Clinical implications and prevalence of benign ethnic neutropenia (BEN) in lymphoma patients of middle eastern ethnicity

Abstract

Abstract Background Benign ethnic neutropenia (BEN) commonly affects patients of African and Middle Eastern descent, and does not represent a true neutropenic state. Patients with BEN have the Duffy-null phenotype on red cells, which has been used as a surrogate marker for diagnosis. There is evidence that cancer patients with BEN are not at increased risk of infection after chemotherapy when compared to other patients, and lower neutrophil thresholds for chemotherapy have been suggested to be safe. Aims The primary aim of this study was to assess the prevalence of BEN among lymphoma patients of Middle Eastern ethnicity using Duffy antigen phenotyping on red cells. The secondary aims were to study treatment delays due to neutropenia and infectious complications in these patients. Methods We conducted this retrospective study at a referral oncology center in Bahrain after obtaining IRB approval. We included 153 Hodgkin (HL) and diffuse large B cell lymphoma (DLBCL) patients treated from January 2018 to June 2023. We identified patients who at the time of presentation had neutropenia (absolute neutrophil count [ANC] of <1.5 ×103/µL) or leukopenia (WBC count less than 4 ×103/µL) without any identifiable secondary causes. Vitamin B12 and folate assays, ANA/auto-Ab screening, peripheral smear and Duffy phenotyping on red cells were part of the standard work-up for neutropenia. Patients with missing Duffy phenotyping results at baseline were subsequently screened (for the purpose of the study) for red cell phenotype using the commercially available anti-Fya and anti-Fyb reagents. Patients with lymphoma infiltration of bone marrow were excluded from diagnosis of BEN. Patients with Duffy-null phenotype and no identifiable secondary causes of neutropenia were presumed to have BEN. Clinical details studied included past history of frequent infections, family history of neutropenia, drug history, treatment delays due to neutropenia, filgrastim responsiveness, and occurrence of febrile neutropenia. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method and univariable and multivariable Cox regression analyses were performed to assess impact of prognostic variables and BEN on survival. Results Of 153 (77 HL and 76 DLBCL) patients, 23 (15%) had a presumed diagnosis of BEN. In the BEN sub-group, none had past history of frequent infections. Family history of neutropenia was elicited in 3 patients. The median WBC count at diagnosis was 3.3×103/µL (range, 2.2–3.9×103/µL) and the median ANC was 1.4 × 103/µL (range 0.7─1.5 × 103/µL).Bone marrow results at baseline were available in 5 patients and showed normal hematopoiesis. Treatment was delayed due to low ANC in 59% of patients, the median ANC at which treatment was delayed was 0.4×109/µL (range 0.3-0.8 ×103/µL). Fifty percent of BEN patients received filgrastim (mostly in the DLBCL group), either prophylactically or for worsening of neutropenia post-treatment, and all were filgrastim responsive. Only two patients had neutropenic fever which recovered without complications. The median follow-up for OS was 2.4 years. The 2-yr OS were 100% and 82.5% for HL and DLBCL patients respectively, and the corresponding 2-yr EFS were 81.6% and 70.1%. In the DLBCL group, receipt of R-CEOP regimen (compared to R-CHOP) and high IPI scores were significantly associated with inferior OS and EFS, while BEN status had no impact on survival. In the HL group, none of the variables assessed like age, stage, BEN status, clinical parameters or chemotherapy regimen had an impact on OS or EFS. Summary Ethnic neutropenia is prevalent among lymphoma patients in Bahrain. Duffy phenotyping can be used in place of more invasive tests like BM biopsy to identify these patients. Treatment delays due to the apparent neutropenia are common, however response to filgrastim is universal, and febrile neutropenia episodes are rarely seen. There was no adverse impact of BEN on the survival of lymphoma patients on chemotherapy. This study is of particular relevance in populations with a high prevalence of ethnic neutropenia. Since BEN patients are not at increased risk of infection, larger studies can potentially identify unique neutrophil count thresholds for holding chemotherapy in these patients to avoid compromising therapy. This can have far-reaching implications for the management of oncology patients of these ethnicities.