Precision medicine in diffuse large B-cell lymphoma: Integrating molecular biomarkers, targeted therapies, and prognostic tools

Table 1 Comparison of diffuse large B-cell lymphoma molecular classification systems

Classification system	Year	Technology platform	Subtypes	Classification basis	Major advantages	Major limitations
COO classification	2000	GEP	2 (GCB/ABC)	Gene expression profiling	Biologically well-defined; established the foundation for molecular subtyping	GEP-dependent; difficult for routine clinical implementation
Hans et al[10], algorithm	2004	IHC	2 (GCB/non-GCB)	CD10/BCL6/MUM1	Simple operation; applicable in routine pathology	Accuracy approximately 80%; low sensitivity for ABC subtype identification
Schmitz et al[13], classification	2018	WES + translocations	4 (MCD/BN2/N1/EZB)	Mutations + chromosomal translocations	Mechanistically clear; provides explicit therapeutic guidance	WES-dependent; high cost
Chapuy et al[14], classification	2018	WES clustering	5 (C1-C5)	Whole-exome clustering	Independently validated; reveals additional subgroups	Clinical significance of some subtypes unclear
LymphGen	2020	Probabilistic classification	7	Naïve Bayes algorithm	Reproducible probabilistic classification; most widely applied	Relies on WES data quality
DLBClass	2025	Deep learning	Probabilistic	Neural network	Higher accuracy	High technical barrier; challenging for clinical implementation

COO: Cell-of-origin; GEP: Gene expression profiling; GCB: Germinal center B-cell-like; ABC: Activated B-cell-like; IHC: Immunohistochemistry; WES: Whole-exome sequencing; MCD: MYD88 (L265P)/CD79B-mutated subtype; BN2: BCL6 fusion/NOTCH2-mutated subtype; N1: NOTCH1-mutated subtype; EZB: EZH2-mutated/BCL2-translocated subtype; C1-C5: Clusters 1-5 in Chapuy classification; LymphGen: A probabilistic classification tool for genetic subtypes of DLBCL; DLBClass: A neural network-based molecular classifier for DLBCL.

Table 2 Risk stratification by integrating end-of-treatment circulating tumor DNA and positron emission tomography/computed tomography findings

EOT PET/CT	EOT ctDNA	Clinical implication	Recommended management
Negative	Negative	Molecular + radiographic dual remission	Routine follow-up
Negative	Positive	High-risk subgroup (specificity 90.8%)	Consider consolidation therapy or intensified surveillance
Positive	Negative	Possible inflammatory or inactive lesions (NLR 0.15)	Avoid unnecessary consolidation therapy/invasive biopsy
Positive	Positive	True residual disease/progression	Intensified therapy

EOT: End-of-treatment; ctDNA: Circulating tumor DNA; PET: Positron emission tomography; CT: Computed tomography; NLR: Negative likelihood ratio.

Table 3 Efficacy of major novel therapeutic regimens in relapsed/refractory diffuse large B-cell lymphoma

Therapy type	Regimen	Key trial	ORR, %	CR rate, %	PFS/OS	Target population
ADC	Polatuzumab + BR	Pola-BR	NA	40 (vs 18)	PFS 10 months vs 4 months; OS 12 months vs 5 months	Transplant-ineligible R/R DLBCL
Anti-CD19 mAb + IMiD	Tafasitamab + lenalidomide	L-MIND	58	40	5-year OS 81% in CR patients	CAR-T intolerant
Bispecific (IV)	Glofitamab	NP30179	52	39	18-month sustained CR 67%	Heavily pretreated
Bispecific (SC)	Epcoritamab	EPCORE NHL-1	63	39	NA	Heavily pretreated
CAR-T (third-line)	Axi-cel	ZUMA-1	83	58	5-year OS 42.6%	≥ 3 prior lines
CAR-T (second-line)	Liso-cel	TRANSFORM	NA	74 (vs 43)	EFS significantly superior to ASCT	Early relapse in the second-line setting

ADC: Antibody-drug conjugate; mAb: Monoclonal antibody; IMiD: Immunomodulatory drug; BR: Bendamustine + rituximab; IV: Intravenous; SC: Subcutaneous; CAR-T: Chimeric antigen receptor T-cell; Axi-cel: Axicabtagene ciloleucel; Liso-cel: Lisocabtagene maraleucel; ORR: Overall response rate; CR: Complete response; NA: Not available; PFS: Progression-free survival; OS: Overall survival; EFS: Event-free survival; ASCT: Autologous stem cell transplantation; R/R: Relapsed/refractory.

Table 4 Genomic differences between human immunodeficiency virus-positive and -negative diffuse large B-cell lymphoma

Gene/feature	HIV+ DLBCL	HIV- DLBCL	P value
TP53 mutation	More frequent, diverse	Less frequent	< 0.05
MYD88 mutation	Significantly reduced	Common (especially in MCD subtype)	< 0.05
CD79B mutation	Significantly reduced	Common	< 0.05
PIM1 mutation	Significantly reduced	Common	< 0.05
MYC mutation (SNV)	More frequent	Less frequent	< 0.05
LRP1B/TYK2 mutation	Higher frequency	Lower frequency	< 0.05
LymphGen ‘unclassified’ proportion	Higher	Lower	< 0.05

HIV: Human immunodeficiency virus; DLBCL: Diffuse large B-cell lymphoma; SNV: Single nucleotide variant; MCD: MYD88 (L265P)/CD79B-mutated subtype; LymphGen: A probabilistic classification tool for genetic subtypes of DLBCL.