How is HLH treated?
In 1994, as a result of an international cooperative effort, the first treatment protocol for patients with HLH/FHL was designed. This included a combination of chemotherapy, immunotherapy and steroids, as well as antibiotics and antiviral drugs, followed by a stem-cell transplant in patients with persistent or recurring HLH or those with FHL. The HLH-2004 protocol was based on the HLH-94 protocol with minor changes such as cyclosporin, an immunosuppressant drug, being started at the onset of therapy rather than week #8. This protocol has been widely accepted internationally and is used in numerous countries on all continents but should still be considered experimental.

Secondary HLH may resolve spontaneously or after treatment of the underlying disease, without the use of chemotherapy. Therefore treatment should be guided in part by the severity of the condition, as well as the cause of the disease.

FHL, however, when not treated, is usually rapidly fatal with an average historical survival of about 2 months. The treatment included in the HLH-2004 research protocol is intended to achieve stability of the disease symptoms so that a patient can then receive a stem-cell transplant, which is necessary for a cure.

In recent years, some transplant centers have adopted the use of reduced intensity conditioning (or “RIC”) to prepare for the stem cell transplant. This approach offers the possibility of better survival with stem cell transplant than the intensive chemotherapy protocols previously used.
As research continues, the outcome for patients with HLH/FHL has improved greatly in recent years. Approximately two-thirds of children with HLH who undergo transplantation can expect to be cured of their disease. However, there are a number of complications that can occur during the process of transplant, including severe inflammatory reactions, anemia, and graft-versus-host disease.

What are the side-effects of the Treatments?
The main drugs used to treat HLH and their common side effects are described below.

Steroids:
Dexamethasone/prednisolone - these are corticosteroids (steroids) that can reduce inflammation and suppress the immune system. They are usually given by mouth, in the form of pills, pills that dissolve in water, or as a liquid medicine.

There are a number of known possible side effects. You will not necessarily experience all of these.

Possible side-effects include: irritation of the stomach lining (indigestion/discomfort/pain), increased appetite, weight gain, changes in behaviour (mood swings/difficulty in sleeping/anxiety/irritability), temporary increase in blood-sugar level (like someone with diabetes), high blood pressure, increased risk of infection due to suppression of the immune system, impaired wound healing, irregular or absent periods, and inflammation of the pancreas. Long-term steroid use may also cause muscle weakness, a reduction in bone density (bones become more fragile), cataracts and growth failure.

Chemotherapy:
Chemotherapy is a drug usually used to treat cancer but some chemotherapy drugs are also very effective against HLH. These drugs work by killing cells that are dividing and reproducing themselves.

Different chemotherapy drugs cause different side effects. Everyone is different and will react to chemotherapy treatment in a different way. Some patients may have very few side effects while others will have a lot. Almost all side effects are only short-term and will gradually disappear once the treatment has stopped.

The main areas of your body that may be affected by chemotherapy are those where normal cells rapidly divide and grow. Examples include the lining of the mouth causing a sore mouth, the digestive system causing diarrhoea, skin and hair, causing hair loss, and the bone marrow (spongy material that fills the bones and produces new blood cells), causing low blood counts.

There are three main types of blood cells that might be affected:

• Red blood cells which carry oxygen around the body
• White blood cells which fight infections
• Platelets which help to clot the blood to prevent bleeding and bruising

Chemotherapy reduces the production and therefore, the number of blood cells in the body. Too few red blood cells cause anaemia, and the person becomes tired and pale. If there are too few white blood cells, particularly those called neutrophils (neutropenia), the person is at increased risk of infection. Too few platelets means the person is at increased risk of excessive bleeding when injured, having nose-bleeds or bruising easily. If the counts get really low, you may need a red cell transfusion or platelet transfusion. Transfusions are also needed to support those patients who undergo intensive chemotherapy.

As the chemotherapy affects your immune system, you may need antibiotics to help fight any infection. This means if you have a temperature of 38°C or more, or becomes unwell (even with a normal temperature) you must go to hospital where you may have to stay for a couple of days whilst being given antibiotics. You may also have to avoid giving paracetamol or ibuprofen until you are reviewed in hospital, as these drugs lower high temperatures and can potentially mask an infection. In addition, if you are in contact with someone who has chickenpox, shingles or measles, then you should let your hospital know as these are dangerous infections for a patient with a low (suppressed) immune system. Both you and the rest of your family should have the annual flu jab during the autumn/winter.

Chemotherapy can also cause nausea and vomiting, but anti-sickness medicines known as anti-emetic drugs can control this side effect.

Hair loss can occur, but this does not always happen with the chemotherapy used to treat HLH. Young patient often get used to hair loss fairly quickly but for others it is far more traumatic, fortunately, all hair loss from chemotherapy is temporary and hair growth returns once treatment has stopped.

Fertility may be affected, depending on which chemotherapy drugs you receive. You should discuss your particular treatment with your oncologist/haematologist for more information.
Other side effects are an increased sensitivity to the sun, so you should keep out of intense sunlight and use sun block.

Treatment Centres
Haemophagocytic Lymphohistiocytosis is a rare disease. Treatment and full investigation are performed at specialist treatment centres that have experience with dealing with patients with HLH and the specialist medications. There are specialist centres in the UK which treat cancer and rare diseases and you care will be co-ordinated from there. To make things a bit easier for your family, you may receive some treatment in a hospital local to your home (shared care), but the overall management plan for your treatment will ultimately be undertaken from your closest treatment centre.

Complementary (Alternative) Therapies
In the past, many doctors dismissed alternative or complementary medicine, but it is now recognised that families often benefit from the positive effects of treatments such as acupuncture, massage, counselling or nutritional therapy.

Several effective chemotherapy drugs are derived from natural sources, especially fungi and plants. The main ‘problem’ with complementary therapy is that individual treatments are hardly ever subjected to the same intense scrutiny and ‘clinical trials’ as official drugs, and that is a matter of considerable concern. It is therefore, important that you discuss with your consultant any of the alternative therapies you plan to use, to ensure that they do not interact in any harmful way with your medication. Herbal ‘remedies’ are a case in point, since some of them are known to interfere with medically prescribed drugs proven to help. The following are just some of the over-the counter treatments that interfere with the action of chemotherapy drugs, or other medicines such as antibiotics: bilberry; Echinacea; fish oils; garlic; glucosamines; meadowsweet; selenium and St John’s wort.


What happens to patients after they had HLH?
Long-term follow-up of survivors of transplants for HLH/FHL indicates that most return to a normal or near-normal quality of life. The results of transplantation are generally better when the procedure is performed at a major transplant center where the doctors are familiar with this disease. Early and accurate diagnosis is essential. However, there is still a high rate of death, indicating that education of the medical community regarding prompt diagnosis and management of the diseases is required.

Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

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What Are Clinical Trials?
HLH is very rare, with only a very small number of patients diagnosed each year. HLH covers conditions with many causes, so each case is different, with less predictable response to treatment. Clinical trials which randomly split the patients into different groups to look at treatment effects and side-effects are thought to be the best. However, because of the small and wide ranging cases, no randomised trials have yet been able to be performed in HLH but are planned for the future.
 
Clinical trials are an essential step in the development of treatment for various diseases and are necessary for improving the outcome of patients. Clinical trials are the only way to find out if a new treatment approach to a disease is better than the standard treatments currently used. Patients volunteering to take part in a trial are randomly assigned to either receiving the standard treatment or a different or experimental treatment. This is known as a randomised trial and is the most common way in which treatments are tested. The choice of which treatment is offered to a particular patient is usually done with the help of a computer and the process ensures that the groups are similar in every way other than the fact that they receive different treatments. Any difference in outcome between the groups is then likely to be caused by the difference in the treatment and not by other differences between the groups. If an experimental treatment proves to be better than the standard treatment and does not cause unacceptable side-effects, it is recommended as the new standard treatment for future patients. This is how new treatments or approaches to treatment are introduced to patients.
 
The conduct of clinical trials is carefully regulated to ensure patients’ well-being is protected. Patients will only be able to participate in a trial if there is an open trial at that time, if they meet the eligibility criteria, and if their treating hospital is taking part. Patients must understand the implications of taking part in a clinical trial and give written consent (agreement) to allow them to be enrolled on a trial. If a trial is available to you your doctor will explain it in more detail and you will be given the necessary information to allow you to decide whether to take part or not. While on a clinical trial you will be very closely monitored.
 
The Histiocyte Society is a non-profit organisation whose members comprise an international group of over 200 doctors and scientists. It is committed to improving the lives of patients with disorders of histiocytes by conducting clinical and laboratory research into causes and treatment.
 
Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

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