Diagnosis of Duffy Null-Associated Neutropenia During Chemotherapy

Duffy-null-associated neutrophil count (DANC), formerly known as “benign ethnic neutropenia,” refers to a reduced absolute neutrophil count (ANC) observed in individuals homozygous for a variant in the promoter of the atypical chemokine receptor 1 (ACKR1) gene. This physiological condition, prevalent among individuals of African and Middle Eastern descent, is characterized by neutropenia without an associated increased risk of infection. A recently published perspective article in the New England Journal of Medicine highlights structural inequities in oncology research and care associated with DANC, including exclusion from clinical trials, inappropriate dose modifications, and misaligned remission criteria, all of which undermine equitable cancer care [1]. A recently published cross-sectional study showed that 54% of curative anticancer regimens for the five most common cancers modified doses or excluded patients with neutrophil counts within the DANC reference range (RR) [2]. The authors advocate for personalized oncology practices, such as revising clinical trial eligibility criteria, tailoring dose adjustments, and re-evaluating adverse effect and remission metrics, while outlining short, medium, and long-term action plans to address these disparities. Echoing the sentiments of this article, we describe the case of a young, African-American patient undergoing chemotherapy for cervical cancer, who had neutropenia disproportionate to chemotherapy leading to the diagnosis of DANC after three cycles of chemoimmunotherapy. Following the diagnosis of DANC, an underreported and frequently missed condition, subsequent chemotherapy cycles were continued with a lowered ANC threshold (from 1500/mm³ to 1000/mm³) and growth factor support, successfully maintaining cancer remission for nearly a year. As the development of novel cancer therapies continues at the rapid pace and efforts to eliminate systemic racism in healthcare gain momentum, this case serves as a vital reminder to consider DANC when evaluating neutropenia in patients of African descent. This real-life scenario highlights the urgent need for greater awareness of DANC and calls for a long-overdue, systemic change to better serve patients with this physiological condition.

A 40-year-old African–American female with a past medical history of human papillomavirus 18 positive high-grade cervical squamous intraepithelial lesion presented with intermittent post-coital vaginal bleeding ongoing for a year. Laboratory investigations revealed hemoglobin of 10.7 g/dL, white blood cell (WBC) count of 6100/mm³ [RR: 4000–11 000/mm³], absolute neutrophil count (ANC) of 3600/mm³ [RR: 1800 to 8000/mm³] and normal platelet count. Magnetic resonance imaging (MRI) of the pelvis showed an anterior uterine exocervical mass measuring 5.0 × 3.2 × 3.3 cm with probable extension to the anterior vaginal fornix. Cervical biopsy and endocervical curettage confirmed high-grade cervical carcinoma with clear cell features. Positron emission tomography/computed tomography (PET/CT) scan showed an intensely avid cervical mass, consistent with known cervical cancer without evidence of adenopathy or metastatic disease. She was ultimately diagnosed with stage IIIB high-grade cervical carcinoma. She was started on definitive chemoradiation with weekly cisplatin (40 mg/m²). MRI pelvis done at treatment completion showed no residual disease. Bloodwork done at the completion of treatment showed WBC count of 2600/mm³ and ANC of 1600/mm³.

Unfortunately, surveillance PET/CT done 1 year after treatment completion showed abnormal activity in a soft tissue mass located in deep right pelvis and a lymph node along left pelvic wall evidencing local disease recurrence. A regimen of carboplatin [area under the curve (AUC): 5], paclitaxel (135 mg/m2), pembrolizumab (200 mg), and bevacizumab (15 mg/kg) every 3 weeks for six cycles was recommended, followed by maintenance pembrolizumab/bevacizumab for a total of 35 cycles per KEYNOTE-826 trial. Paclitaxel was dosed at 135 mg/m² instead of 175 mg/m2 as used in trials due to history of neuropathy. Pertinent details related to six chemotherapy cycles are illustrated in the table below (Table 1). With cycles 1 and 2 of chemotherapy, ANC nadired at 1000/mm³ (grade 3 neutropenia) on days 34 and 27, respectively. In both cycles, neutropenia persisted for more than 10 days, qualifying as prolonged neutropenia. Chemoimmunotherapy was delayed by 16 days in cycle 2 due to prolonged, grade 3 neutropenia consistent with NCCN guidelines. Disproportionate neutropenia prompted Duffy-null testing through red blood cell (RBC) phenotyping. An ongoing workup for DANC resulted in a further 16-day delay for cycle 3. Bone marrow biopsy was initially considered but deferred after the diagnosis of DANC. ANC threshold was lowered from 1500/mm³ to 1000/mm³ for subsequent cycles. After completing a total of 14 cycles of treatment (six cycles of chemoimmunotherapy followed by eight cycles of maintenance pembrolizumab/bevacizumab) uneventfully with growth factor support and without any infectious complications, she was noted to have progression of disease. She is currently undergoing treatment with tisotumab vedotin, an antibody-drug conjugate.

After DANC diagnosis, on further questioning, she denied a history of recurrent or unusual infections. On review of her historical blood counts a decade ago, her WBC count was 4900/mm³ and ANC was unavailable. She was 10 weeks pregnant at this time. Another blood work obtained at the time of a regular primary care visit showed a WBC count of 6300/mm³ with ANC unavailable. Normal ANC at the time of initial presentation with vaginal bleeding was attributed to be due to a stress response masking the neutropenia associated with the DANC phenotype.

DANC, formerly known as “benign ethnic neutropenia”, refers to ANC in individuals who are homozygous for a variant in the promoter of the ACKR1 gene. Homozygosity in this promotor variant leads to loss of gene expression resulting in erythroid Duffy-null [Fy(a-b-)] phenotype. The mechanism of neutropenia in this condition is not completely understood. Despite neutropenia, there is no increased risk of infections with normal bone marrow cellularity and maturation [3]. The geographic distribution of DANC mirrors that of malaria. Since ACKR1 is utilized by Plasmodium vivax to gain access to RBCs, Duffy-null individuals are protected from vivax malaria infections [4]. Testing for DANC can be done using genotyping or RBC phenotyping using serologic testing [5].

In a cross-sectional study evaluating the impact of Duffy status on ANCs in a healthy population of individuals self-identifying as Black or African American (n = 120) presenting for non-urgent care visits at a single primary care center, complete blood count with differential and phenotyping for Fy^a and Fy^b were performed. Two-thirds of Black individuals (n = 80) were found to have the Duffy-null phenotype. Out of 80 individuals with the Duffy-null phenotype, eight individuals (10%) had an ANC of < 1500 cells compared to no Duffy non-null individuals. A statistically significant difference in ANC was found between Duffy-null and Duffy non-null individuals (median, 2820 vs. 5005; p < 0.001). A statistically significant difference was also found between the Duffy-null ANC median and the reference median (p < 0.001) [3].

Failing to recognize DANC can lead to patient harm due to reduction in chemotherapy dose and delays in chemotherapy administration, potentially compromising treatment efficacy. Patients could also be subjected to unnecessary growth factor support for neutropenia. Although most side effects from pegfilgrastim are minor and manageable, serious side effects like splenic rupture and sickle cell crises have been reported. These side effects, especially seen in patients with homozygous sickle cell disease, are especially relevant given sickle disease is more prevalent in patients of African descent. In our patient, prolonged and severe neutropenia after chemoimmunotherapy led to the diagnosis of DANC after three cycles. Bone marrow biopsy was initially considered but later withheld after the diagnosis of DANC was established. A retrospective study showed that among African–American individuals who underwent bone marrow biopsy for neutropenia, 97% had Duffy-null phenotype, and 97% of these Duffy-null individuals had normal bone marrow biopsy results [6]. Performing bone marrow biopsy would have subjected our patient to an unnecessary, low-yield procedure with its inherent complications.

A number of teaching points can be gleaned from our case. Firstly, testing for DANC should be considered in patients of all ancestries, especially those of African and Middle Eastern descent with unexplained, severe, and prolonged neutropenia after chemotherapy, even if their pre-chemotherapy ANC is normal. Given the high prevalence of DANC and low cost of testing, we propose that all patients of African descent undergoing oncologic care should be tested for DANC at the outset. Secondly, lack of severe baseline neutropenia should not dissuade clinicians from considering DANC. Although Duffy null status is highly prevalent and can be seen in over 60% of African-American individuals [7], not all individuals with the Duffy-null phenotype have an ANC < 1500. In a cross-sectional study, only 10% of those with this phenotype had an ANC below 1500. Our patient likely belonged to the majority of Duffy-null individuals who present with an ANC > 1500 [3]. Thirdly, ANC should be interpreted contextually and a careful chart review and history taking are important. Although our patient did not have a lot of historical ANCs to review, it is interesting to note her previous “normal” ANC was in the setting of a stressed physiological state (ongoing vaginal bleeding) leading to de-margination of neutrophils. Unexplained, severe, and prolonged neutropenia after chemotherapy could be due to the combined effects of concurrent chemoradiation to the pelvis and subsequent chemotherapy, which may have depleted bone marrow reserves, ultimately unmasking the neutropenia. Lastly, after diagnosing DANC, lowering of ANC threshold for chemotherapy should be considered on a case-by-case basis after a thorough risk–benefit discussion. Short, medium, and long-term strategies outlined in this recent NEJM article can be taken as guidance until clearly defined, evidence-based thresholds are established [1]. This approach could help prevent unnecessary delays and interruptions in treatment, especially for curable malignancies. In conclusion, there is a pressing need for increased recognition of this condition and development of a Duffy-null–specific ANC reference range in order to avoid pathologizing a physiological condition.

Z.K.: involved in conception and design, collected the data, drafted the manuscript, and finally approved the version to be published. N.J.R., R.J.D., and P.K.: revised the manuscript and finally approved the version to be published.

This case report was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Informed consent was obtained from the patient for the publication of this report, including relevant clinical details and any accompanying images. All efforts have been made to maintain patient anonymity, and no identifiable information has been disclosed.

Patient consent was obtained.

The authors declare no conflicts of interest.