Researchers have recently discovered that clinical trials, including those of new cancer drugs, may inappropriately exclude some people with a common benign trait (Duffy-null phenotype), which is found mainly in people of African or Middle Eastern genetic ancestry, and which results in lower neutrophil counts.
Failure to account for Duffy-null phenotype also means recommendations for many standard cancer drugs then call for less effective doses for some individuals, they said.
In their findings of the collaborative study, published in JAMA Network, the scientists call for revision of neutrophil criteria for clinical trials and dose modifications, to reflect expected and normal differences in neutrophil levels, and to ensure that Duffy-null patients are not disadvantaged.
The Duffy-null phenotype results in relatively lower levels of white blood cells (neutrophils) in the blood, not because there are less neutrophils overall, but because these are more frequently located in other body tissues.
For patients to qualify for a clinical trial, or a standard dose of many cancer drugs, their neutrophil levels need to be above a specified threshold to ensure they will retain enough of these cells after treatment. The threshold was established by studies conducted primarily in patients of European descent, who rarely have the Duffy-null phenotype.
This study examined 289 major phase 3 trials of drugs for the five most prevalent cancers in the USA and UK (prostate, breast, colorectal, and lung cancer, and melanoma) to determine the extent to which people with the Duffy-null phenotype are excluded from clinical trials.
Researchers also assessed the extent to which clinical trial protocols require drug doses to be modified for patients with lower neutrophil counts.
Results show that 76.5% of the trials excluded patients whose blood neutrophil counts were in the normal range for people with the Duffy-null phenotype. Even trials of hormonal cancer therapies, which generally do not decrease neutrophil levels, had a significant exclusion rate.
In a further review of 71 clinical trials that led to National Comprehensive Cancer Network (NCCN) recommended treatment regimens, the researchers found that >50% required reducing the drug dose, delaying its administration, or stopping it if a participant’s neutrophil count fell below a level that was still normal for people with the Duffy-null phenotype.
Recommended changes based on individual US Food and Drug Administration (FDA) labels for each therapy used showed a similar rate of dose changes. The authors say the effect of these recommendations is to inappropriately reduce the intensity of treatment for patients who would probably tolerate regular doses.
Based on their findings, the researchers recommend that everyone being screened for trial entry should be tested for the Duffy-null phenotype, and that clinical trials of cancer drugs should allow entry to patients with lower, but normal-for-them neutrophil counts.
They say tests that restrict clinical trial eligibility to patients with certain blood levels of neutrophils may be unfairly discriminating against patients who could potentially benefit from trial therapies.
Stephen Hibbs (Wolfson Institute of Population Health, Queen Mary University of London), who led the study, said: “We need to re-examine the ways in which neutrophil count misinterpretation can affect patient care. Health inequity in cancer treatment and research has many causes, and some are more difficult to address than others. Neutrophil criteria for clinical trials and dose modifications are a hidden contributor to inequity that can be rectified. Action to amend these criteria is needed to ensure Duffy-null patients are not disadvantaged.”
Chief executive of the NHS Race and Health Observatory, Professor Habib Naqvi, said: “We have a duty of care to ensure treatments and medications are safe and work for all people. However, this is not always possible where clinical trials are focused on mainly white European populations.
“This innovative work is welcome, as we collectively seek to increase diverse representation in clinical trials, personalised medicine and in genetic testing among black, Asian and ethnic minority communities. Such efforts will help us to tackle ethnic and racial inequalities in health.”
Study details
Cancer trial eligibility and therapy modifications for individuals with Duffy null–associated neutrophil count
Stephen Hibbs, Laura Aiken, Kruti Vora et al.
Published in JAMA Network on 11 September 2024
Abstract
Importance
Absolute neutrophil counts (ANCs) are used to determine cancer clinical trial (CCT) eligibility and systemic anticancer therapy (SACT) dose modifications. Duffy null–associated ANC (DANC) is a non-pathologic phenotype associated with lower ANC and most frequently seen in individuals with African and Middle Eastern ancestry. It is unclear whether CCTs exclude or SACT regimens modify doses for individuals with ANC within the DANC reference range.
Objective
To investigate CCT exclusions and SACT dose modifications for ANC within the DANC reference range.
Design, Setting, and Participants
This cross-sectional study of contemporary CCTs and SACT regimens included adult, interventional, phase 3 CCTs for the 5 most prevalent cancers in the US and United Kingdom (prostate, breast, melanoma, colorectal, and lung cancers) testing SACTs with start dates between November 1, 2021, and November 1, 2023, and that were registered on ClinicalTrials.gov. Preferred curative-intent SACT regimens were listed in National Comprehensive Cancer Network guidelines.
Exposure
Cancer clinical trial exclusions and SACT regimen modifications.
Main Outcome and Measures
Proportions of CCTs that exclude and SACT regimens that modify doses for individuals with an ANC within the DANC reference range.
Results
For CCTs, 289 of 382 trials (75.7%) were eligible, of which 221 (76.5% [95% CI, 71.1%-81.2%]) excluded patients with ANC values within the DANC reference range. Colorectal CCTs had the highest (38 of 44 [86.4% (95% CI, 72.6%-94.8%)]) and prostate CCTs had the lowest (11 of 23 [47.8% (95% CI, 26.8%-69.4%)]) proportions of exclusions. Of CCTs testing cytotoxic chemotherapy, 116 of 142 (81.7% [95% CI, 74.3%-87.7%]) had exclusions; 93 of 123 (75.6% [95% CI, 67.0%-82.9%]) CCTs testing targeted therapies alone and 12 of 24 (50.0% [95% CI, 29.1%-70.9%]) testing hormonal therapies alone had exclusions. Among the 113 US- and UK-based trials, exclusions were present in 89 (78.8% [95% CI, 70.1%-85.9%]). Of 71 SACT regimens, 38 (53.5% [95% CI, 41.3%-65.5%]) included dose modifications for ANC values within the DANC reference range. Lung cancer regimens had the highest (23 of 31 [74.2% (95% CI, 55.4%-88.1%)]) and prostate cancer had the lowest (0 of 12 [0 (95% CI, 0%-26.4%)]) proportions of modifications. Regimens including chemotherapy had modifications in 32 of 44 (72.7% [95% CI, 57.2%-85.0%]); 11 of 20 (55.0% [95% CI, 31.5%-76.9%]) of targeted therapy regimens and 0 of 16 (0% [95% CI, 0%-20.6%]) of hormonal therapy regimens had modifications. Among regimens including chemotherapy and/or targeted therapy, modifications were present in 38 of 55 (69.1% [95% CI, 49.7%-73.2%]).
Conclusions and Relevance
In this cross-sectional study, substantial proportions of CCTs excluded and SACT regimens modified doses for patients with ANCs in the DANC reference range. These practices structurally discriminate against patients of African and Middle Eastern ancestry. While determining optimal SACT dose modifications requires further study, CCT exclusion criteria should be revised.
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