What is it?
Amyloidosis is a rare and devastating disease. The term amyloidosis covers a spectrum of diseases where protein fibrils, which have in common a particular abnormal chemical structure called a beta-pleated sheet, are deposited within the tissues and organs of the body. These abnormal protein deposits (or amyloid) are relatively insoluble and therefore cannot be easily broken down by the body. They build up in the tissues leading to progressive organ failure and, in the absence of effective treatment, eventually to death.
Are there different types of amyloidosis?
The many different types of amyloidosis are now classified according to the type of protein fibril that the amyloid deposits are made up of (see Table 1). Each type of amyloid is given a “name” consisting of a capital A (for Amyloid) followed by an abbreviation for the fibril protein. For example: in AL amyloid, the L refers to the light chain component of the immunoglobulin protein; in AFib, the Fib refers to the fibrinogen protein.
Amyloidosis can be due to the overproduction of a normal protein (e.g. AA, seen with long-term inflammatory illness) or due to inheritance of an abnormal (or mutated) protein (e.g. AFib, ATTR). The most common type of amyloidosis, however, is AL. Correctly diagnosing the type of amyloidosis is critical as treatment is very different for the various types of amyloid (e.g. chemotherapy and stem cell transplantation will not work for hereditary types of amyloid).
AL amyloidosis was previously known as “primary systemic amyloidosis”. In AL amyloidosis, the amyloid forming protein is derived from the light chain component of a protein in the blood called monoclonal immunoglobulin. These light chains are produced by abnormal cells (called plasma or B cells) which are usually in the bone marrow. The underlying bone marrow disorder is known by many different names (MGUS - monoclonal gammopathy of undetermined significance, plasma cell dyscrasia, paraprotein disorder etc) and in most cases is very subtle.
In about 20% of cases, the monoclonal plasma cells in the bone marrow behave in a cancerous fashion, in which case the underlying bone marrow disorder is multiple myeloma. A patient with myeloma may have or develop AL amyloidosis, but it is rare for a patient with AL amyloidosis (who does not have myeloma at presentation) to progress to full blown myeloma. Rarely, AL amyloidosis can be due to abnormal light chains produced by lymphomas or chronic lymphocytic leukaemia (CLL). AL amyloidosis is not inherited or contagious.
The symptoms of AL amyloidosis are multiple and reflect the predominant organs involved. Kidney, heart, nerve and liver dysfunction most commonly arise, although any organ apart from the brain can be affected. Symptoms are often non-specific and include weakness, tiredness, weight loss and poor appetite. Other symptoms relate to specific organ involvement and include swollen ankles (kidney or heart), shortness of breath (heart), and tingling in the fingers and toes (nerve). It is a rare disease with an estimated age-adjusted incidence of 5.1 to 12.8 cases per million person-years in the United States, which equates to approximately 160 new cases per year in Australia.
AL amyloidosis is a serious condition, which in the absence of treatment inevitably progresses, leading ultimately to death, usually within five years. Amyloid deposition is a dynamic process, however, and treatments that reduce the production of monoclonal light chains frequently result in the stabilisation or regression of amyloid deposits and, subsequently, in the preservation and improvement of organ function.
Treatments utilised in AL amyloidosis have mirrored those that are used in the related plasma cell disease multiple myeloma, and range from low-dose chemotherapy to high-dose chemotherapy with autologous stem cell transplantation. Autologous stem cell transplantation is very effective at reducing the amyloid forming light chains, but unfortunately is unsuitable for many patients who are not well enough to receive this treatment. Transplantation is too dangerous a procedure for most patients with advanced cardiac amyloidosis. Lower dose chemotherapy based around the steroid dexamethasone is also effective and a recent trial in France found that patients treated with a tablet, melphalan, and dexamethasone did just as well as those treated with stem cell transplantation. Other drugs such as low-dose thalidomide, Velcade and Revlimid are also useful treatments or are currently being trialled in AL amyloidosis. These drugs are not currently funded through Australia’s PBS system.
The aim of the various chemotherapy treatments is to reduce the production of the amyloid forming monoclonal free light chains. A test, the free light chain assay, is now available to monitor free light chains in the blood. It can detect monoclonal light chains in virtually all patients with AL amyloidosis. In addition, reduction in the serum free light chains following chemotherapy correlates with reduction in the whole body amyloid load and improved survival.
Whatever the type of chemotherapy, it is important to appreciate that improvement in amyloid related symptoms is often slow and may not be apparent for 12-18 months. The success rate varies between treatments but is about 40% to 60% on average. In addition to chemotherapy, supportive measures can help to reduce symptoms, maintain general wellbeing and assist the function of affected organs.
Australia and New Zealand’s first therapeutic trial in AL amyloidosis is currently underway in several major centres and is organised through the Australasian Leukaemia and Lymphoma Group (ALLG). This study will evaluate a risk-adapted intravenous melphalan dosing strategy to deliver a safe stem cell transplant to those who can tolerate the procedure, reserving the less toxic intermediate-dose melphalan and dexamethasone for patients who are not candidates for transplantation.
The Leukaemia Foundation has produced a booklet called Understanding Amyloidosis which is available free of charge. The Foundation also runs a number of services for people with AL amyloidosis including: support groups, education activities, online and telephone support networks, and accommodation and transport to allow people to access best practice treatments. The Foundation funds research into amyloidosis treatment.