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DENIED! BEN AND THE FIGHT FOR CHEMO

By Godswill Boni, PharmD

Benign ethnic neutropenia (BEN) is an inherited condition in which the absolute neutrophil count (ANC) is consistently below 1500 in a microliter of blood with no increased risk of infection. Commonly seen in individuals of African, Middle Eastern, and West Indian descent, BEN is not widely known among physicians, often resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals and, in some cases, denying them necessary treatment such as chemotherapy. 

Before I discuss the relationship between BEN and chemotherapy, let me give a little background about neutrophil and neutropenia, a common side effect of chemotherapy used for cancer treatment, such as breast cancer.

General information about neutrophils

Neutrophils are essential components of the white blood cells that play a critical role in the immune system and in fighting infection. Neutrophil level is measured in complete blood cell count. It is reported as the number of neutrophils in a microliter of blood and classified as follows:

  • Between the level of 2000 and 7500 = Normal
  • Below 2000 = Neutropenia

Image by sakurra

There are three degrees of neutropenia:

  • ANC of 1000 to 2000 = Mild (meaning a minimal risk of infection)
  • ANC of 500 to 1000 = Moderate (associated with a moderate risk of infection)
  • ANC less than 500 = Severe (indicating a high risk of infection)

Symptoms of neutropenia include:

  • Extreme tiredness 
  • A fever, which is a temperature of 100.5°F (38°C) or higher
  • Chills or sweating
  • Sore throat, sores in the mouth, or a toothache
  • Abdominal pain
  • Pain or burning when urinating, or urinating often
  • Diarrhea or sores around the anus
  • A cough or shortness of breath
  • Any redness, swelling, or pain (especially around a cut, wound, or catheter)
  • Unusual vaginal discharge or itching

What can reduce or increase the neutrophil level?

Several medical conditions and treatments can lower neutrophil levels, including infections such as HIV, sepsis, hepatitis, cancer, cancer treatment, e.g., chemotherapy, and blood and blood marrow disorders. 

The neutrophil level can be increased by treatment such as granulocyte colony-stimulating factor, often called GCSF injections, and used to boost neutrophil level before stem cell donation and transplant or after the chemotherapy cycle. In addition, some research suggests that diet and supplements can increase neutrophil levels, but no proven research evidence exists. 

Clinically, the neutrophil level is considered low when the count is below 2000. Conversely, the risk of infection increases as the neutrophil level decrease. Therefore, infection associated with neutropenia is a serious concern for patients receiving chemotherapy. Generally, patients can receive chemotherapy if their neutrophil level is between 1000 and 2000 (a level considered low risk of infection); in most cases, a minimum of 1500 is required. Below 1000, chemotherapy is generally delayed, dosage reduced, or denied. 

However, there are some patients with naturally low neutrophil levels below 1500. These individuals are said to have BEN. They are genetically predisposed to low neutrophil levels, but they are not at any higher risk of infection compared to individuals with an average neutrophil level of between 2000 and 7500.

Herein lies the challenge of treating patients with BEN because what is considered a ‘normal’ neutrophil level does not apply to them. Interestingly, guidelines on which neutrophil level of between 1000 and 2000 is required for chemotherapy are based on clinical research that often excludes the BEN population. So, what is the consequence of treating a disease such as breast cancer with chemotherapy for the population with BEN?

Benign ethnic neutropenia

Image by shidlovski

Benign ethnic neutropenia is characterized by chronically low neutrophil levels below 1500. Clinically, patients with BEN are at no increased risk of infection. However, many physicians are unfamiliar with this benign condition despite its worldwide prevalence.

BEN becomes challenging in the setting of some diseases and their treatment. For example, it can impact the treatment pathway for chemotherapy and mental health medication such as clozapine; both require a neutrophil count above 1500 before treatment is given. As a result, patients needing chemotherapy or clozapine are at risk of being unnecessarily denied treatment or delayed or the dosage reduced, which in some cases only results in poor patient outcomes. 

Impact of BEN on cancer treatment  

During chemotherapy treatment, the infusion is generally halted if neutrophils fall below 1500 and remain suspended until neutrophils rise to 1500 or above. The consequence is perpetual start-stop chemotherapy, risking suboptimal disease treatment and cancer spread. This is not a theoretical scenario but one shared by a cancer patient of African descent. 

The patient commented that chemotherapy was denied due to her persistently low neutrophil count below 1500. The patient said her oncologist admitted not being familiar with BEN and planned her chemotherapy treatment using the guideline-recommended neutrophil count of at least 1500. Unfortunately, the guidelines were developed for a specific population that did not include people with BEN! However, the patient noted a comment made by a consultant haematologist more familiar with BEN, stating, “it’s a tall order to demand that your neutrophil levels reach 1500 before treatment when it is clear that for years you have functioned perfectly adequately at a range between 55 and 1920, with no evidence of a greater risk of infection.”

But where does the 1500 neutrophil count threshold come from before chemotherapy can be given? Why is this level considered the norm for all ethnic groups? The consequence is far-reaching because inclusion criteria for clinical trial participation often require a neutrophil count of 1500 or above. Guidelines are developed from the results of these trials that exclude the population with BEN; therefore, the guideline recommendations may not apply to them. Indeed some studies have raised this very question – what is normal neutrophil count, and can neutrophil level be a barrier to clinical trial participation? 

Could this rule out a population of patients who can provide valuable data but are traditionally overlooked because they did not make the arbitrary neutrophil count cut-off of 1500? And it gets worse because these patients are then denied treatment, have their treatment delayed, or the dose reduced because of their genetic predisposition to BEN – with potentially worse clinical outcomes. Perhaps the reported outcomes statistics bear some correlation to this assertion. According to the American Cancer Society, women of African descent have a 4% lower incidence rate of breast cancer than Caucasian women but a 40% higher breast cancer death rate. Could BEN be a contributing factor? There is a need for more research, specifically focused on patients of African descent and other ethnic populations with BEN. 

So, should a suspicion of BEN  be a starting point for clinical consideration if a patient presents with no indication of infection, rather than an end conclusion after a battery of tests creating a significant delay in necessary life-saving treatment? For example, in the case of breast cancer, triple negative presentation currently has to be treated only by surgery and chemotherapy. However, a delay of even a few weeks and disruption to treatment is too long, rendering chemotherapy treatment less effective.

I spoke about BEN with Dr. Emmanuel Mduma, a Clinical and Radiation Oncologist based in Dar-es-Salaam, Tanzania. Dr. Mduma admitted that he had not seen benign ethnic neutropenia in his practice. He only sees it in the literature and has not managed a patient with such a condition. He admitted, “It’s either we are not good at diagnosing it, or it’s very rare.” 

This warrants sensitization of health care professionals in Africa and the diaspora about BEN among people of African descent and should not be a reason to deny treatment such as chemotherapy. 

There is a need for CME/CPD for clinicians focused on BEN to have the confidence to treat patients with BEN who have no other indication of a greater risk of infection. Collaboration between oncologists and heamtologists is essential to the comprehensive approach to individualized patient care central to evidence-based practice.

What is the way forward?

Here are my thoughts:

1) More clinical knowledge about BEN as this variant of normal. This knowledge can be achieved through CME/CPD, and multidisciplinary discussion (e.g., haematology and oncology coming together in the case of cancer treatment (e.g., chemotherapy), or haematology and mental health practitioners in the case of administering medication related to managing mental health (e.g., clozapine) were neutrophil levels need to be considered. 

2) BEN being at the forefront of consideration if there are no other indications of a history of infection/illness or increased hospitalisation.  

3) Renaming BEN, so it is not seen as a disorder but a variation of normal for some ethnic groups.  

Bottom line

A neutrophil level below 2000 microliter of blood is classified as neutropenia and is generally associated with an increased risk of infection. Some individuals have chronically low neutrophil levels below 1500 with no increased risk of infection. These individuals are said to have BEN, commonly seen in individuals of African, Middle Eastern, and West Indian descent. However, BEN is not widely known among physicians, often resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals. BEN becomes challenging in the setting of some diseases and their treatment. For example, patients needing chemotherapy or clozapine are at risk of being unnecessarily denied treatment or delayed or the dosage reduced, which in some cases only results in poor patient outcomes. Education and awareness about BEN in some populations may improve clinical outcomes.

Where available, following the Ministry of Health guidelines in your local setting is advised.

Godswill Boni, PharmD, is a multi-talented pharmacist who loves health blogging and medical writing. You can reach him here.  

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