Eligibility criteria more likely to exclude minorities from lymphoma clinical trials
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Up to one-quarter of those seeking clinical trial enrollment for novel front-line therapies to treat diffuse large B-cell lymphoma are excluded based on organ function laboratory values, study results showed.
An analysis presented during a virtual press briefing prior to ASH Annual Meeting and Exposition revealed that five lab-based criteria were used to disqualify patients from participating in front-line clinical trials, the acceptable ranges of which often prohibited Black and Hispanic patients from enrollment.
“These criteria are often boilerplate and may come from previous trials unrelated to lymphoma,” Matthew J. Maurer, DSc, lead faculty statistician for the lymphoma research program at Mayo Clinic, told Healio.
“We need to be more thoughtful about how we pick these criteria,” he said. “We keep adding more and more eligibility criteria to trials, and what’s happening is that studies are becoming too restrictive and we are keeping out the patients who could most benefit.”
Background
Recent analysis has shown increasingly restrictive eligibility criteria for front-line trials in DLBCL over the past 3 decades, according to Arushi Khurana, MBBS, an advanced hematology fellow in the clinical cell therapy/lymphoma group at Mayo Clinic in Rochester, Minnesota.
“Some of these criteria are arbitrary,” she told Healio. “We need to be mindful of how they may lead to exclusion of patients who are otherwise healthy and should be included in a clinical trial.”
Use of regional data and lack of racial/ethnic diversity limited the results of a previous analysis by University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) to evaluate the impact of race and ethnicity on lab-based trial eligibility criteria, Khurana said.
Khurana and colleagues aimed to confirm the results of previous study in a larger and more diverse group of patients known as the Lymphoma Epidemiology of Outcomes (LEO) Cohort.
Methodology
The LEO cohort is an expansion of the MER cohort that has been enrolling patients with DLBCL at eight additional centers throughout the U.S. since 2015.
Enrollment of Black and Hispanic patients in the LEO cohort makes it broadly reflective of the overall U.S. population with DLBCL, Maurer noted.
LEO included 2,510 patients with DLBCL who received standardized front-line anthracycline plus CD20-directed monoclonal antibody-based immunochemotherapy.
A total of 2,330 patients had three or more of the five lab-based values available and comprised the analysis set. The analysis group included 1,972 non-Hispanic white patients (85%) and 272 Hispanic and/or nonwhite patients (12%).
Investigators obtained laboratory values from medical records and followed patients prospectively for treatment outcomes. They identified hemoglobin, absolute neutrophil count, platelet count, creatinine and bilirubin as organ function parameters used for exclusion criteria in recent front-line clinical trials.
Association between trial eligibility, OS and EFS served as the study’s primary outcomes, with outcomes compared with results from the POLARIX trial, which served as a benchmark for clinical benefit of standard-of-care treatment over R-CHOP.
Key findings
Fewer Black (7.1%) and Hispanic patients (4.9%) enrolled in clinical trials for front-line treatments when compared with their white counterparts (9.5%).
Black and Hispanic patients also received their diagnosis at a significantly younger median age compared with white patients (median [IQR], 51 years [39-62] and 56 years [41-66] vs. 65 years [55-73]).
“We observed significant differences in hemoglobin, neutrophil counts and creatinine clearance by race and ethnicity,” Maurer told Healio. “The results suggest that patients from minority groups are more likely to fall short of the criteria used in trial protocols to determine eligibility.”
For example, Maurer noted, hemoglobin levels varied significantly depending on race and ethnicity, with 13% of white patients being disqualified due to low levels, whereas 28% of Black patients and 19% of Hispanic patients were excluded using the same cutoff level of less than 10 g/dL.
A comparison of five recent trials for front-line treatment of DLBCL showed that between 17% and 26% of patients would have been excluded based on one of the five lab criteria, with minority participants being most impacted, Maurer said.
Those who did not qualify for one of the recent front-line trials had significantly inferior EFS compared with trial participants and had the highest rates of lymphoma-related mortality. Investigators observed the largest gap in outcomes between Black patients who were trial-eligible vs. ineligible.
Clinical implications
Mikkael A. Sekeres, MD, MS, chief of the division of hematology and professor of medicine at Sylvester Cancer Center at University of Miami, told Healio the results reinforce research he and others have conducted showing eligibility criteria in malignancy trials are too restrictive.
“If you bring it all together, [the next step would be] to liberalize eligibility criteria so that they're not overly restrictive against patients who have, for example, kidney disease or liver disease or heart disease,” said Sekeres, who chairs the ASH Committee on Communications and was not involved with the study.
“Hopefully, that would lead to expanded enrollment of Hispanic and nonwhite patients,” he added.
Results of the analysis suggest patients from minority groups who are capable and willing to participate in a clinical trial — especially Black patients — are at greater risk of being left out of trials examining novel front-line therapies for DLBCL, Maurer said.
“Thoughtful clinical trial designs are needed to increase inclusivity in our clinical trials,” he told Healio. “Improving clinical trial designs will require better identification of the patient populations who should be considered for trials vs. those who would not be good candidates due to frailty or comorbidities.”
Carefully crafted exclusion criteria matter because a large number of otherwise healthy minority individuals were prevented from participating in trials despite having an overall ability and willingness to enroll, according to Khurana.
“These are people who want to participate in our research, and we are still excluding them,” she told Healio. “We need to be thoughtful about not excluding those who could benefit the most from some of the novel strategies being tested in trials.”
Perspective
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Paolo Caimi, MD
Diversity and inclusion in clinical trial participation has received increasing attention from regulatory and funding agencies, as well as from investigators and scientific publishers. The results presented by Khurana and colleagues demonstrate commonly used laboratory-based eligibility criteria can result in the exclusion of minority patients from clinical trials of DLBCL. This important study highlights a problem that lies at the intersection of health equity, cultural bias and statistical bias.
As observed in this study, Black and Hispanic patients diagnosed with DLBCL who did not meet inclusion criteria for trials had worse disease-related outcomes. This underscores the fact that this patient population also is underserved from a clinical standpoint, and that their ability to access novel agents may be of particular importance.
From a statistical standpoint, this study demonstrates how eligibility criteria can be a source of sampling bias in lymphoma clinical research. This should be of concern to all investigators designing studies and enrolling patients, given adequate sampling is central to statistical inference. Sampling biases — such as the systematic exclusion bias described in the study by Khurana and colleagues — can significantly affect the generalizability of the results of clinical trials. In light of these observations, how confident are we that the results of recent trials of initial therapy apply to the broad DLBCL population?
Equitable access to clinical trials continues to be a challenge, and these results suggest that enrollment of a more diverse patient population can start with re-evaluating our “standard” laboratory inclusion criteria. Broadening these criteria can increase access to trials for those patients who may need them most, as well as increase our confidence that trial results are applicable to a wide majority of patients.
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Khurana A, et al. Abstract 850. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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