rate was 67.9% (95% CI, 65.2%-70.4%). The primary treatment was immunochemotherapy with rituximab. Specific lymphoma involvement sites, especially the bones, bone marrow, and central nervous system, were identified as independent adverse prognostic factors. A high prevalence of non-germinal center B-cell (non-GCB) phenotype and myeloid differentiation primary response 88 (MYD88)/CD79B mutations were noted in lymphomas affecting the breasts, skin, uterus, and immune-privileged sites. Conversely, the thyroid and gastrointestinal tract showed a low occurrence of non-GCB phenotype. Remarkably, patients with multiple ENIs exhibited a high frequency of MYD88, tet methylcytosine dioxygenase 2 (TET2), CREB binding protein (CREBBP) mutations, increased MYD88^L265P and CD79B mutation (MCD)-like subtypes, and poor prognosis. Genetic subtype-guided immunochemotherapy showed good efficacy in subgroup analyses after propensity score matching with 5-year OS and progression-free survival rates of 85.0% (95% CI, 80.6%-89.5%) and 72.1% (95% CI, 67.3%-76.7%).

Conclusions: In the rituximab era, this large-scale retrospective analysis from Asia confirmed the poor prognosis of DLBCL with multiple ENIs and underscored the efficacy of genetic subtype-guided immunochemotherapy in treating extranodal DLBCL.

Keywords: Diffuse large B‐cell lymphoma; disease progression; extranodal involvement; oncogenic mutation; prognosis; targeted therapy.

FIGURE 1

Flow chart of the patient selection and methodology. Abbreviations: DLBCL, diffuse large B‐cell lymphoma.

FIGURE 2

Distribution of involvement sites of the 4,784 patients with extranodal DLBCL. (A) Distribution of specific ENI sites in DLBCL patients. (B) Distribution of extranodal sites comparing single ENI and multiple ENIs. (C) Correlations between ENI sites. Red indicates a positive correlation between two sites of involvement, and blue indicates a negative correlation. Abbreviations: ENI, extranodal involvement; DLBCL, diffuse large B‐cell lymphoma; CNS, central nervous system.

FIGURE 3

Prognosis of patients with extranodal DLBCL who received first‐line treatment. (A) PFS and OS of patients with single ENI/multiple ENIs. (B) PFS and OS of the single ENI group according to sites of ENI. Abbreviations: DLBCL, diffuse large B‐cell lymphoma; PFS, progression‐free survival; OS, overall survival; ENI, extranodal involvement. CNS, central nervous system.

FIGURE 4

Relationship between oncogenic mutations and extranodal involvement in DLBCL. (A) Prevalence of genetic mutations in DLBCL patients with multiple ENI (n = 372) compared to those with single ENI (n = 678). (B) Mutation rates in the eight most common ENI sites and CNS. (C) Mutation rates in cases with involvement of the above sites were analyzed separately for patients with single ENI and multiple ENIs. The eight genes with the highest mutation frequencies are listed. (D) Prevalence of subtypes classified by LymphPlex in patients with multiple ENIs and those with single ENI. (E) Correlations between common mutations (overall mutation rate >10%) and co‐occurring mutations visualized in a correlation matrix. Bivariate correlation was calculated using Spearman's rank correlation. Asterisks indicate significant bivariate correlations (P < 0.05). Red indicates a positive correlation, and blue indicates a negative correlation. (F) PFS and OS of patients in the R‐CHOP‐X group and the R‐CHOP/R‐CHOP‐based group. Abbreviations: GI, gastrointestinal; DLBCL, diffuse large B‐cell lymphoma; ENI, extranodal involvement; CNS, central nervous system; R‐CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

FIGURE 5

Relationship between intratumoral immune cells and ENI sites in DLBCL. (A) Immunity activity scores of indicated immune cells in patients with multiple ENIs (n = 220) and those with single ENI (n = 214). (B) KEGG terms in the multiple ENI group compared to the single ENI group. The color of points indicates the ‐log (adjusted P value) of dysregulated pathways in the two groups, and the size of points indicates the number of genes included in each gene set. (C) Downregulated GSEA terms in the multiple ENI group compared to the single ENI group. The color of points indicates the ‐log (P value) of dysregulated pathways in the two groups, and the size of points indicates the number of genes included in each gene set. (D) Pathways downregulated at different extranodal sites in cases with single ENI and multiple ENIs. (E) Patients were categorized into four groups based on LME clusters, and the percentage of each group in patients with different numbers and locations of ENI was observed separately. Abbreviations: DLBCL, diffuse large B‐cell lymphoma; ENI, extranodal involvement; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; GSEA, Gene Set Enrichment Analysis; GI, gastrointestinal tract.