A new study finds that clinical trials, including trials of new cancer drugs, may inappropriately exclude some people with a common benign trait (Duffy-null phenotype) found predominantly in people of African or Middle Eastern genetic ancestry, that results in lower neutrophil counts. Failure to account for Duffy-null phenotype also means that recommendations for many standard cancer drugs inappropriately call for less-effective doses for some individuals. Authors 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 that they will retain enough of these cells following 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 III 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 Food and Drug Administration (FDA) labels for each therapy used showed a similar rate of dose changes. The authors say that 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 (WIPH), 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. Now, 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 majority White European populations. The innovative work undertaken by colleagues at Queen Mary University of London is welcome, as we collectively seek to increase diverse representation in clinical trials, personalised medicine and in genetic testing amongst Black, Asian and ethnic minority communities. Such efforts will help us to tackle ethnic and racial inequalities in health.’
The study was funded by the National Institutes of Health, the American Society for Clinical Oncology, and the Wellcome Trust.
Hibbs SP, Aiken L, Vora K, et al. Cancer Trial Eligibility and Therapy Modifications for Individuals With Duffy Null–Associated Neutrophil Count. JAMA Netw Open. 2024;7(9): e2432475. doi:10.1001/jamanetworkopen.2024.32475