ANC Criteria May Unnecessarily Exclude Individuals with Duffy-Null Phenotype from Cancer Trials

New research suggests that individuals with Duffy null-associated absolute neutrophil count (DANC) — largely those of African and Middle Eastern ancestry — are often excluded from cancer trials and are more likely to receive suboptimal cancer drug doses due to the low levels of circulating neutrophils that are the hallmark of the phenotype.

The Duffy null phenotype is associated with 40% lower levels of circulating ANCs, as they tend to localize in the spleen. However, individuals with this phenotype do not appear to be at increased risk of infection.

Given that at least 80% of individuals from West Africa and about 66% of African Americans have the Duffy null phenotype – with 10%-15% having absolute neutrophil counts (ANCs) less than 1,500/μL – the findings, published in JAMA, suggest that these individuals may often be unnecessarily excluded from cancer clinical trials (CCTs) and are commonly subject to less intense cancer drug therapy. Importantly, dose intensity is closely linked to improved survival outcomes.

“This is an example of structural racism that impacts those with African or Middle Eastern ancestry and is highly amenable to remediation,” the researchers wrote.

The researchers conducted two analyses to assess the exclusion of individuals with DANC from CCTs and quantify modifications of systemic anticancer therapy (SACTs), including treatment delays, dose reductions, or discontinuations, based on neutrophil criteria.

The researchers found that 76.5% of CCTs included in the analysis excluded patients with ANC values within the DANC reference range, which had a lower threshold of 1,200/μL. Exclusions were highest in colorectal cancer trials (86.4%) and lowest in prostate cancer trials (47.8%).

The study focused on adult phase III interventional trials for the five most common cancers in the United States — breast, prostate, lung, colorectal and cutaneous melanoma — between November 2021 and November 2023. They identified 289 eligible trials and categorized ANC-based exclusion criteria as explicit (ANC >1,500/μL), implicit (qualitative exclusions like “abnormal lab values” or “requiring adequate hematologic function”) or absent.

In the second analysis, the researchers used guidelines from the American Society of Clinical Oncology for safe chemotherapy administration practices to identify regimens and recommended dose modifications for these cancers. They also examined National Comprehensive Cancer Network (NCCN) guidelines to identify SACT regimens with curative intent; then the researchers identified recommended dose modifications from manuscripts of cited trials. Regimens were also classified as explicitly, implicitly, or not dose-modifying based on ANC. They also examined Food and Drug Administration labels for drugs included in SACT drugs included in the identified regimens to assess the robustness of this analysis.

Among the 71 curative SACT regimens identified, 53.5% recommended dose modifications for patients with ANC levels within the DANC range. Lung cancer regimens had the most dose modifications (74.2%), while no dose modifications were identified for prostate cancer. FDA labels confirmed ANC-based modifications in 62% of regimens.

Based on these findings, the researchers recommend that cancer clinical trials immediately revise their eligibility criteria to include a DANC-specific ANC threshold, suggesting that 900/μL would be a reasonable value.