Treatment for Severe Chronic Neutropenia

The treatments that have been tried or are being used in the management of congenital, cyclic and idiopathic neutropenia include:

• Granulocyte-colony stimulating factor (G-CSF)
• Bone Marrow transplant (BMT)
• Others: including other cytokines, antibiotics, vitamins, immunosuppressive drugs, immunoglobulins, corticosteroids and white cell transfusions
• Supportive care

As well as the treatment prescribed by your physician, nutrition and good hygiene, including good dental hygiene are extremely important in overall care to decrease the potential for infection. Nutritional treatments will not however raise the neutrophil count in severe chronic neutropenia.

The specific treatment for you should be discussed with your physician. These discussions should include any benefits of treatment and potential risks.

Granulocyte-Colony Stimulating Factor (G-CSF)
G-CSF is a cytokine normally produced by the human body itself. G-CSF, which is given as treatment is NOT from human beings but is safely made by industrial processes to produce an identical substance (by genetic engineering) that has all the normal activity and function of the naturally occurring cytokine. Therefore there is no risk of viral infection from G-CSF therapy.

G-CSF stimulates the production and also enhances the activity of mature neutrophils thus improving their bacteria-killing function. It acts via a receptor localized on granulocytes that binds the G-CSF to the cell and produces a signal to maturate, to divide or to enhance function.

SCN patients produce their own G-CSF, but for unknown reasons it does not produce the normal effects within the blood system and, therefore, extra (treatment) G-CSF is required.

The dose and frequency of injection of G-CSF that is required to increase and maintain the neutrophil count to 1000 per mm3 (1.0 x 109 /1) varies widely. For most patients, 5 - 20 micrograms (mcg) per kilogram (kg) of body weight of G-CSF is given as a daily subcutaneous injection is usually sufficient but some patients need very high doses, even up to 120/mcg/kg/day (potentially applied in more than one injection per day or even by continuous i.v. infusion) and some will require very low doses, as low as 0.01 mcg/kg/day. For some patients with severe chronic neutropenia the frequency of administration of G-CSF may be required less than daily, but short-term amendments may be necessary if illness due to infection occurs.

G-CSF is usually administered by subcutaneous injection (i.e. an injection just under the skin) and recommended sites include the abdomen below the navel, upper outer arms, and upper outer thighs. It is possible to self-administer G-CSF and this should be encouraged as it promotes a sense of independence and control over at least one aspect of treatment. As with any frequent and regular subcutaneous injection, rotation of the sites is recommended to prevent scarring and discomfort to the patient. The injection is not usually painful, but, occasionally, a stinging sensation may be experienced for a short period of time on administration.

Administration of G-CSF may result in dramatic increase in the numbers of neutrophils in the blood and is without a doubt, the most effective therapy in treating SCN. Some SCN patients receiving G-CSF report bone or muscle pain and splenomegaly. Other side effects are infrequent but few patients have experienced thrombocytopenia, injection site reactions, rash, hepatomegaly, arthralgia, osteoporosis, cutaneous vasculitis, haematuria/proteinuria, alopecia and exacerbation of some pre-existing skin disorders (e.g. psoriasis). If you are concerned that you may experience these or other side effects, report them to your doctor. In addition, cytogenetic abnormalities, transformation to MDS and AML have been observed in patients with congenital neutropenia treated with G-CSF. It is unknown whether the development of these abnormalities is related to chronic daily G-CSF administration or to the natural history of congenital neutropenia.

Bone Marrow Transplant
BMT is a treatment option for SCN. It may be considered for failure to respond to treatment, or for patients who develop leukaemia or MDS in the course of their disease. BMT is a very intensive procedure, carrying serious risks and therefore it is not recommended as first choice treatment. Your physician will be able to discuss this with you.

See our Research Centre section or more information on bone marrow transplants,

Other Treatments
Corticosteroids
In some conditions steroids have long been effective an increasing neutrophil counts in the blood. Steroids work by encouraging neutrophils to leave the bone marrow and enter the blood stream. However, they do not induce the production of new neutrophils in the bone marrow and they may decrease the number of other types of white cells, thus increasing the risk of infection. In general, steroids have not proven useful for patients with SCN, except for very few SCN patients not responding to other therapies, in whom steroids may be beneficial. In addition to the unwanted side effects of increasing the risk of infection, long-term use of steroids has many other side effects, e.g. it may induce the development of diabetes mellitus.

White Cell Transfusions
White blood cell transfusions are rarely used. They are generally reserved for severe life threatening infections. The replacement of neutrophils by transfusion is not feasible in the long term for various reasons. The collection of these cells is quite difficult, the mature neutrophil has quite a short life span and storage of the cells for more than a few hours only is impossible. As with all blood product transfusions, there is also a potential problem of viral infection with the transfusion.

Supportive Care
There are a variety of supportive therapies; only the most important are addressed below:

• Mouth care - this should include regular dental check ups. Excellent oral hygiene is very important and the use of an antibacterial mouthwash is recommended.
• Immunizations and vaccinations - people with SCN have an intact immune system that allows them to make normal antibodies protecting from the devastating effects of viral illnesses. Therefore all routine immunizations according to the standard vaccination schedule of your country are recommended.
• Monitoring temperature - if you have a fever above 38.5° C/101.3° F you must seek medical attention.
• Good general hygiene including thorough hand washing.
• Oral prophylaxis - antibiotics/antifungals, either oral or intravenous, may be given to SCN patients but this is very much based on individual physician choice.
• Prompt contact of hospital/clinic - it is important to have the contact telephone numbers of your physician and clinic.
• Foreign travel - should be raised with your physician, as special precautions, emergencies and contact telephone numbers need discussion.

Long Term Management of Severe Chronic Neutropenia
The key issue in the treatment of SCN is the promotion of a "normal life" for you. This includes schooling, vacations, family life and social life.

A CBC/FBC evaluation gives the physician the information needed to monitor your ANC. Monitoring the ANC alerts the physician to the need to adjust the G-CSF dosing.

When G-CSF treatment is initiated, your doctor will follow your ANC closely, generally for the first 4 - 10 weeks to check that the dose of G-CSF is correct for you. The Registry suggests that when the dose has been stabilized the SCN patient be monitored with monthly CBC/FBC. Blood should be drawn approximately 18 hours after dosing for patients on a daily administration of G-CSF. Patients taking G-CSF on a less frequent program should have the CBC/FBC done just prior to the next administration of the medication. This allows the physician to monitor the ANC at its lowest point prior to the next dose of G-CSF.

Bone Marrow Monitoring
Bone marrow aspirate and biopsy procedures are done to help the physician diagnose the patient’s medical condition. The bone marrow evaluation will help confirm if the patient has congenital neutropenia. After the diagnosis is confirmed, the Registry suggests that patients with congenital neutropenia be followed on a yearly basis with bone marrow and cytogenetic evaluations to monitor for changes in their bone marrow. SCN patients with types of neutropenia other than congenital should have annual bone marrow testing at the discretion of their physician.

Pregnancy
The SCNIR collects information on SCN patients and pregnancy; however, the number of pregnancies reported to date is relatively small and thus little information is known about the potential effects of G-CSF during pregnancy. Therefore, the use of G-CSF during pregnancy should be evaluated individually with your primary physician, who can weigh the currently known risks and benefits of treatment in the context of your individual situation. Because the safety of G-CSF administration during pregnancy is not yet established, the current recommendation given by the experts of the SCNIR is that if possible, G-CSF should be avoided or minimized during the first trimester. You should discuss this issue with your physician well in advance of any decisions regarding pregnancy. It will then be possible for your physician to review the current pregnancy data with you and develop a plan for G-CSF dosing.

Psychosocial Effects
Family dynamics, school and employment can all be affected by the increased stress caused by the chronic illness of a family member. Families and patients with SCN may experience similar stresses to those found in families with a family member with diabetes, epilepsy, cystic fibrosis, or other long-term conditions. Children with SCN will experience the normal milestones of childhood along with the added stress caused by having a chronic condition.

After the diagnosis of SCN the patient and family may experience the common feelings of confusion, bewilderment, and possibly anger. SCN is difficult to diagnose. Some patients will have life threatening infections, others constant infections, while some experience only intermittent infections. There may be disruptions to normal family life because the untreated SCN patient may have unpredictable illnesses. Vacations or travel may be avoided or delayed because of the unpredictable nature of infections that may occur. Families may feel isolated from friends and community, needing to speak with other families that are dealing with this rare problem. Joining support groups, family or professionally led, will help with those feelings.

All pre-school children’s development milestones include the mastery of their environment. Children with SCN need to be involved in their health care as is appropriate for their age. This may include learning to clean cuts and scrapes, proper hand washing, and helping with the administration of G-CSF. At this age it may be beneficial for a child to be given a doll to care for that also is "neutropenic" allowing the child to act as the doll’s caregiver. The treated SCN child may want to act out giving the doll medication. This allows the child to act out the frustrations he/she is feeling regarding the neutropenia and to begin the process of learning necessary copying mechanisms.

All school-aged children utilize school for socialisation and academic development. This development is essential to help the child move through the milestones of childhood. The SCN child will need all caregivers (such as schoolteachers, school nurses, day-care providers, coaches) to understand SCN.

Adolescence is a difficult time for most children. Children with SCN will realize, often for the first time that they are different from their peers. This may be the first time the child understands that he/she will have SCN for the rest of their life. The adolescent may feel that SCN affects school or relationships with peers. It is not uncommon for the adolescent to respond with denial of their condition. They may develop behaviors such as not caring for skin infections, lack of good oral hygiene or stopping the administration of the G-CSF.

At this stage the adolescent is struggling to maintain a positive self-image. The child may struggle against anything that appears to label them negatively. It is important for the parent to be alert to signs of change in habits or patterns that might indicate signs of depression or unusual anger (such as decreased interest in school or extreme behavior). Parents need to trust their intuition and knowledge of the child’s normal behavior. If a parent becomes alerted or worried about changes in the adolescent’s behavior they should contact the primary health care provider to discuss their concerns.

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