In a study reported in the Journal of Clinical Oncology, Khurana et al found that up to 24% of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) receiving standard immunochemotherapy are excluded from participation in clinical trials on the basis of organ function eligibility requirements alone, with exclusion affecting generalizability of trial findings to the real-world setting.
As stated by the investigators, “Exclusion of patients needing urgent treatment or requiring novel biomarkers before enrollment has impacted the ability to enroll real-world patients in frontline trials of DLBCL. The impact of baseline organ function–based eligibility criteria on this effect and clinical trial exclusion is less well-understood.”
The study included consecutive patients with newly diagnosed lymphoma enrolled from 2002 to 2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence. The current analysis included 1,265 patients with DLBCL who received frontline R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP–like immunochemotherapy. Organ function–based criteria from seven recent U.S.-based or international DLBCL trials (PHOENIX, ROBUST, ECOG 1412, REMoDL-B, GOYA, ENGINE, and CALGB 50303) adding an additional drug to the R-CHOP backbone were identified and applied to the MER cohort. Organ function parameters were identified from criteria for hemoglobin, absolute neutrophil count, platelet count, creatinine clearance, and bilirubin from the trials.
“Current national and international trials exclude up to 24%of patients from participation on the basis of organ function alone. A significant difference in the outcomes, notably lymphoma-related death, suggests issues with generalization and potential exclusion of high-risk patients. These data will help future clinical trial development and meet U.S. Food and Drug Administration and ASCO recommendations to increase trial accrual.”— Khurana et al
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Across the seven trials, between 9% and 24% of patients in the MER cohort were excluded on the basis of baseline organ function alone.
Using the eligibility criteria across trials, compared with eligible patients in the MER cohort, those who were considered ineligible based on organ function had significantly poorer event-free survival (hazard ratios [HRs] = 1.67–2.16), overall survival (HRs = 1.87–2.56), and 24-month event-free survival (odds ratios [ORs] = 1.71–2.16).
After adjustment for International Prognostic Index score, results were attenuated for event-free survival (HRs = 1.19–1.61), overall survival (HRs = 1.30–1.89), and 24-month event-free survival (ORs = 1.13–1.52), with the differences in risk remaining clinically relevant.
Ineligible patients were more likely to die from lymphoma progression, with risk of therapy-related deaths being similar between organ function–eligible and organ function–ineligible patients. For example, using the ENGINE trial criteria (most stringent criteria and highest percent exclusion rate), the 5-year risk of death from progressive disease in the MER cohort was 25% for ineligible vs 15% for eligible patients.
As noted by the investigators, the exclusion of patients from clinical trials based on organ function and the poorer outcomes among excluded patients also has potential implications on estimating outcomes in control patients, affecting a primary component of trial biostatistical calculations.
The investigators concluded, “Current national and international trials exclude up to 24%of patients from participation on the basis of organ function alone. A significant difference in the outcomes, notably lymphoma-related death, suggests issues with generalization and potential exclusion of high-risk patients. These data will help future clinical trial development and meet U.S. Food and Drug Administration and ASCO recommendations to increase trial accrual.”
Thomas E. Witzig, MD, of the Division of Hematology, Mayo Clinic, Rochester, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.