Febrile neutropenia in patients with Duffy-null–associated neutrophil counts and multiple myeloma or AL amyloidosis

TO THE EDITOR:

Individuals with Duffy-null–associated neutrophil counts (DANCs) have a lower peripheral absolute neutrophil count (ANC) and do not express the Duffy antigen (Fy) on red blood cells. This biological variation is related to a homozygous single nucleotide polymorphism in the promoter region of a gene (atypical chemokine receptor 1) detected in individuals with ancestry from sub-Saharan Africa and the Arabian Peninsula. DANC is associated with preserved myeloid maturation and neutrophil function, without increased incidence of infection.^1-4 In the United States, the prevalence of DANC is ∼70% in Black individuals and <1% in White individuals.^3,5 Individuals with DANC have different degrees of neutropenia, with ∼10% having baseline ANC ≤1500 ×10⁹/L.³ 

The impact of DANC on adverse events such as febrile neutropenia in patients with hematologic malignancies is largely unknown. The Common Terminology Criteria for Adverse Events define grade 2 neutropenia as an ANC <1500×10⁹/L and febrile neutropenia as a temperature >38.3°C with an ANC <1000×10⁹/L.⁶ These definitions are potentially inappropriate for individuals with DANC. Here, we evaluate the impact of Duffy antigen status on the incidence of febrile neutropenia and chemotherapy dose reductions in patients treated for multiple myeloma (MM) or systemic light chain (AL) amyloidosis at the largest safety net hospital in New England, United States.

We conducted a retrospective study of patients treated for MM or AL amyloidosis at the Boston Medical Center (BMC) between 06 January 2020 and 06 January 2023. Because all patients treated with daratumumab undergo red blood cell phenotyping before the first dose per BMC institutional standard, daratumumab therapy was selected as an inclusion criterion. Demographics and clinical characteristics; Duffy antigen status, ANC; diagnosis and treatment; antibiotic and IV immunoglobulin (IVIG) supplementation, treatment modifications, and incidence of febrile neutropenia (excluding during stem cell transplantation [SCT] pre-engraftment). Data were extracted from electronic medical records by an information technology specialist and manually validated by 3 independent clinicians for accuracy; any novel information from manual validation was reviewed by another reviewer. The BMC Institutional Review Board approved this research.

Among the 136 patients identified, the mean age at chemotherapy initiation was 65 (±11.3) years, 62 of 136 (46%) were female, and the most common self-identified race/ethnicity was non-Hispanic Black (74/136 [54%]), followed by non-Hispanic White (34/136 [25%]), Hispanic (18/136 [13%]), and other (10/136 [7%]). DANC was present in 52 of 136 patients (38%), of whom 48 of 52 (92%) self-identified as Black (Table 1; supplemental Table 1). The diagnoses included MM (94/136 [69%]), AL amyloidosis (34/136 [25%]), MM-associated AL amyloidosis (5/136 [4%]), and other plasma cell disorders (3/136 [2%]). Among patients with MM, the distribution of stage did not differ according to Duffy status.

Baseline ANCs were lower in individuals with DANC (Figure 1): ANC <1800×10⁹/L (lower limit of normal at BMC) was more frequent in patients with DANC (17/50 [34%]) than in those without DANC (8/79 [10%]; Table 1). ANC <1000×10⁹/L was observed in 3 patients with DANC.

Although receiving cancer-directed therapy (excluding during SCT), more patients with DANC (44/52 [85%]) had neutropenia than those without DANC (39/82 [48%]). Patients with DANC without baseline neutropenia had a higher frequency of neutropenia during treatment (25/33 [76%]) than those without DANC (29/71 [41%]). No occurrences of febrile neutropenia were observed in patients with DANC (0/52 [0%]) compared with 7 of 84 (8%) of patients without DANC. Antibiotics (prophylactic and therapeutic) were prescribed in most patients (111/136 [82%]), without differences by Duffy status. Similarly, IVIG supplementation (4/136 [3%]) did not differ by Duffy status (Table 1).

Upfront initiation of dose-reduced immunomodulatory drugs (IMiDs; pomalidomide <4 mg or lenalidomide <25 mg in MM or <15 mg in AL amyloidosis per BMC institutional standard) was observed in 62 of 106 patients (59%) and did not differ by Duffy status in multivariable-adjusted analysis (supplemental Table 2). During treatment, dose reductions or delays due to any cause were frequent (95/136 [70%]) but did not differ by Duffy status: 37 of 52 patients (71%) with DANC vs 58 of 84 patients (69%) without DANC (Table 1). Among the 28 patients who underwent SCT, neither the average number of stem cells collected nor the mobilization regimens differed by Duffy status (supplemental Table 3).

Our cohort’s high proportion of patients with DANC (52/136 [38%]) reflects the diverse patient population treated at BMC, the largest safety net hospital in New England, United States: 92% of patients with DANC were Black and most patients with MM were Black (59%), consistent with known data that MM disproportionately affects Black people.⁷ The presence of DANC may affect the clinical care of Black patients with MM, as many drugs, including IMiDs, require ANC monitoring and dose adjustments for specific (currently universal) ANC cutoffs.⁸ Further, strict universal ANC cutoffs likely contribute to racial/ethnic disparities in clinical trial enrollment, with Black patients with MM are less likely to be eligible for trials than patients of other ethnicities/races.⁷ 

Using the current universal grading of neutropenia by the Common Terminology Criteria for Adverse Events, 78 of 136 (57%) of our cohort experienced grade 2 neutropenia during treatment; yet 21 of 126 (15%) had a baseline ANC within the range for grade 2 neutropenia. Despite higher frequencies of baseline (including ANC <1000×10⁹/L in 3 patients) and treatment-related neutropenia, patients with DANC did not have a higher incidence of febrile neutropenia or treatment reductions/interruptions. Although treatment modifications for any reason are common in patients with MM or AL amyloidosis and were observed in ∼70% of our cohort, this was not impacted by Duffy status. The clinical impact of dose reductions is unknown and requires further investigation. Duffy status was also not associated with differences in IMiD upfront-dose reductions, stem cell mobilization or collection, or supportive treatments (antibiotics or IVIG supplementation). Our data add to the growing literature that a strict universal ANC cutoff may be less applicable to patients with DANC, as it is not clear if lower ANCs affect clinical outcomes.

Our study has several limitations, including being a relatively small, retrospective, single-center study. Because universal Duffy testing is not routinely conducted, we restricted our study sample to patients who received daratumumab, which could reflect an inclusion bias; however, the current standard of care for first- and second-line treatments for patients with MM and AL includes daratumumab. We only captured febrile neutropenia episodes requiring hospital admission but may have missed additional instances of infectious complications managed within other health systems. Additionally, we used antibiotic prescriptions as a surrogate marker for infections, and could not systematically retrospectively define their use as prophylactic or therapeutic. Lastly, as a center with a high proportion of patients with DANC, institutional knowledge and practices may have introduced a positive bias, resulting in fewer dose reductions and treatment interruptions. Despite these limitations, our findings address an area of unmet need: understanding the impact of Duffy status on clinical outcomes, including febrile neutropenia, in patients with malignancies.

To our knowledge, this is the first study focusing on the impact of Duffy status on MM or AL amyloidosis treatment. Further prospective studies evaluating the impact of the Duffy status on responses to therapy, treatment complications, and progression-free and overall survival are needed. Our data suggest that clinicians should routinely consider evaluating the Duffy status in patients with hematologic malignancies and neutropenia. The inclusion of Duffy status in clinical trials should be considered to allow different metrics by Duffy status, including enrollment criteria (eg, ANC cutoffs) and unbiased subgroup analyses of outcomes.

Acknowledgment: The authors acknowledge Matthew Lefebvre for his assistance with data collection.

Contribution: M.A. and R.S. designed research, performed research, analyzed data, and wrote the manuscript; K.B. performed research, analyzed data, and contributed to writing the manuscript; F.A. and J.P. designed research, performed research, and contributed to writing the manuscript; A.S. performed research and contributed to writing the manuscript; and all authors contributed to writing the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Raphael Szalat, Section of Hematology & Oncology, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA, 02118; email: rszalat@bu.edu.