Simonsen Mikkel Runason, Haunstrup Laura Mors, Severinsen Freja Tang, Jensen Rasmus Kuhr, Brown Peter de Nully, Maurer Matthew J, Khurana Arushi, Jensen Paw, Jørgensen Judit Mészáros, Stauffer Larsen Thomas, Clausen Michael Roost, Poulsen Christian Bjørn, Dessau-Arp Andriette, El-Galaly Tarec Christoffer, Jakobsen Lasse Hjort
Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.
Leuk Lymphoma. 2024 Dec;65(14):2173-2181. doi: 10.1080/10428194.2024.2390561. Epub 2024 Sep 3.
Up to 50% of diffuse large B-cell lymphoma (DLBCL) patients are ineligible for participation in clinical trials. Ineligible patients have inferior outcomes, but less is known about the impact of commonly used organ-function-based inclusion criteria on drug efficacy estimates. Data on DLBCL patients treated with CHOP+/-rituximab were retrieved from the Danish Lymphoma Registry. Trial inclusion criteria were extracted from four international DLBCL trials (REMoDL-B, GOYA, POLARIX, and HOVON-84). Differences in overall survival (OS) and 5-year restricted mean survival differences (5 y-RMSDs) between trial eligible and ineligible patients were computed. The effectiveness of adding rituximab to CHOP was quantified by the 5 y-RMSD between CHOP and R-CHOP-treated patients and the impact of individual trial criteria on estimated effectiveness was quantified by Shapley-values. In total, 4,083 R-CHOP-treated and 890 CHOP-treated DLBCL patients were included. Across the trials, 18.6-29.3% of the included R-CHOP-treated patients were deemed ineligible for trial based on organ function and performance status alone. Ineligible patients had significantly worse survival, with adjusted absolute differences in 5-year OS of 9-15%. The impact of individual criteria on the estimated effectiveness of adding rituximab to CHOP was small (Shapley-value range, -2.74-0.31). Using a smaller set of criteria derived from a data-driven approach, the number of eligible patients increased by 16-38% and the 5 y-RMSD increased by 0.7-3.1 months. In conclusion, OS among trial ineligible DLBCL patients is inferior as expected, but relaxing trial criteria would have increased the number of trial participants without making major changes in estimated efficacy for a hypothetical CHOP versus R-CHOP trial. This does not necessarily imply that trial findings based on selected patients are unreliable, as the estimated effectiveness of adding rituximab to CHOP was only slightly affected by omitting selected inclusion criteria.
高达50%的弥漫性大B细胞淋巴瘤（DLBCL）患者不符合参与临床试验的条件。不符合条件的患者预后较差，但对于常用的基于器官功能的纳入标准对药物疗效评估的影响了解较少。从丹麦淋巴瘤登记处检索了接受CHOP±利妥昔单抗治疗的DLBCL患者的数据。试验纳入标准从四项国际DLBCL试验（REMoDL-B、GOYA、POLARIX和HOVON-84）中提取。计算了试验合格和不合格患者的总生存期（OS）差异以及5年受限平均生存期差异（5年RMSD）。通过CHOP与R-CHOP治疗患者之间的5年RMSD量化了在CHOP中添加利妥昔单抗的有效性，并通过Shapley值量化了各个试验标准对估计有效性的影响。总共纳入了4083例接受R-CHOP治疗的DLBCL患者和890例接受CHOP治疗的患者。在各项试验中，仅基于器官功能和体能状态，18.6%-29.3%的纳入R-CHOP治疗的患者被认为不符合试验条件。不符合条件的患者生存期明显更差，5年OS的调整后绝对差异为9%-15%。各个标准对在CHOP中添加利妥昔单抗的估计有效性的影响较小（Shapley值范围为-2.74至0.31）。使用从数据驱动方法得出的一组较小组的标准，合格患者数量增加了16%-38%，5年RMSD增加了0.7-3.1个月。总之，正如预期的那样，试验不合格的DLBCL患者的OS较差，但放宽试验标准会增加试验参与者的数量，而对于假设的CHOP与R-CHOP试验，估计疗效不会有重大变化。这不一定意味着基于选定患者的试验结果不可靠，因为在CHOP中添加利妥昔单抗的估计有效性仅因省略选定的纳入标准而受到轻微影响。
