Genetic Characteristics of Patients Aged ≥80 Years with Diffuse Large B-Cell Lymphoma
Authors: Yun Xiaoya , Bai Jiefei , Feng Ru , Jing Hongmei , Liu Hui 
Published: December 2024

Introduction
As a highly heterogeneous and aggressive heterogeneous lymphoid neoplasm, diffuse large B-cell lymphoma (DLBCL) exhibits various genetic alterations, leading to diverse clinical course, and varying sensitivity to treatment regimens. With a median age of 67 years at diagnosis, 19.02% of the patients were 80 years and above. Although the molecular characteristics of adult DLBCL has been well documented, the genetic alterations in patients aged ≥80 years remain poorly understood. The study aims to elucidate the genetic landscape in patients aged ≥80 years with DLBCL, and explore the possible targeted therapeutic pathways for them.
Methods
A total of 179 patients aged ≥80 years with DLBCL was included in the study. Sixteen patients were from Beijing Hospital, while data for 40 patients was collected from R. Schmitz et al. N Engl J Med. 2018, 51 from George W. Wright et al. Cancer Cell. 2020, 24 from Tatsuzo Mishina et al. British Journal of Haematology. 2021, 16 from Wyndham H. Wilson et al. Cancer Cell. 2021, and 32 from Rong Shen et al. Signal Transduction and Targeted Therapy. 2023. Patients were identified for different genetic subtypes by LymphoGen classifier, expect for 32 patients from Rong Shen et al. Signal Transduction and Targeted Therapy. 2023, who were defined by the LymphoPlex classifier.
Results
The median age of the patients was 83 years (range: 80-96), with 49.2% being male. Regarding the cell of origin (COO), 32.1% (53/165) of the patients were classified as germinal center B-cell (GCB) subtype, 58.8% (97/165) as non-GCB subtype, and 9.1% (15/165) remained unclassified. Additionally, 58.8% (97/165) of the patients were at Ann Arbor stage Ⅲ/Ⅳ, and 48.5% (80/165) of them had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2. Among these patients, 57.5% (77/134) had elevated lactate dehydrogenase (LDH), and 31.2% (43/138) had ≥2 extranodal sites. Furthermore, 60.2% (97/161) of the patients had an International Prognostic Index (IPI) score ≥3. In terms of the therapy, 60.4% (93/154) of the patients received the R-CHOP-like regimens. The median overall survival (OS) time was 74 months, while the median progression-free survival (PFS) time was 21 months. According to the LymphoGen classifier, 18% of the patients were MCD subtype, followed by EZB (14%), BN2 (11%), ST2 (6%), A53 (5%), and N1 (2%). Notably, 9% of the patients genetically composite, and 35% were classified as others. Among the 32 patients classified by LymphoPlex classifier, 22% of them were allocated as MCD subtype, followed by TP53 (19%), EZB (13%), ST2 (9%), BN2 (3%), and 34% as NOS. There was no statistically difference between the molecular subtypes and OS or PFS (all p &gt; 0.05). Among the 90 patients whose genetic alternations available, PIM1 (47%) was the most frequent mutation, followed by KMT2D (32%), BTG2 (26%), MYD88 (26%), CD79B (24%), and TP53 (23%). The univariate and multivariate Cox regression analyses identified BCL7A mutations (p = 0.032) and HLA-DRB1 mutations as independent prognostic biomarkers for OS of the patients. The enrichment analyses indicated that the mutant genes were primarily enriched in the lymphocyte activation and differentiation pathways, as well as JAK-STAT signaling pathway, Wnt signaling pathway, p53 signaling pathway, and NF-κB signaling pathway.
Conclusions
In the patients aged ≥80 years with DLBCL, the most common molecular subtype was MCD, and the most frequent mutated gene was PIM1. Mutations in BCL7A and HLA-DRB1 were identified as independent prognostic biomarkers for OS of the very old patients. The mutated genes were enriched in pathways related to the lymphocyte activation and differentiation, as well as JAK-STAT signaling pathway, Wnt signaling pathway, p53 signaling pathway, and NF-κB signaling pathway. Targeting these pathways may potentially benefit patients over 80 years old.