Duffy null phenotype may lead to unjustified exclusion from cancer drug trials

Many clinical trials of new cancer drugs may inappropriately exclude some people with the “Duffy null phenotype,” a phenotype found predominantly in people of African or Middle Eastern descent, researchers from the Dana-Farber Cancer Institute and Queen Mary University of London report in a new study.

The Duffy null phenotype results in relatively lower levels of white blood cells called neutrophils when measured in the blood. This is not because they have fewer neutrophils overall, but because they are more abundant in other body tissues. Tests that limit participation in clinical trials to patients with certain levels of neutrophils in the blood could therefore represent unfair discrimination against patients who could potentially benefit from trial therapies.

The failure to account for the Duffy null phenotype also means that recommendations for many standard cancer drugs incorrectly indicate less effective doses for some people, researchers say.

Tests to count neutrophils in a blood sample are done to make sure patients can be safely treated with chemotherapy or other cancer drugs. The number of neutrophils – white blood cells that kill bacteria and other foreign microbes – is often reduced by cancer drugs, potentially increasing the risk of infection. For patients to qualify for a clinical trial or a standard dose of many cancer drugs, their neutrophil count must be above a certain threshold to ensure they retain enough of these cells after treatment.

The cutoff was determined by studies conducted primarily on patients of European descent, who rarely have the Duffy null phenotype. However, many healthy people with the Duffy null phenotype (mainly people of African and Middle Eastern descent) typically have lower neutrophil levels in their blood and relatively higher levels in their other tissues.

“Natural differences in neutrophil counts between people of different ancestry have historically been described with the inaccurate and now outdated diagnosis of 'benign ethnic neutropenia,'” says Stephen Hibbs of Queen Mary University of London, who led the study published today. JAMA network openedand for which Andrew Hantel, MD, of Dana-Farber is senior author. “But since this variation has been found to be caused by the Duffy null phenotype, we need to reexamine the ways in which misinterpretation of neutrophil counts can affect patient care.”

People with the Duffy null phenotype are equally able to fight infections compared to others. The concern is that they have been excluded from clinical trials because the blood neutrophil levels that are normal for them can fall below the thresholds for trial participation. In this study, we looked at the extent to which this occurs.”

Andrew Hantel, MD, senior author, Dana-Farber Cancer Institute

The researchers examined the eligibility criteria for 289 large Phase III trials of drugs for the five most common cancers in the US and UK: prostate, breast, colon, lung and melanoma. The drugs included chemotherapy drugs, targeted therapies and hormone therapies (which generally do not lower neutrophil levels).

They found that 76.5% of studies excluded patients whose blood neutrophil counts were within the normal range for people with the Duffy null phenotype. The studies with the highest exclusion rate – 86.4% – involved patients with colon cancer. Even studies of hormonal cancer therapies – which generally do not lower neutrophil levels – had a significant exclusion rate.

The researchers also examined the extent to which clinical trial protocols require adjustment of drug dosage for patients with lower neutrophil counts.

“The National Comprehensive Cancer Network (NCCN) treatment guidelines are based on the clinical trials that tested these drugs,” Hantel explains. “If a study specifies that dosing should be lowered or delayed when a patient's blood neutrophil count is below a certain level, doctors often implement these changes once the drug is approved as standard therapy. We know that in many cases, survival rates are lower in patients who receive lower or delayed dosing.”

The researchers reviewed 71 clinical trials that resulted in the treatment regimens recommended by the NCCN. They found that in more than half of the cases, a reduction in drug dose, a delay in administration, or discontinuation was necessary when a participant's neutrophil count fell below a level that was still normal for people with the Duffy null phenotype. When they looked at the recommended changes based on the individual Food and Drug Administration labels for each therapy used, a similar rate of dose changes was found.

“The effect of these recommendations is to inappropriately reduce the intensity of treatment in patients who would likely tolerate normal doses,” says Hantel.

Based on their findings, the researchers recommend that clinical trials of cancer drugs should also allow patients with low but normal neutrophil counts to participate. “Everyone who is eligible to participate in trials should be tested for the Duffy null phenotype. If they are Duffy null and their neutrophil count is within the reference range for that group, they should be allowed in,” Hantel notes.

Current and future trials should apply the same principle to determine whether trial participants need lower or delayed doses: People with the Duffy null phenotype whose neutrophils are in the healthy range should be eligible for the full dose of the study drug. For trials already completed, follow-up studies are needed to determine whether giving the full dose to people with the Duffy null phenotype and lower neutrophil counts is safe and effective, researchers say.

“Health inequalities in cancer care and research have many causes, and some are harder to address than others. Neutrophil criteria for clinical trials and dose adjustments are a hidden factor in inequality that can be addressed. Action is now needed to change these criteria to ensure Duffy-null patients are not disadvantaged,” Hibbs said.

The study was funded by the National Institutes of Health, the American Society for Clinical Oncology and the Wellcome Trust.