AL amyloidosis is a very serious condition. If left untreated it is progressive and may lead to death within a year. However, many patients benefit considerably from current standard therapies for AL amyloidosis, and survive for many years after the diagnosis, with improved health and good quality of life. In addition, there have been substantial recent advances in treatments available, so there is cautious optimism regarding the future.
Principles of AL Amyloidosis Treatment
Treatment of all types of amyloidosis is currently based on the following principles:
- Reducing the supply of amyloid forming precursor proteins.
- Supporting the function of organs containing amyloid.
SAP scans in thousands of patients with various forms of amyloidosis have shown that when amyloid precursor protein supply is controlled:
- Existing amyloid deposits often regress (become smaller).
- New amyloid deposits stop appearing.
- Organ function is often preserved and may also recover.
In AL amyloidosis, treatment is directed towards the abnormal plasma cells (usually in the bone marrow), which produce the abnormal light chains that form amyloid deposits. Treatment regimes are referred to as “chemotherapy”. The drugs used are similar to those used in the related condition of multiple myeloma. In recent years, newer types of drugs have been introduced, which appear to be more effective than previous regimes, with fewer side effects.
A sink analogy
It may be helpful to envisage amyloid deposits blocking up the organs as somewhat similar to the everyday situation of a blocked sink.
Water running from the tap at full blast represents the amyloidogenic free light chains pouring out of abnormal plasma cells. The small sink outlet represents the body’s limited capacity to clear amyloid deposits away from the organs.
If the tap is turned on fully so that the rate of running water far exceeds the drainage rate, water builds up in the basin despite some drainage. If the tap is turned down sufficiently, the water can drain away slowly.
In AL amyloidosis, if the rate of light chain production can be turned down sufficiently, amyloid stops accumulating in the tissues. Amyloid deposits may even be cleared away faster than they are produced.
AL amyloidosis is a very varied disease. Each patient’s disease is caused by their own, unique abnormal light chains. Manifestations of illness differ considerably between patients. The most suitable treatment for each individual depends on a number of factors including:
- quantity of amyloid
- organs affected- heart and kidney function are especially important for treatment decisions
- other diseases and general health
- personal preference
Treatment should be individually tailored after consultation with the NAC doctors. Occasionally chemotherapy is not recommended, under the following circumstances:
- mild or non-progressive amyloidosis
- localised amyloidosis
- a patient who is too ill to benefit from chemotherapy (very rare)
For most patients, doctors at the NAC do recommend drug treatment. There are several drugs which have been shown to:
- halt progression of AL amyloidosis
- improve symptoms
- prolong patients’ lives
Patients receiving treatment for AL amyloidosis usually do not start to feel better straight away. They may actually feel worse (due to drug side effects) for some time before they start feeling better. Although the drugs prevent the build up of new amyloid deposits they do not directly affect the existing amyloid deposits. Once the drugs are preventing the build-up of new fibrils, existing amyloid deposits may regress as they are cleared by the body’s own mechanisms, but this may take some time.
Drugs for AL amyloidosis
Both AL amyloidosis and multiple myeloma are caused by abnormal plasma cells in the bone marrow, as explained here. Treatment regimens for AL amyloidosis have essentially been adapted from those developed for multiple myeloma. The percentage of plasma cells in the bone marrow is far smaller in AL amyloidosis than in myeloma. So treatment for AL amyloidosis is often less prolonged and requires less intense dosage of drugs than myeloma.
Patients with AL amyloidosis are usually treated with a combination of different drugs, taken simultaneously. Each drug acts by a different mechanism to block the activity of the abnormal plasma cells in the bone marrow.
When making treatment decisions about which drugs to recommend for patients with AL amyloidosis, doctors at the NAC aim to achieve a balance between:
- Achieving a good response to treatment as rapidly as possible in order to halt the damage caused to organs by the amyloid deposits.
- Minimising illness due to drug side effects.
Many patients achieve a good response to treatment after just 3 cycles of treatment, and laboratory tests sometimes show improvement even earlier than this.
General information about drug side effects
Detailed information on each of the drugs that may be used in treatment of AL amyloidosis is provided in patient Infoguides published by the charity Myeloma UK. These are distributed to patients at the NAC, and are available here.
Assessment of treatment response
Response to treatment is assessed regularly using a number of different tests. Some of these tests take place at the local treating hospital and some at the NAC follow up visits.
It is very important that all patients receiving chemotherapy for AL amyloidosis come back to the NAC for a thorough assessment after completing three cycles of chemotherapy.
This used to be called ‘the three month visit’. However, it may take a few weeks after the first NAC appointment before local doctors start chemotherapy treatment. Also, many chemotherapy regimens involve five week cycles. So in fact this crucial appointment which must take place after three chemotherapy cycles is often scheduled for four months or longer after the first visit to the NAC. Subsequent visits to the NAC are usually recommended every six months – 1 year, depending on individual considerations.
A number of measures are used to evaluate the response at the level of:
- the abnormal plasma cells (haematological response)
- amyloidotic organ function deposits (organ response)
Improvement in organ function occurs slowly and is dependent on the haematological response.
Why is it so important for all patients to attend the three cycle visit?
The three cycle visit is an important turning point for AL amyloidosis patients treated with chemotherapy. It is the earliest opportunity for assessment of how well the patient is responding to chemotherapy. Plans for continued treatment are based on the assessment at this visit. The ongoing ALchemy study has shown that the earlier that we pick up on treatment responses, and adjust management accordingly, the better the patient’s outcome in the long term.
Some patients live a long way from the NAC, and they may be feeling unwell after three cycles of chemotherapy. Nevertheless, the NAC consultants recommend very strongly that all patients should attend this appointment, as it can have a critical impact on the patient’s progress and the outcomes of the treatment. The NHS funds all travel expenses for this visit. Overnight accommodation is also funded by the NHS and can be arranged close to the Royal Free Hospital. Please contact 0207 433 2813.
Free light chains (FLCs)
AL amyloidosis is caused by abnormal plasma cells which produce amyloidogenic free light chains (FLCs). The abnormal light chains are called ‘free’ light chains because they are not linked to heavy chains within antibodies, like normal light chains. For further detail on normal antibodies see here . Free light chains exist freely in the bloodstream until they deposit in the organs as amyloid fibrils which then cause organ damage.
There are two different types of light chain:
• kappa (k) chains
• lambda (l) chains
Under normal circumstances, concentrations of both kappa and lambda light chains are very low in the bloodstream. In AL amyloidosis, abnormal plasma cells produce a large quantity of one particular type of light chain – either kappa chains or lambda chains. The concentration of the other free light chain usually remains at or close to normal levels in the blood.
FLC concentration is measured to assess plasma cell response to treatment. Introduction of this test about 10 years ago was a landmark advance in the management of patients with AL amyloidosis. Sensitive blood tests can detect abnormal FLC concentrations in about 95% of patients with AL amyloidosis.
Blood concentration of FLCs is a sensitive measure of treatment effects on the abnormal plasma cells.
Understanding FLC results
It is often helpful for patients and carers to understand what their FLC results mean. When AL amyloidosis is first diagnosed, the free light chain ratio is checked:
- If the abnormal plasma cells are secreting kappa chains, the kappa/ lambda ratio is checked.
- If the abnormal plasma cells are secreting lambda chains, the lambda/kappa ratio is checked.
After that, when monthly FLC tests are used to follow the patient’s response to chemotherapy, the most useful test is called the dFLC (difference between involved and uninvolved FLCs). For this test, the concentration of the normal light chain type is subtracted from the concentration of the abnormal light chain type:
- If a patient with AL amyloidosis has amyloid due to abnormal production of kappa chains, dFLC concentration is kappa chain concentration minus lambda chain concentration.
- If a patient with AL amyloidosis has amyloid due to abnormal production of lambda chains, dFLC concentration is lambda chain concentration minus kappa chain concentration.
When treatment is successful, the earliest test which shows improvement is the FLC concentration.
FLC concentration drops before there is measurable improvement in the function of affected organs, before patients start to feel better and before there is any visible change in amyloid deposits seen on SAP scans.
The goal of therapy is to achieve either a complete response (CR) or a very good partial response (VGPR). In the event of a partial response (PR), doctors often consider a change in treatment regime. Responses are defined as follows:
- Complete response (CR): negative serum and urine immunofixation and normal FLC concentration with normal kappa/lambda ratio
- Very good partial response (VGPR): dFLC concentration below 40 mg/L
- Partial response (PR): more than 50% reduction in FLC concentration
At the first visit to the NAC, patients are provided with several empty vials for blood samples and padded envelopes addressed to the NAC. They can go to the GP or the local hospital clinic for the blood to be taken and then send the sample to the NAC in the post. The FLC concentration is then measured in the NAC laboratories so the NAC doctors can assess the results and make appropriate treatment recommendations.
When heart muscle is damaged by amyloid deposits, the results of the following specialised blood tests may be abnormal:
1. N-terminal fragment of brain natriuretic peptide (NT-proBNP)
2. High sensitivity troponin
High levels of these 2 markers may be due to severe heart disease. But doctors need to bear kidney function in mind when interpreting NT-proBNP levels. Since NT-proBNP is partially cleared from the body by the kidneys, raised levels may reflect kidney disease rather than heart disease. This test is therefore most useful in patients with normal kidney function.
The results of these blood tests often help to provide doctors with information in AL amyloidosis patients. This information may be used to stage and evaluate risk at the time of diagnosis and to assess treatment response. The levels of NT-proBNP may fall dramatically within weeks after chemotherapy, before any change is observed on echocardiography or cardiac MRI. Patient outcome is often good when a dramatic fall is observed. But there is sometimes a transient early increase in NT-proBNP in patients receiving the immunomodulatory drugs thalidomide and lenalidomide. The reason for this is unknown.
Other measures of response
A combination of patient symptoms, blood tests and imaging tests may be used to assess the function of the different organs affected by AL amyloidosis. Organ function improvement is often seen some time after there is evidence of a haematological response, according to the FLC levels.
The SAP scan was developed at the NAC and this is the only place in the world where SAP scans are routinely available. In most patients, a scan is performed approximately every 6 months. In some patients regression of amyloidosis deposits is observed and in others there is stabilisation. There is not necessarily a clear correlation between SAP scan findings and organ response. Sometimes organ function improves significantly despite SAP scan appearance of stable amyloid deposits.
For patients and their families, the most important measure of treatment success is how they actually feel. Sometimes there is a good response according to blood tests before the patient actually starts to feel better. This may be because of the side effects of the drugs. Many patients start to actually feel the benefits of the drugs once they stop taking them. There are often improvements in breathlessness and leg swelling as heart function and kidney function improve. Successful treatment also prolongs life. When Professor Sir Mark Pepys first started looking after patients with amyloidosis in 1980, most patients with AL amyloidosis could only expect to live for a few months and progress thereafter was slow. Since the NAC was established in 1999, treatments have improved more rapidly and with modern management, many patients survive for years after their diagnosis, sometimes over a decade.
Therapy to support the function of organs containing amyloid deposits is critical in AL amyloidosis. Such therapy can:
- delay organ failure
- help to reduce symptoms
- maintain quality of the patient’s life
- prolong survival
This allows time for the underlying disorder to respond to the drug treatment.
Usually patients’ regional hospital consultants and GPs are responsible for supportive therapy. Doctors treating patients with AL amyloidosis need to be aware of some special considerations. Supportive therapy for organs affected with amyloid differs in many ways from therapy for other, more common causes of organ impairment. Many doctors have seen few patients with amyloidosis. It is therefore important for patients and their doctors to keep in contact with the NAC doctors and nurses.
Diuretics (water tablets) and careful maintenance of fluid balance through salt and drinking restriction are the mainstays of treatment for patients with AL amyloidosis affecting the heart and kidneys.
If kidney function deteriorates to such a degree that the kidneys effectively stop working altogether (end stage renal failure), patients require dialysis, and may sometimes be candidates for kidney transplantation.
It is very important that all AL amyloidosis patients should tell the doctors and nurses at the NAC and at their own hospital about all drugs they are taking, and all complementary, natural or homeopathic medications. Please note that the information here is general and patients should always consult their doctors and nurses regarding their own medications.
There is more detailed discussion of treatments that can help with patients’ symptoms here.
Relapsed disease and advanced disease
For most patients there are treatment options available.
In the case of relapsed disease, the doctors at the NAC often recommend different chemotherapy drugs from the drugs that were used previously. Such patients may then respond well to the new regime.
Even in patients who have advanced disease at the time of diagnosis, there is sometimes a good response once treatment is started.
Each patient’s situation is unique and should be discussed with the NAC doctors and nurses.
Some patients with AL amyloidosis may benefit from organ transplantation. This is most likely to be the case in patients under the age of 60 years with single organ disease. However, transplantation is not suitable for most patients. This is because AL amyloidosis usually affects several organs, and many patients are too old or generally unwell for transplantation to be considered.
The results of kidney transplants in carefully selected patients are promising. Kidney transplants have been performed in AL amyloidosis patients who have had a good response to chemotherapy and in some patients who had no response to therapy.
Heart transplantation in patients with AL amyloidosis has had disappointing results.
Around 15 years ago, AL amyloidosis was widely regarded as an untreatable and rapidly fatal disease. However, the field is rapidly changing. Most patients can now expect to survive and experience a good quality of life for several years after diagnosis. Treatment results are best in patients who are diagnosed early or who do not have severe organ damage at the time of diagnosis. Results are also best at specialist centres, such as the NAC.
Several newer and better chemotherapy drugs have become available and entered routine use over the last few years. Patients are already experiencing significant benefits from these treatments. In addition, there are a number of new drugs currently in development in research centres around the world. A new approach to eliminate existing amyloid deposits, invented in the Wolfson Drug Discovery Unit, is being developed and undergoing clinical testing in collaboration with GlaxoSmithKline. The field of AL amyloidosis has moved into a very exciting era with hope for more effective treatments and even an eventual cure for this disease.