AL Amyloidosis

AL amyloidosis is the most commonly diagnosed type of amyloidosis in the Western world.

  • It is not inherited or contagious.
  • It is acquired, meaning it just happens.
  • It is an extremely complicated systemic disease which varies in presentation from person to person.
  • Usually more than one organ is involved.
  • No one knows why some people develop AL amyloidosis while others do not.
  • Without treatment the prognosis is poor, especially when heart function is impaired by the amyloid deposition.
Refer to section on “what is amyloidosis”

Prognosis

Over the last 20 years with improved awareness, earlier diagnosis and better techniques to diagnose, type and treat AL amyloidosis, many people are achieving a disease remission and living normal lives. However, AL amyloidosis remains a complicated disease that without treatment often has a very poor outcome, particularly if the heart is involved or the disease is diagnosed late. Early diagnosis is still the key to more effective treatment.

Read Crystal’s story about her father’s late diagnosis.

What causes AL amyloidosis?

Normal plasma cells, antibodies and free light chains

Before talking about what causes AL amyloidosis, first a few words about the normal situation in the human body.

Plasma cells are a special kind of white blood cell which are part of the body’s immune system. Plasma cells live in the bone marrow and their job is to make antibodies which are also known as immunoglobulins. Antibodies are a special type of protein and are part of the body’s defense system against infection. The human body is very adaptable and can make thousands of different antibodies in order to deal with many different infections. Once antibodies have done their job they are broken down and recycled in the body.

Each antibody molecule (or immunoglobulin) is made of two “heavy” chains and two “light” chains joined together (see diagram at right). The light chains can be of two types, Kappa or Lambda. When the immune system makes antibodies, light chains are made in excess of the amount needed to produce an antibody. These excess light chains circulate in the blood as free light chains.. Normally everyone has small amounts of kappa and lambda free light chains in their blood. These light chains circulate in the blood, cause no harm, and are excreted in the urine.

Plasma cells diseases and amyloid forming free light chains

In AL amyloidosis, plasma cells in the bone marrow begin to proliferate or grow abnormally, a situation known as a plasma cell disorder. Usually this buildup of plasma cells is benign but in some cases the growth of plasma cells can be malignant, that is, a cancer of the bone marrow called multiple myeloma. These abnormal plasma cells make large amounts of a single type of free light chain. The free light chain proteins fold in an abnormal way, become amyloid fibrils and progressively deposit in any of the tissues and organs of the body, except the brain. This deposition slowly interferes with organ and tissue function. Without treatment to slow or stop this amyloid being produced and deposited, organ failure occurs.

Plasma cell proliferation Does the free light chain form amyloid? Disease
Cancerous (malignant) No Myeloma
Cancerous Yes Myeloma + AL amyloidosis
Non-malignant No MGUS (monoclonal gammopathy of undetermined significance)
Non-malignant Yes AL Amyloidosis

Organ Involvement

  • AL amyloidosis is a complex systemic disease, meaning that any tissues of the body except the brain can be affected by the deposition of the amyloid protein.
  • There is no common pattern and great variation between patients in the way the amyloid protein is laid down.
  • In most patients more than one organ will be affected.

The most common organs affected are:

  • Kidneys
  • Heart
  • Nerves, with both autonomic and peripheral neuropathy.
  • Liver
  • Gastrointestinal tract.
Organ involvement in Amyloidosis

Symptoms

Symptoms may be vague and nonspecific and often mimic other diseases.

  • Loss of appetite
  • Tiredness
  • Loss of weight
  • Weakness

More specific symptoms will depend on which organs are affected by the amyloid deposition.

  • Swollen ankles (oedema) – Kidney or heart involvement
  • Breathlessness, especially on effort and going up a slope – Heart involvement
  • Tingling in the fingers and toes – Nerve involvement
  • Frothy urine – Kidney involvement
  • Bruising, especially around the eyes (raccoon eyes) – Amyloid in the blood vessels
  • High cholesterol – Kidney involvement
  • Diarrhea and constipation – Gut or autonomic nerve involvement
  • Swollen tongue (macroglossia) – Tongue involvement

 

Diagnosing AL Amyloidosis

Early diagnosis is essential but often very difficult. Unfortunately, many patients visit a number of doctors before the diagnosis is made and then present with severe organ damage, which can compromise treatment.

Read results from ARC survey

No single blood test exists to diagnose amyloidosis.

Diagnosis begins when a doctor suspects the patient’s symptoms may be due to amyloidosis and starts to run tests or makes a referral to a specialist with knowledge in treating amyloidosis.

AL amyloidosis can only be definitively diagnosed through a tissue or organ biopsy.

  • A tissue biopsy involves removing a small piece of tissue for microscopic examination from the symptomatic organ thought to be involved by amyloid or from a distant site such as the fat pad on the tummy, the gastrointestinal tract, the lip or the bone marrow.
  • The biopsy is stained with the dye Congo red in the laboratory.
  • If amyloid is present, the biopsy will appear red under normal light and green (apple-green birefringence) under special polarized light.

  • Further testing may be undertaken on the biopsy to identify the type of amyloidosis. This is important, as the treatment for each type of amyloidosis is different.
  • However in the case of a patient being diagnosed with amyloidosis and macroglossia (swelling of the tongue) this testing will not be needed as this is only seen in AL amyloidosis.

See section on amyloidosis for information on different types.

A series of further tests will be run to:

  • Identify which organs are affected by the amyloid deposition and to what degree.
  • Check the general health of the patient including other health problems that may affect treatment.
  • Help with typing the disease.
  • To enable a treatment plan to be made.

Tests may include:

  • A number of blood tests to amongst other things: kidney (creatinine), liver (liver function tests) and heart function (serum troponin and BNP or NT-proBNP)
  • Echocardiogram
  • ECG
  • CT scan, MRI
  • Genetic testing may be performed to exclude one of the hereditary types of amyloidosis.
  • A bone marrow biopsy to establish the presence of abnormal plasma cells
  • Urine analysis to measure the amount of protein and any light chains in the urine (Bence Jones proteinuria)
  • Free Light Chain assay and serum protein electrophoresis

It is usually only when all these results have been collated and consideration has been given to:

  • Patients age
  • Where they live
  • Whether a treatment trial is available and appropriate

that a treatment plan will be recommended in consultation with the patient.

Treatment

In AL amyloidosis, the goals of treatment are:

  • To stop or reduce the production of the amyloid forming light chain protein and therefore stop the amyloid depositing into the organs and tissues to support and preserve the affected organs.
  • To maintain and improve quality of life.
  • Other goals such as disrupting amyloid fibril formation or enhancing clearance of already deposited amyloid are the subject of ongoing research

Patients should be assessed and treatment decisions made by an experienced amyloidosis team.

Treatment for patients with AL amyloidosis is risk-adapted and customized on the basis of individual patient characteristics. Treatment is usually delivered by a multidisciplinary team of doctors and health professionals which may include:

  • Haematologists: A doctor that specializes in blood diseases (usually the leader of the AL treatment team)
  • Cardiologists: A doctor that specializes in the heart.
  • Gastroenterologists: A doctor who specializes in the gastrointestinal tract.
  • Nephrologists: A doctor that specializes in the kidneys.
  • Neurologists: A doctor that specializes in the nerves.

Other team members may include:

  • Specialist nurses
  • Dieticians/ occupational therapists.
  • Social workers/psychologists/counsellors

Patients will usually only see the relevant specialists for the care of their unique disease and affected organs. These specialists may not always be in the same clinic or building but will work together to deliver the best treatment for the individual patient.

Patients will usually only see the relevant specialists for the care of their unique disease and affected organs. These specialists may not always be in the same clinic or building but will work together to deliver the best treatment for the individual patient.

Treatments have progressed considerably over the last 20 years. Although AL amyloidosis remains an extremely serious disease and is considered incurable, many patients are enjoying long periods of remission.

All patients diagnosed with AL amyloidosis have a slightly different presentation. Organ damage and age can mean patients are fragile and highly sensitive to treatment. Therefore, an individualized approach is used when the treatment team is selecting the most effective and best tolerated treatment regimen for each patient.

Historically the treatment of AL amyloidosis has been directed at the underlying bone marrow disorder with the aim of reducing as quickly as possible the free light chains which are causing the production of the amyloid protein.

How does chemotherapy work in AL amyloidosis

  • The chemotherapy drugs have been traditionally borrowed from those proven to work in treating multiple myeloma. This is because drugs that kill cancerous plasma cells (i.e. multiple myeloma) are also good at killing the benign plasma cells underlying AL amyloidosis. Killing the plasma cells results in less amyloid forming free light chain being produced
  • Once the production of light chains is greatly reduced or stopped, referred to as a haematological response, it has been shown that the amyloid already deposited in the organs may slowly leech out of those organs (organ response), improving function. This is often an extremely slow process and it may take 12 months or more after the end of treatment.

Types of chemotherapy

  • Traditional chemotherapy drugs (Melphalan, Cyclophosphamide) with or without an autologous stem cell transplant, were for many years the only treatments available. These treatments are still very effective today
  • Corticosteroids (dexamethasone), while not traditional chemotherapy, are also very effective at killing plasma cells
  • Newer chemotherapy drugs such as the proteasome inhibitors (bortezomib, ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide)
  • Most patients take one or two chemotherapy drugs plus steroid medication. The drugs work together to destroy the plasma cells that make the light chain proteins.

N.B. Unfortunately not all drugs are registered for use in Australia or available through the Australian Pharmaceutical Benefit PBS scheme. There may be other ways of funding these treatments which the doctors will discuss with their patient

Side effects of treatment

Treatments can cause a number of side effects which may include:

  • Retention of fluid in feet and legs
  • Worsening of heart failure
  • Neuropathy
  • Palpitations
  • Infection
  • Nausea
  • Diarrhoea
  • Constipation
  • Hair loss

Patents will be closely monitored throughout treatment and constantly offered support and information about their treatment and side effects.

If a patient is worried about any new symptoms they should contact their doctor or specialized nurse at once.

Other treatments under investigation

More recently different approaches targeting the actual amyloid deposits have been developed and tested in clinical trials with the hope that they will complement chemotherapy agents. For example, doxycycline, an antibiotic, has been shown to disrupt amyloid fibrils and is being investigated in clinical trials.

Anti-amyloid fibril antibodies which may enhance removal of amyloid deposits already in the organs are being tested in clinical trials.

How is the progress of treatment monitored?

The aim of treatment is to reduce the production of light chains and support and improve organ function.

  • Blood tests (free light chain assay, serum protein electrophoresis) and urine tests (urine protein electrophoresis) will be performed from time to time to measure the haematological response to treatment (CR, VGPR or PR). This is assessing whether the amyloid forming light chain protein is being reduced by the treatment.
  • Blood tests will be run routinely to check on any negative effects from the treatment.
  • Other tests mentioned above will be run routinely to check on the state of the patient’s organs and general health (Organ response).

What happens if the drug treatment is not working?

If the elected treatment is shown not to slowing the production of the amyloid protein fairly rapidly or the patient is having difficulty tolerating the treatment, other drugs may be suggested or the dosages of the drugs may be altered.

Autologous stem cell transplant

  • In the late 1990’s and early 2000’s, an autologous stem cell transplant (ASCT) was a favored treatment in the USA.
  • A very high mortality rate forced changes to the assessment procedure and supporting drug regimens.
  • Although an ASCT is still considered an effective treatment for achieving a deep clonal response, it will only be considered today in highly selected patients with early organ damage and no or very slight heart involvement.
  • There are differing opinions among amyloid experts around the world about the role of ASCT in the treatment of AL amyloidosis. At the Mayo clinic in the USA where there has always been a strong preference for ASCT, about 25% of newly diagnosed patients are eligible because of age, renal function and the extent of cardiac damage. Alternatively, in the UK or France, very few patients are treated with ASCT as part of their initial therapy.

A stem cell transplant should always be carried out in a hospital unit experienced in transplanting patents with AL amyloidosis.

Read Coral’s story

See section on stem cell transplant for information on this procedure

In spite of some patients achieving a complete haematological response (CR) after treatment their organs may remain very damaged. An organ transplant may be recommended in such circumstances to improve quality of life.

Read Robin’s story

Supportive treatments are very important at all times. These may include:

  • Salt restriction as salt intake may cause the body to retain fluid.
  • Careful fluid balance.
  • Diuretics to help get rid of fluid from the body when the heart or kidneys are affected
  • Medications to treat low blood pressure, diarrhea, constipation and nausea.
  • Medications to treat pain from neuropathy.
  • Consultation with a dietician.
  • Consultations with occupational therapist or physiotherapist for help with everyday living issues
  • Support and counselling as needed (see section on support)

Palliative Care

Some patients are very unwell when diagnosed or become very unwell with deteriorating disease in spite of treatment. A consultation may be suggested with a palliative care team who are highly skilled in symptom control.

Read about Clinical Trials

video
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Professor Morie Gertz: What is AL Amyloidosis?

Future AL amyloidosis treatment

AL amyloidosis treatment including stem cell transplantation – Mayo Clinic