Risks and benefits for patients with relapsed or refractory diffuse large B-cell lymphoma in early-phase clinical trials: a systematic review and meta-analysis

Abstract

BACKGROUND: The treatment landscape for relapsed or refractory diffuse large B-cell lymphoma has changed profoundly with the introduction of novel drug classes, some approved solely on the basis of single-arm early-phase trials. We aimed to evaluate antitumour activity and safety outcomes across drug classes in early-phase trials in relapsed or refractory diffuse large B-cell lymphoma since 2000. METHODS: We did a systematic review and meta-analysis of phase 1-2 trials. We searched PubMed, Embase.com, Web of Science and Wiley/Cochrane Library from database inception to May 9, 2025. We included English-language studies published between Jan 1, 2000, and May 9, 2025, enrolling adults aged 18 years or older with relapsed or refractory diffuse large B-cell lymphoma treated with experimental agents alone or combined with CD20-antibodies; trials including other B-cell malignancies were eligible if diffuse large B-cell lymphoma-specific responses could be extracted. Trials restricted to highly-selected subgroups, supportive-care, administration-routes, country-specific approvals, and conference abstracts were excluded. Two investigators independently extracted summary data. The primary outcomes were objective response rate and complete response rate, and were pooled using random-effects generalised linear mixed models. Adverse events were secondary outcomes. Prespecified subgroup analyses evaluated drug class and publication period. The study was registered with PROSPERO, CRD42023394451. FINDINGS: We identified 2797 citations, of which 1824 unique records remained after removal of duplicates. 132 trials including 7786 patients were eligible for analysis. 3375 (43%) of 7786 patients were female and 4411 (57%) were male. Objective response rate was 30·5% (95% CI 26·0-35·5, I 2=84·7%) and complete response rate 14·3% (11·5-17·7, I 2=82·2%). Response rates varied across drug classes, with the highest objective response rate or complete response rate for cellular therapies (70·0%, 95% CI 61·0-77·0 and 51·0%, 95% CI 43·0-59·0), followed by bispecific antibodies (46·0%, 38·0-53·0 and 30·0%, 24·0-36·0) and antibody-drug conjugates (40·0%, 32·0-47·0 and 18·0%, 13·0-24·0). Objective response rate increased over time, from 16·6% (95% CI 9·0-29·0) in 2000-08 to 36·8% (30·0-45·0) in 2018-25. The overall rate of dose-limiting-toxicities or discontinuations was 6·0% (95% CI 4·7-7·6). The rate of grade 3-4 adverse events was 61·5% (95% CI 54·2-68·3), treatment-related-mortality was 0·6% (0·4-1·0), and non-relapse-mortality was 3·6% (2·9-4·5). Treatment-related mortality remained below 1% over time. INTERPRETATION: Since the year 2000, early-phase trials in relapsed or refractory diffuse large B-cell lymphoma have shown more than a doubling of response rates, driven primarily by cellular and bispecific antibody therapies, while maintaining low treatment-related mortality. These results provide risk-benefit trends in early-phase trials and define contemporary benchmarks for clinicians, investigators and regulators. FUNDING: None.