Genotype-Guided Therapy Demonstrates High Response and Survival Rates for Patients With R/R DLBCL
Personalized immunochemotherapy regimens based on genetic subtypes demonstrated promising efficacy and tolerability among patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), according to study results published in Signal Transduction and Targeted Therapy.
Researchers conducted a phase 2 clinical trial to evaluate the efficacy of molecularly defined targeted agents (X) combined with rituximab and ifosfamide, carboplatin, and etoposide phosphate (R-ICE-X) for the treatment of R/R DLBCL. The primary objectives were safety and efficacy, while secondary objectives included identification of predictive biomarkers and characterization of tumor immune microenvironment dynamics.
Between April 26, 2022, and July 31, 2024, 76 patients were included in the trial, and the median age of the patients was 61 years. Following initial induction therapy with R-ICE, patients received additional therapy guided by genotype, which included:
- MCD-like (25%) and BN2-like (20%): R-ICE + zanubrutinib
- N1-like (5%) and NOS (34%): R-ICE + lenalidomide
- TP53-mutated (12%): R-ICE + decitabine
- EZB-like (3%): R-ICE + chidamide
- ST2-like (1%): R-ICE + tofacitinib
Overall, the complete response rate was 56.6% (95% confidence interval [CI], 45.2 to 68.0), with an overall response rate (ORR) was 76.3% (95% CI, 66.5 to 86.1). Stable disease was identified among 4% of patients, while 17% of patients had progressive disease. The 2-year progression-free survival (PFS) rate was 69.3% (95% CI, 56.6 to 79.0) and the 2-year overall survival (OS) rate was 88.3% (95% CI, 77.6 to 94.0).
Subgroup analysis demonstrated the highest ORR was found among patients who received additional zanubrutinib (79.4%), followed by decitabine (67%) and lenalidomide (57%).
The most common grade 3 or 4 adverse events were neutropenia (30%) and thrombocytopenia (25%). Among patients with progressive disease, significant activation of the PI3K-AKT-mTOR pathway was identified (normalized enrichment score [NES]= 1.846; P < .001).
The researchers concluded, “Collectively, this precision medicine paradigm validates R-ICE-X as a genotype-guided therapy, concurrently disrupting oncogenic signaling pathways and reprogramming immune-evasive niches, demonstrating clinically meaningful efficacy with a favorable safety profile in R/R DLBCL.”
Source:
Shen YG, Shi Q, Tang W, et al. Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06). Signal Transduction and Targeted Therapy. Published July 26, 2025. doi:10.1038/s41392-025-02316-6
