HISTORY AND PHYSICAL
A man in his 50s diagnosed with a gastrointestinal cancer was undergoing treatment with an immune checkpoint inhibitor (ICI). Three months into his treatment, he developed grade 3 neutropenia with an absolute neutrophil count (ANC) less than 1.0 × 109 cells/L or 1,000/µL. His platelets and hemoglobin were normal.
He had no neutropenia prior to the start of his cancer treatment.
A detailed history and physical revealed that the patient was Black of African ancestry and his family and social histories were unremarkable concerning neutropenia. In his past medical history, his primary care physician noted occasional low white blood cell (WBC) count in his annual checkups. However, because he had no illnesses, he was told that he likely had a benign neutropenia seen in many people of African descent.
Therefore, a referral was not made to evaluate previous neutropenia. The patient also did not have other health complications and was not undergoing concurrent therapies.
FURTHER ASSESSMENT: BENIGN HEMATOLOGY CONSULT
A peripheral blood smear was ordered to assess the morphology and count of the blood cells. Cobalamin, copper, and serum methylmalonic acid (MMA) levels were tested for vitamin and mineral deficiencies. A red blood cell (RBC) test called “RBC antigen genotyping” test or “RBC antigens molecular methods” test was ordered.
It detects the presence of the Fy(a-b-) phenotype, which supports the diagnosis of BEN/DANC (Elhadad et al., 2022; Gay et al., 2023; Merz et al., 2023).
Neutrophils are one of the five types of WBCs and are the most abundantly produced, accounting for 40% to 70% of the total WBC count. However, only a small fraction of neutrophils circulates in the peripheral blood, as the majority remain in the bone marrow. The absolute neutrophil count (ANC) normally ranges from 1.8 to 7.5 × 109 cells/L or 1,800 to 7,500/µL (Awan et al., 2021).
DISCUSSION
PREVALENCE OF BEN/DANC
As shown in Figure 1, BEN/DANC is prevalent among Africans and people of African descent from the diaspora (Caribbean, West Indies), occurring in approximately 25% to 50% of individuals. It is observed in approximately 4.5% of African Americans, 10.7% in Arabs and some individuals from the Middle East (Israeli Bedouins, Jordanians, and natives of the United Arab Emirates), 11.8% of Yemenite Jews, 15.4% of Black Ethiopian Jews, some individuals from the Mediterranean area such as those of Greek descent, and some individuals from South America, and in less than 1% of the White population in the US (Awan et al., 2021; Berliner, 2022; Elhadad et al., 2022; Morrissey, 2024).
GENETIC ETIOLOGY OF BEN/DANC
A polymorphism on chromosome 1q22.239 contains the Duffy antigen receptor for chemokines (DARC) gene, also known as the atypical chemokine receptor 1 (ACKR1) gene. This gene includes a single nucleotide polymorphism (SNP), rs2814778, which results in a nonfunctional allele (Gay et al., 2023). The SNP rs2814778 resides in the promoter region of the DARC gene that prevents transcription and results in the RBC Duffy-null phenotype Fy(a-b-) (Merz et al., 2023).
Therefore, individuals with BEN/DANC exhibit homozygosity for the SNP of the DARC/ACKR1 gene called rs2814778. DARC is broadly expressed on RBCs, kidney, brain, and endothelial cells but is not found on leukocytes. The DARC protein on RBCs is expressed as a transmembrane glycoprotein known as the Duffy blood group antigen (Fy).
This protein acts as a “cytokine sink,” binding to inflammatory cytokines. As a result, Duffy-null RBCs are less effective at attracting neutrophils into the periphery. Additionally, the SNP rs2814778 affects hematopoiesis and results in phenotypically distinct neutrophils that readily leave the periphery (Merz et al., 2023).
Another mechanism is a rapid egress of activated DARC-null neutrophils from circulation to the spleen. Neutrophil function remains normal, while in DARC-null HIV-1 patients with BEN/DANC, a lack of recurrent and/or serious infections is noted (Gay et al., 2023). Figure 2 summarizes the genetic mechanism of BEN/DANC.
CASE STUDY CONTINUED
Benign hematology, also called classical hematology, was consulted to evaluate the neutropenia of nonmalignant etiology. A referral was expedited to prevent a long interruption of treatment. The results in the following week showed that the peripheral blood smear was normal.
Cobalamin, copper, and serum MMA were normal. The RBC antigen genotyping test or RBC antigens molecular methods test confirmed the Duffy-null status associated with BEN/DANC by evidencing the Duffy-null RBC Fy(a-b-) phenotype.
Table 1 displays the RBC antigen genotyping test result of this patient and shows both Fya- and Fyb- phenotype, which are evidence of BEN/DANC status.
TREATMENT
The benign hematologist recommended resuming cancer treatment since the patient was asymptomatic and the BEN/DANC status was confirmed. They also recommended for as-needed use of granulocyte colony-stimulating factor (G-CSF) if neutropenia reached grade 4 with ANC less than 0.5 × 109 cells/L or 500/µL.
DISCUSSION: AWARENESS AND IMPACT OF BEN/DANC
In this case, the cancer therapy was interrupted for 1 week while the neutropenia was evaluated. However, if the patient's BEN/DANC status had been previously confirmed, the therapy interruption would have been avoided. Table 2 highlights ways in which BEN/DANC has implications for patient care, with instances of treatments being held, delayed, or dose reduced.
IMPLICATIONS FOR ONCOLOGY ADVANCED PRACTITIONERS
The success of cancer treatments relies a great deal on timeliness and efficacy of therapeutic agents. Delays, interruptions, or dose reductions trigger concern for the negative effects on patient outcomes. Clarifying BEN/DANC status during the initial cancer evaluation will strengthen evidence-based clinical practice that fosters population-based, patient-centered care and enhance the oncology care paradigm.
Hantel and colleagues (2024) and Morrissey (2024) highlighted that the BEN/DANC status has become a source of discrimination in cancer research and care practices.
The first step in improving this situation is to promptly clarify the BEN/DANC status of new cancer patients within this specific population, as outlined in Figure 3 of the new algorithm titled “Algorithm for Clarification of the BEN/DANC Status to Prevent Disruptions During Cancer Treatments.” Documenting the BEN/DANC status in the medical record will serve as a constant reminder to the clinical team to remain vigilant in preventing therapy disruptions that can hinder the optimization of oncology care for this patient population.
CONCLUSION
For a certain population, a cancer diagnosis can be significantly impacted by an inherited classical hematologic condition known as BEN/DANC. Patients with BEN/DANC receiving cancer therapies often experience delays, interruptions, dose reductions, exclusion from clinical trials, and inaccurate assessments of adverse events and remission status due to reference ranges based on ANC levels of individuals without BEN/DANC. The lack of awareness and the time required to evaluate the cause of neutropenia can disrupt lifesaving treatments.
A solution exists through the prompt clarification of BEN/DANC status during the initial cancer evaluation. The newly designed algorithm (Figure 3) will aid oncology advanced practitioners (APs) in preventing therapy disruptions and foster a population-based, patient-centered approach for cancer patients with BEN/DANC. Oncology APs, who are at the forefront of practice changes, can incorporate the use of the algorithm in Figure 3 into their practice.
When combined with the actions outlined in Figure 4, this approach will enhance oncology care for patients with BEN/DANC. It is cost-effective, timesaving, and therapy-optimizing to clarify cancer patients' BEN/DANC status. Oncology APs are gaining a tool that facilitates the prevention of therapy disruptions for certain patients with cancer.