Low White Blood Counts (Neutropenia)

Overview

A low white blood cell count or “neutropenia” is a condition characterized by abnormally low levels of neutrophils in the circulating blood. Neutrophils are a specific kind of white blood cell that help prevent and fight infections. The most common reason that cancer patients experience neutropenia is as a side effect of chemotherapy. Chemotherapy-induced neutropenia increases a patient’s risk of infection and disrupts cancer treatment. Fortunately, neutropenia can be prevented. The prevention of neutropenia allows patients to receive their scheduled treatment and reduces the risk of infection and hospitalization. Currently, the two drugs approved by the Food and Drug Administration for the prevention of chemotherapy-induced neutropenia are Neupogen® (filgrastim) and Neulasta® (pegfilgrastim), a longer lasting drug requiring less frequent injections.

• What is neutropenia?
• Why is chemotherapy-induced neutropenia important?
• How is neutropenia diagnosed?
• Can neutropenia be prevented?
• What treatments are administered to prevent neutropenia?
• What are the strategies to improve treatment?

What is neutropenia?

Neutropenia is a condition characterized by abnormally low blood levels of infection-fighting neutrophils, a specific kind of white blood cell. Neutropenia increases your risk of bacterial and fungal infections.

The most common reason that cancer patients experience neutropenia is as a side effect of chemotherapy. Chemotherapy involves the use of drugs to destroy cancer cells. Chemotherapy works by destroying cells that grow rapidly, a characteristic of cancer cells. Unfortunately, chemotherapy also affects normal cells that grow rapidly, such as blood cells in the bone marrow, cells in the hair follicles, or cells in the mouth and intestines. Chemotherapy-induced neutropenia typically occurs 3-7 days following administration of chemotherapy and continues for several days before neutrophil levels return to normal. The type and dose of chemotherapy affects how low the neutrophil count drops and how long it will take to recover.

Infrequently, cancer patients may also experience neutropenia from other medications or as a consequence of their underlying cancer. When discussing the consequences and management of neutropenia, it is important to distinguish between chemotherapy-induced neutropenia and neutropenia resulting from other causes because they may be managed differently.

While receiving chemotherapy, you will frequently have your complete blood count (CBC) checked to determine whether you have enough neutrophils. Typically there are billions of neutrophils in the blood; however, certain chemotherapy drugs will lower the neutrophil count. When a doctor or nurse discusses CBC test results, they frequently refer to the "absolute neutrophil count" (ANC) or the number of neutrophils in the patient’s blood. A "low white blood count" is another common term used to describe a low neutrophil level in the blood. Fortunately, having a low level of neutrophils can be corrected.

Why is chemotherapy-induced neutropenia important?

Chemotherapy-induced neutropenia is important because it may:

• Increase your risk of life-threatening infection.
• Disrupt delivery of your cancer treatment, resulting in a change to the planned dose and time.

The fewer the neutrophils in the blood and the longer you remain without enough neutrophils, the more susceptible you are to developing a bacterial or fungal infection. Neutrophils are a major component of antibacterial defense mechanisms. As the neutrophil count falls below 1.0, 0.5, and 0.1 x 10⁹/L, the frequency of life-threatening infection rises steeply from 10% to 19% and 28%, respectively. If you develop a fever during neutropenia you may require treatment with intravenous antibiotics and admission to the hospital until the number of neutrophils in the blood returns to sufficient levels to fight the infection.

Ask your doctor how neutropenia can be prevented.

Another reason neutropenia is important is that, in some cases, it can be severe enough that your chemotherapy treatment may need to be delayed or dose reduced, which reduces some patients’ chance for cure. When you are treated with chemotherapy, it is for the purpose of destroying cancer cells in order to reduce symptoms from your cancer, prolong your survival or increase your chance of cure. The dose and time schedule of chemotherapy drugs administered have been scientifically determined to produce the best chance of survival or cure. If you develop neutropenia, your doctors may have to delay your treatment or reduce the doses of your chemotherapy until your neutrophil counts have recovered. Clinical studies have shown that, for certain cancers, reducing the dose of chemotherapy or lengthening the time between treatments lowers cure rates compared to full-dose, on-time treatment. Fortunately, there are strategies for the prevention of chemotherapy-induced neutropenia that have been proven to reduce the incidence of fever, infection, admission to the hospital and allow you to receive your treatment on schedule.

Who is at a higher risk for chemotherapy-induced neutropenia?

• Patients receiving chemotherapy that decreases the number of white blood cells
• Patients who already have a low white blood cell count, or who have previously received chemotherapy or radiation treatment
• Patients age 70 and older who may be at risk of more severe infection and longer hospitalizations
• Patients with other conditions affecting their immune system

How is neutropenia diagnosed?

A test called the complete blood count (CBC) is used to determine whether have neutropenia. The CBC measures the levels of the three basic blood cells: red, white, and platelets.

In the United States, the CBC is typically reported in the format shown below. If your blood counts fall outside of the normal range, which is shown in the “Reference interval” column, their values will be reported in the “Flag” column with an ‘L’ for low and an ‘H’ for high. The example CBC below shows that white blood cells are low.

Result: The result column shows counts that fall within the normal range.

Flag: The flag column shows counts that are lower ("L") or higher ("H") than the normal range.

Reference Interval (or Reference Range column: The reference interval shows the normal range for each measurement for the lab performing the test. Different labs may use different reference intervals.

White blood cells: White blood cells help protect individuals from infections. The above CBC report shows that the patient’s total white cell count is 1.5, which is lower than the normal range of 4.0-10.5. The low white cell count increases the risk of infection.

Differential: This portion of the CBC shows the counts for the 5 main kinds of white cells, either as percentages (the first 5 counts), or as the absolute number of cells (the second 5 counts).

Absolute neutrophil count: Neutrophils are the main white blood cell for fighting or preventing bacterial or fungal infections. In the CBC report, neutrophils may be referred to as polymorphonuclear cells (polys) or neutrophils. The absolute neutrophil count (ANC) is a measure of the total number of neutrophils present in the blood. When the ANC is less than 1,000, the risk of infection increases. The ANC can be calculated by multiplying the total WBC by the percent of polymorphonuclear cells. For example, this patient's ANC is 0.34, which equals the white blood cell count (1.5) times 23%.

Red blood cells: Red blood cells carry oxygen from the lungs to the rest of the body. The above CBC report indicates that the patient has a red cell count of 3.5, which is lower than the normal range of 4.70-6.10, and therefore, shown in the flag column.

Hemoglobin (Hb or Hgb): Hemoglobin is the part of the red cell that carries the oxygen. The above CBC report indicates that the patient's Hb count is 10.8, which is below the normal range of 14.0-18.0. The hematocrit (HCT), another way of measuring the amount of Hb, is also low. This means that the patient has mild anemia and may be starting to notice symptoms.

These three ranges will vary depending on age and gender. For women, they will be lower than those shown here. For example, the Hb reference interval for a woman is 12.0-16.0.

Platelets: Platelets are the cells that form blood clots that stop bleeding. The above CBC report indicates that the platelet count for this patient is normal.

Can neutropenia be prevented?

Chemotherapy-induced neutropenia can be prevented in most patients with the use of Neulasta® or Neupogen®, blood cell growth factors that increase your white blood cell production. Blood cell growth factors are naturally occurring substances called cytokines that regulate certain critical functions in the body. They are responsible for stimulating your cells in the bone marrow to produce more white blood cells. Chemotherapy drugs destroy many of the normal, rapidly dividing cells in the bone marrow, thereby reducing white blood cell production. With today’s technology, two blood cell growth factors, Neulasta® and Neupogen®, are manufactured in large quantities and can be administered to help the recovery of your bone marrow white blood cell production.

Prior to the development of blood cell growth factors, neutropenia commonly prevented patients from receiving their chemotherapy treatment at the full dose according to the treatment schedule. Moreover, bacterial and fungal infections, as well as fatalities from these infections were more frequent. Doctors have long known that, in certain malignancies, the administration of more chemotherapy kills more cancer cells, resulting in more patients being cured of their cancer. However, neutropenia has long prevented doctors from giving full-dose chemotherapy treatment.

What treatments are administered to prevent neutropenia?

The blood cell growth factors approved by the Food and Drug Administration for the prevention of chemotherapy-induced neutropenia are Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). Neupogen® has been extensively studied and used for the treatment of chemotherapy-induced neutropenia since 1991. Neulasta® was approved by the FDA in 2002. Neulasta® helps the bone marrow create more neutrophils, which are crucial to the body’s ability to fight infection. With acceptable neutrophil counts, patients are also more likely to stay on their chemotherapy schedule as originally planned.

Multiple clinical trials have shown that Neulasta® and Neupogen® reduce the severity and duration of neutropenia associated with many kinds of chemotherapy regimens. By reducing the duration and severity of neutropenia, Neupogen® has been shown to decrease a patient’s risk of fever and admission to the hospital for treatment of neutropenic fever. The drawback of Neupogen®, however, is that it must be administered daily. In an effort to address the daily dose requirements of Neupogen®, researchers developed Neulasta®. Neulasta® may be administered as a single dose for each chemotherapy cycle. In two clinical trials, a single dose of Neulasta® has been proven to be as effective as an average of 11 daily injections of Neupogen® for the management of neutropenia.[1][2] The most common side effect you may experience with Neulasta® is aching in the bones and muscles. If this happens, it can usually be relieved with a non-aspirin pain reliever, such as acetaminophen. It is also possible to have an allergic reaction to Neulasta®.

Use of Neupogen® and Neulasta® has also been shown to increase the likelihood that patients will receive their chemotherapy according to the treatment plan. Neulasta® is generally well tolerated, with minimal side effects. Approximately 1 of 4 patients treated will experience some mild aching or discomfort in their bones. Symptoms persist only while being used and can typically be treated with non-narcotic analgesic medicines. To learn more or to read about the results of specific clinical trials evaluating Neulasta® for the treatment of chemotherapy-induced neutropenia, go to www.neulasta.com.

Given the option, most patients would prefer to take steps to help protect themselves against infection caused by neutropenia, rather than deal with the problems cause by an infection after it develops. However, on average, fewer than 10% of patient receive protection from infection at the beginning of their chemotherapy.[3] Yet up to half of patients receiving chemotherapy develop dangerously low white blood cell counts, potentially placing them at risk of life-threatening infections.[4] That’s why patients should ask their doctor about treatment with an approved blood cell growth factor.

What are the Strategies to Improve Treatment?

The reduction in the frequency and severity of neutropenia and its associated complications has resulted from scientists developing a better understanding of the basic biology of bone marrow blood cell production and from participation in clinical trials designed to evaluate strategies directed at reducing neutropenia and its complications. Currently, there are several areas of active investigation aimed at improving the prevention and management of neutropenia.

Peripheral blood stem cells: Stem cells responsible for the production of neutrophils can be collected in large quantities from the peripheral blood. Delivery of peripheral blood stem cells following very high doses of chemotherapy has been demonstrated to result in more rapid neutrophil recovery than with stem cells collected from bone marrow. Many doctors have begun evaluating the use of peripheral blood stem cells to support multiple cycles of dose intensive chemotherapy alone or in combination with Neulasta® or other blood cell growth factors for the purpose of reducing the frequency and severity of neutropenia and its complications.

Ex vivoexpansion: Stem cells responsible for the development of neutrophils can be removed from a patient's body and grown or expanded in the laboratory. When large numbers of neutrophils have been grown in the laboratory, they can be infused into a patient to support delivery of chemotherapy with the goal of preventing neutropenia. The process of ex vivo expansion is currently being evaluated in clinical trials at some centers around the country.

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References

[1] Vose J, Crump M, Lazarus H. Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. Journal of Clinical Oncology. 2003;21: 514-519.

[2] Green M, Koelbl H, Baselga J. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Annals of Oncology. 2003:14:29-35.

[3] ADVANCE: Awareness of neutropenia in chemotherapy. 2001;1:3-4.7.

[4] Adams, VR. Adverse events associated with chemotherapy for common cancers. Pharmacother. 2000;20(7 pt 2):96S-103S.