Hundreds of millions of people who live in, or are descended from, regions where the malaria-causing protozoan Plasmodium vivax is prevalent have inherited a unique blood type that evolved to prevent malaria infection. People with the Duffy null phenotype—who are primarily of African and Middle Eastern descent—have red blood cells that lack a surface protein called the Duffy antigen, which is what P. vivax uses to infect cells.
But because this adaptation also leads to lower levels of white blood cells called neutrophils in the blood, Duffy null individuals are systematically excluded from cancer clinical trials and given lower drug doses that may be ineffective, a new study has found.
“Increasing diversity in clinical trials is crucial for eliminating racial inequities in cancer treatment and outcomes,” Jordan Baeker Bispo, Ph.D, a cancer disparity researcher at the American Cancer Society who was not involved with the study, told Fierce Biotech in an email. “Overly restrictive eligibility criteria limit the generalizability of trial findings to historically underrepresented groups.”
Cancer trials often include cutoff points for neutrophil levels in the blood. Many cancer treatments reduce neutrophil levels as a side effect, so low starting levels can add to the danger of treatment. But, while Duffy null individuals have about 40% fewer neutrophils in their blood than Duffy non-null individuals, that doesn’t mean they’re at higher risk of dangerous side effects.
“Neutrophils will reside in their spleen versus floating around in their bloodstream,” Andrew Hantel, M.D., an oncologist at the Dana-Farber Cancer Institute, told Fierce in an interview. “It seems like these people have lower neutrophils, but that’s just because they’re in the spleen.”
Hantel’s colleague at Dana-Farber, Lauren Merz, M.D., has recently done work quantifying the typical range of blood neutrophils in healthy Duffy null individuals. With that information in hand, Hantel and Merz teamed up with Merz’s collaborator Stephen Hibbs at Queen Mary University of London to comb through cancer trials and see how many of them excluded patients who fall into the Duffy null range.
Of 289 clinical trials in the U.S. and the U.K. covering the five most common types of cancer (prostate, breast, melanoma, colorectal and lung), 221 of them excluded patients with neutrophil levels typical of Duffy null individuals. This was true even for half of the trials testing hormonal therapies alone, which Hantel said aren’t expected to reduce neutrophil levels.
“That was somewhat surprising, because in general, I am not sure the reasoning behind why those need neutrophil count exclusion criteria at all,” he said.
It was also common for trials to give patients with low blood neutrophil counts reduced treatment doses. Of 44 treatment regimens that included chemotherapy, 32 of them lowered the dose for patients with neutrophil levels in the Duffy null range.
“There’s good data that if you give people reduced doses of chemotherapy, they will respond and survive less from their cancer,” Hantel said. “You’re essentially reducing the dose or delaying or omitting a chemotherapy drug for a neutrophil count that is ostensibly normal for some of these patients, and therefore potentially making it so that their cancer may not respond as well, or they may not survive as long because of that.”
These dosage concerns extend beyond clinical trials, Hantel said, as many physicians look to trial designs for guidance when deciding how to administer approved drugs to their patients.
There is an easy fix, and that’s testing for Duffy null in patients and adjusting the allowed neutrophil levels if they have the blood type.
“An important aspect of this study is that the findings may be intervenable in the near term,” Baeker Bispo said. Hospitals that work with blood, like for transfusions, already test regularly for Duffy null, Hantel said. “It’s both widely available and not a high-cost test.”
“For trials that are being developed right now, there should be changes in the eligibility criteria to account for Duffy null,” Hantel said. “Then within those trials, we also need to augment the dose modification guidelines to be able to account for Duffy null. Those are two things that can happen immediately.”
A model for how to deal with Duffy null in clinical trials is Gilbert syndrome, a non-pathological condition that leads to higher levels of bilirubin in blood. Though both affect about 10% of the U.S. population, only Gilbert is routinely tested and accounted for in clinical trials—and it also happens to be seen predominantly in white people.
With this study and others in the works on the extent of how Duffy null individuals are excluded from cancer trials and care, Hantel said he hopes to “try to undo some of those things that we as a community have inadvertently allowed to persist and impact these patients.”