One of the most important measurements for cancer patients is the neutrophil count. Certain cancer therapies, such as chemotherapy, can harm these white blood cells. Therefore, cancer patients must have their neutrophil counts within a certain range when undergoing these treatments or before enrolling in certain clinical trials. That can be a problem for people with a natural blood variation, the Duffy null phenotype.
About 67% of African Americans have the Duffy null phenotype, which causes them to naturally have lower numbers of neutrophils in their blood. It won’t affect their health or ability to fight infections, but it can drop their neutrophil count to a range that is considered low. That could lead to some people with the Duffy null phenotype being wrongly excluded from most cancer clinical trials, which could negatively impact their treatment, according to a new study published in JAMA network opened on Wednesday.
That inappropriate exclusion may also help explain historically low participation in African-American cancer studies, says Andrew Hantel, a medical oncologist and researcher at the Dana-Farber Cancer Institute and the study’s senior author. “There are a number of systematically racist reasons why people are disproportionately excluded from clinical trials,” he said. “This may be part of that.”
The Duffy null phenotype, previously called “the somewhat derogatory term ‘benign ethnic neutropenia,'” Hantel said, is a variation in the red blood cell. It is most common in places where malaria is endemic, namely Africa and the Middle East. People with ancestry from these regions are more likely to have this phenotype, which can also lead to neutrophils being concentrated more in the spleen and less in the bloodstream than people who are not Duffy-null. “So when we take a tube of blood from someone, it looks like he or she has fewer neutrophils,” says Hantel.
This can make it seem as if a patient’s immune system is less prepared to fight infections than it actually is. Neutrophils are one of the body’s first responders against viruses and bacteria, and their numbers give doctors an idea of how capable the immune system is. Low numbers may indicate that the patient is vulnerable to serious infections, and it would be dangerous to give chemotherapy or other medications or to include them in clinical trials of medications that can lower neutrophil levels.
“That concern is why many studies include neutrophil criteria,” Hantel said. “And after a trial leads to approval of the drug, we can delay the drug or reduce the dose or omit the drug altogether if a person’s neutrophils get too low or stay low.” That applies to virtually any drug that affects neutrophil counts, Hantel added.
But when Hantel and his colleagues looked at hundreds of cancer clinical trials conducted between 2021 and 2023, they found not a single protocol that took into account the different healthy neutrophil range for people with a Duffy null phenotype. That’s despite the fact that standards for adequate neutrophil count in the United States are based on people who don’t have the phenotype. Instead, the team found that of more than 289 studies, 76.5% contained criteria that would exclude people who would naturally fall at the lower end of a healthy Duffy-zero neutrophil range.
When the team looked at protocols for drug regimens that instructed physicians to adjust dosage, they found that 53.5% of 71 regimens recommended dosage adjustments based on neutrophil counts that could negatively impact Duffy-null individuals. “If you reduce the dose intensity of someone on chemotherapy, he or she will have inferior overall survival,” says Hantel.
The study highlights how medical standards based on populations of European ancestry can lead to harm and bias against certain other populations, said Consuelo Wilkins, a physician and health equity expert at Vanderbilt University who did not collaborate on the study. “This is specifically medical racism. I would say that, in terms of structural racism, this is an area of reference that is determined within a clinical or medical setting, and it has a disproportionate impact on people,” she said.
It’s just one example, Wilkins added. There are numerous other factors that can lead to exclusion of marginalized and minority communities from participation in clinical trials, including language or transportation requirements. “These social factors somehow creep into the inclusion and exclusion criteria,” Wilkins said. “Your insurance status may determine whether you can participate. That is an example of structural racism. A citizen service number is required for some investigations. That is structural racism.”
And these are all things that can be removed from the criteria for participation in studies to make medical research more inclusive. Hantel gave an example of another benign condition, Gilbert’s syndrome. This condition can lead to elevated bilirubin levels; high levels of this compound may indicate liver or biliary disease. Gilbert syndrome “particularly affects white individuals,” Hantel said. “There are exceptions to dose adjustments and trial eligibility. If you have Gilbert’s disease, you may continue even if your bilirubin is higher. It’s an interesting, disappointing analogy.”
Hantel can think of no good reason why studies now being designed cannot include similar exceptions and conditions for Duffy-null individuals. For cancer therapies and regimens that have already been approved, Hantel said doctors and scientists should work to understand appropriate neutrophil ranges for people with the Duffy null phenotype.
This, he hopes, will lead to more accurate and fairer treatment of cancer patients of African or Middle Eastern descent.