AL Amyloidosis

By Professor Arnaud Jaccard – CHU Dupuytren LIMOGES – FRANCE

What is AL amyloidosis?

AL (or immunoglobulin related) amyloidosis is a rare disease linked to deposits in the different organs of a part (the light chain) of an abnormal antibody known as monoclonal in the form of fibrils. Fibrils are insoluble and are deposed in the organs and prevent them from functioning properly.

These deposits can affect all the organs except the brain and consequently the symptoms differ greatly depending on which organ is affected.

It is estimated that there are 500 to 700 new cases in France every year. The average age for diagnosis is about 65.

What are the causes of the disease?

Unlike other forms of amyloidosis, AL amyloidosis is not a hereditary disease but an acquired one.

Plasma cells and B cells produce antibodies, or immunoglobulins, the tools which defend the body. They are made of two heavy chains and two light chains.

Sometimes a plasma cell or a B cell can become immortal, multiply and form clones. All the plasma cells and B cells thus produced therefore secrete the same antibody which is said to be monoclonal. Most of the time this is of no consequence but, in about one case out of a hundred, the light chains – sub-parts of the monoclonal antibodies – can build up one on top of the other to form the fibrils which constitute the deposits of amyloidosis.

By studying the bone marrow, various blood diseases can be diagnosed according to the nature and number of cells. In 90% of causes, the cells are those which in their normal state produce antibodies to defend against infections i.e plasma cells. When there are only a small number in the bone marrow, less than 10%, we speak of simple monoclonal immunoglobulin. When they represent more than 10% of the cells, we speak of myeloma.

Simple monoclonal immunoglobulin is a relatively frequent phenomenon and it becomes increasingly frequent with age, affecting 5% of people around 60 years old, with up to 10% in people over 80.

Myeloma is a much less frequent blood cancer but when it is combined with amyloidosis it does not usually develop much. This is known as indolent myeloma.

What are the manifestations of the disease?

They are multiple and depend on the organs that are affected.

The most frequently affected organ is the kidney, concerning two thirds of patients. The kidney is a filter responsible for eliminating toxins produced by the body and present in the blood. Deposits of amyloidosis damage the filter and allow proteins which do not usually get into the urine, to be evacuated, mainly albumin. Loss of albumin in urine lowers the amount in the blood causing oedema in the legs or more wide spread. After a while, the kidney functions less and less efficiently and kidney failure occurs making it necessary sometimes to put the patient on dialysis.

The most serious cases are those where the heart is affected, concerning 60% of patients. The deposits of amyloidosis thicken the heart muscle and make it less supple. The consequence is a so-called “restrictive” heart condition because the heart is unable to fill up and the cardiac outputis slower causing fatigue and breathlessness, firstly with effort then even when the patient is resting.

The other consequence of cardiac deposits is disturbances to electric circulation in the heart with the appearance of abnormal heartbeat, either too fast or too slow, or cardiac arrest. This can require a pacemaker, a battery placed under the skin to control the heartbeat.

About 20% of patients have a neurological condition which is manifested by abnormal sensations in the feet then legs, thighs and hands. Affected nerves can also cause digestive problems and a decrease in blood pressure when moving from a lying to a standing position, causing dizziness and possibly falls. 

The digestive tract may also be affected with diarrhoea or constipation or bleeding. The tongue can also be the seat of amyloid deposits which make it thicker and modify the taste of food. 

The presence of amyloidosis in the small blood vessels of the skin can cause bleeding particularly in areas which move like the eyelids which can have bruises which contribute to the diagnosis of amyloidosis.

All these forms of AL amyloidosis are said to be systemic, meaning that they affect different organs by the depositing of light chains. There are also forms of localised amyloidosis in which a small population of cells produces a monoclonal light chain and deposits it around them without any dissemination. These forms are rarer and generally less serious and are usually located in just one place: conjunctiva of the eye, the larynx and bronchial tubes, the bladder, digestive tract etc.

How is an AL amyloidosis diagnosed?

Diagnosis requires a biopsy.

Amyloidosis is recognised in biopsies thanks to Congo Red staining. Then typing is carried out to differentiate AL amyloidosis from another form, particularly a hereditary one.

Once the amyloidosis diagnosis has been made it is necessary to determine which blood disease is responsible for the production of monoclonal antibodies and this requires puncturing the marrow at the level of the sternum (myelogram) and other biological examinations. 

Then a detailed check-up has to be carried out on the organs affected by amyloidosis, particularly the heart with an ultrasound scan and if necessary an cardiac MRI scan, a dosing of blood markers for heart condition, BNP or NT-proBNP and troponin, an electrocardiogram and sometimes the recording of the heartbeat for 24 hours (Holter-ECG).

Other examinations will be made to assess the functioning of the kidneys and liver, dosing of creatinine, albumin, proteinuria, liver enzymes. Imagery can also be used, like an ultrasound scan of the abdomen or a scanner. 

Treatment of AL amyloidosis

Treatment aims first to eliminate the cells which produce monoclonal antibodies by chemotherapy protocols most often derivatives of those of myeloma. The most frequently used ones are MDex and VCD.

MDex is a combination of two medicines: Melphalan (also called Alkeran) and dexamethasone which is a powerful corticosteroid.

VCD combines bortezomib therapy (or Velcade), cyclophosphamide (Endoxan) and dexamethasone. Bortezomib can also be added to MDex if the response is insufficient.

The effectiveness of the treatment is monitored on the dosage of free light chains determined by a blood test. To enable the amyloidosis to get better the light chains have to be reduced as much as possible. The test used to measure the free light chains should be carried out in a hospital if possible as the cost cannot be reimbursed and is charged to the patient if it is done in a private laboratory.

When a good response is obtained with a sufficient decrease in the number of free light chains, the damage will decrease more or less rapidly depending on which organs are affected and will vary from one patient to another.

In patients who do not respond (insufficient decrease of the free light chains) or in case of a relapse, other molecules may be used, particularly those in the category of IMIDs. The most commonly used one is lenalidomide (or Revlimid) generally combined with a dose of dexamethasone each week.

Among several new treatments which are being tested in AL amyloidosis, the most promising is a monoclonal antibody, Daratumumab. Daratumumab is produced in a laboratory to recognize and eliminate plasma cells, which produce light chains. It is currently tested in a protocol in France in patients with insufficient response after treatment.

Finally, several treatments to eliminate amylose deposits more quickly are under development. Several therapeutic trials using antibodies directly or indirectly recognizing amyloid deposits and likely to recruit immunity cells to remove amyloid deposits have been conducted or are in progress. NEOD001 was the most advanced but 2 trials that included more than 300 patients failed to demonstrate efficacy in heart disease and the product was removed by the laboratory that developed it. Two other antibodies are being tested in England and the United States.

Monitoring and evolution of AL amyloidosis

Follow-up care is fundamental for AL amyloidosis patients.

  • During the treatment the patient has to be monitored to make sure it is effective with the dosage of free light chains in the blood (or monoclonal antibodies if the light chains are not numerous at the time of diagnosis) for each cycle of treatment and the different biological tests to ensure that it is well tolerated.
  • Check-ups after the treatment every two or three months to detect any relapse involving an increase in the free light chains which could be cause for a new course of treatment.
  • Finally, regular check-ups during and after the treatment of different markers to seek an improvement in the organs affected by amyloidosis.

The prognosis of AL amyloidosis is very dependent on the type and seriousness of the damage to the organ, particularly the heart and has improved greatly in the past fifteen years with the introduction of new molecules (bortezomib, lenalidomide etc….) which ensure a haematological response (i.e on free light chains) in more than 80% of patients. 

If patients with the most serious heart conditions can unfortunately still die in a few weeks, the survival rate of other patients is very good with most often a gradual improvement of the affected organs if the treatment began before irreversible damage was caused by amyloidosis.

Questions frequently asked by patients about AL amyloidosis

Is AL amyloidosis hereditary?

No, it is an acquired disease which occurs when a monoclonal antibody is produced of which a part, called a light chain,  is capable of building up into amyloid fibrils. This is not hereditary.

Is AL amyloidosis a form of cancer?

Even if AL is associated in 40% of cases with myeloma which is a form of blood cancer, it is not considered as cancer because generally when it is combined with amyloidosis, there is no development of the myeloma or gradual increase in the number of abnormal cells in the bone marrow.

Why has my doctor stopped chemotherapy when there’s no improvement in my symptoms

The purpose of chemotherapy is to lower as far as possible the number of free light chains in the blood to stop the formation of new amyloid deposits. It does nothing for existing deposits which are gradually eliminated by the body. The treatment is continued for long enough to reduce the light chains as far as possible and prevent the disease from coming back too quickly. The treatment generally lasts between 6 and 9 months.

My doctor told me I only had two years to live. What do you think?

Some patients with the most serious heart conditions die even more quickly but if you have a good haematogical response and you are monitored adequately to detect any relapse, there is no reason to believe that you will not go on living.

I am often out of breath and incapable of climbing stairs. What is the reason for this and will it get better with chemotherapy?

Breathlessness is most often caused by the heart condition which prevents the blood from entering the heart correctly and slows the cardiac output which are unable to increase in case of effort. This breathlessness can be worsened by medication which slows down the heartbeat. Consequently, diuretics are often prescribed to eliminate water through the urine to relieve the heart, which generally improves breathlessness. Then, if chemotherapy is effective in lowering the number of light chains, there is rapid improvement, because abnormal light chains are toxic for the heart followed by a slow improvement over several months which correspond to the gradual elimination of the cardiac deposits. This improvement is accompanied by a lowering of the cardiac markers (NT-proBNP or BNP).

How long will it take for my oedema to disappear?

There may be a rapid decrease in the oedema thanks to a diuretic treatment. After that, it depends on the haematological response to chemotherapy. If it is good (complete or very good partial response) the proteinuria decreases slowly, often over several months, leading to an increase in albumin in the blood and a decrease of the oedema. It is the decrease in albumin which causes the oedema and increasing it makes them disappear gradually.

Food is tasteless. Why is this?

It is the amyloid deposits present in the buccal mucosa which cause this loss of taste which affects one patient out of three. Generally, taste comes back gradually when there is a positive response to the treatment.

What are the secondary effects of the treatments? Will I lose my hair?

The most commonly used treatments are generally well tolerated and do not cause hair loss. Dexamethasone has the side effects of steroids; risk of diabetes, hypertension, infection and sleeplessness. Melphelan can lower white blood cells and the blood count (studied through a blood test) must be monitored regularly. Bortezomib can cause tiredness, a decrease in the number of platelets and discomfort in the nerve endings of the arms and legs causing a sensation of electric shock or pain. An injection is made under the skin sometimes causing a local reaction but rarely any severe discomfort. Lenalidomide and other molecules of the same class (thalidomide and pomalidomide) favour the formation of blood clots in the veins and arteries and must be accompanied by aspirin or a blood thinner. All these treatments make the patient more prone to infection, so you will be given preventive antibiotic or antiviral treatment.

I saw on an American forum that the best treatment was a marrow transplant. Why haven’t I been offered one?

Intensive treatment with marrow transplants is very serious and difficult, with a risk of severe complications in the period following the transplant. This method is offered to about 20% of less seriously affected patients in the United States and Germany. But in France, like in many European countries, this is reserved only for special cases. We consider that treatment using these new agents are at least as effective and much less dangerous. 

Is progress being made in amyloidosis research?

Amyloidosis research is benefitting from all the advances made in myeloma. The rapid introduction of all the new molecules has enabled the response rate to increase from 30% in the 2000s to over 80% today with some like bortezomib even more active among patients with amyloidosis. Many others are being developed. Specific research into amyloidosis is investigating the means to eliminate the deposits more rapidly than the slow natural elimination. Three antibodies which recognise the fibrils either directly or through fixation onto a protein, SAP, present in the deposits, are currently being tested with very promising results.