Many phase III cancer clinical trials exclude individuals with absolute neutrophil counts (ANCs) within the reference range for individuals with the Duffy null–associated ANC (DANC) phenotype. Many individuals with DANC are of African and Middle Eastern ancestry, and current clinical trials exclude some of these participants because of these predefined criteria. Individuals with DANC may also be receiving modified doses of systemic anticancer therapy (SACT) based on data that do not account for their lower neutrophil counts. These results were published in JAMA Network Open.
“There are inequities in clinical trial participation and cancer outcomes for minority populations,” said study author Andrew Hantel, MD, of Dana-Farber Cancer Institute in Boston. “While minimum neutrophil counts are frequently used as eligibility criteria for clinical trials and for modifying cancer therapy, we had not seen an analysis of if and how trials and regimens accounted for Duffy status. In preliminary searches, we did not see any trials or regimens account for it explicitly, so we designed this study to see how this Duffy-agnostic approach could impact individuals with DANC.”
Dr. Hantel and his colleagues conducted a cross-sectional study of 289 current phase III cancer trials being conducted in the U.S. and the U.K. for the top five most prevalent cancers — prostate, breast, melanoma, colorectal, and lung — initiated between November 1, 2021, and November 1, 2023. They also analyzed 71 curative-intent SACT regimens recommended by the National Comprehensive Cancer Network’s (NCCN) treatment guidelines. The team looked at how frequently the trials excluded individuals with ANC within the DANC reference range and how frequently regimen dose modifications were present for these individuals.
The authors found that 76.5% (221 trials) of the phase III clinical trials for these five cancers had an explicit or implicit exclusion criteria that excluded patients with a neutrophil count that was within the normal reference range for people with DANC. Colorectal cancer clinical trials had the highest proportion of exclusions (38 of 44, 86.4%), and prostate cancer clinical trials had the lowest proportion of exclusions (11 of 23, 47.8%).
“Notably, such criteria were present in 50% of the trials that only tested hormonal therapies without targeted therapy or chemotherapy, where the expectation of treatment-associated neutropenia is very low,” Dr. Hantel said.
Of the 71 SACT regimens, 38 (53.5%) included dose modifications for ANC values within the DANC reference range.
According to the study results, 54% of curative-intent SACT regimens preferred by NCCN guidelines for the same five tumor types had dose modifications for a neutrophil count that was within the normal reference range for people with DANC.
“Notably, inappropriate modifications were present across the two main data sources that physicians look to when making dose modification decisions — the trial that led to the regimen being recommended and the U.S. Food and Drug Administration (FDA) label of the drugs that make up the regimen. In fact, when going off the FDA labels, 62% of regimens had inappropriate modifications,” Dr. Hantel noted.
“We were surprised that no trials accounted for Duffy status, and that the majority of trials and regimens excluded or recommended dose modifications for neutrophil counts within the reference range for individuals with Duffy null phenotype,” Dr. Hantel said.
“There is no reason for trials to not immediately change their neutrophil criteria to account for Duffy null phenotype and lower any eligibility thresholds to at least below the lower limit of normal for individuals with Duffy null phenotype. Similarly, trials should not require dose modifications for neutrophil counts that are normal for people with DANC,” he added.
The team is investigating the extent to which individuals with DANC are excluded from clinical trials or have their doses modified as a result of these exclusions and dose modifications.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
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.
