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.
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.
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.
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, I2=84·7%) and complete response rate 14·3% (11·5-17·7, I2=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.
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.
None.
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.
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, I2=84·7%) and complete response rate 14·3% (11·5-17·7, I2=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.
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.
None.
Authors
Spanjaart Spanjaart, Bakker Bakker, de Vries de Vries, Hutten Hutten, van Nieuwenhuijzen van Nieuwenhuijzen, Minnema Minnema, Kuipers Kuipers, Kersten Kersten
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