A Concise Review
of the Disease and
Treatment Options
Al
Amyloidosis
Prepared by
Dr Raymond Comenzo
Dr Diana Samson
Acknowledgements
International Myeloma Foundation (UK) gratefully acknowledges the help and support
of the following for preparing and reviewing this publication.
Publication prepared by:
Dr Diana Samson (Hammersmith Hospital, London)
Dr Raymond Comenzo (Memorial Sloan Kettering Hospital, New York)
Publication reviewed by:
Dr Jane Apperley (Hammersmith Hospital, London)
Prof Brian GM Durie (Cedar Sinai Comprehensive Cancer Centre, Los Angeles)
Prof Philip Hawkins (Royal Free Hospital, London)
Dr Atul Mehta (Royal Free Hospital, London)
Published by International Myeloma Foundation (UK), November 2001
9 Gayfield Square, Edinburgh EH1 3NT
Tel (Admin): (44) 0131 557 3332
Freephone Support Line: 0800 980 3332
Fax: (44) 0131 556 9720
E-mail: TheIMF@myeloma.org.uk
#
Website: www.myeloma.org.uk
Contents
p 2
Introduction
p 5
Clinical Features
p 10
Diagnosis
p 14
Investigation of Organ Involvement
p 17
Prognosis
p 19
Treating AL Amyloidosis
p 23
Conclusions
p 25
References
p 27
Appendices
p 29
Contacts
1
Introduction
Amyloid deposition can occur in a wide range of disorders, including
Alzheimer's disease, dialysis arthropathy and reactive systemic amyloidosis
(AA amyloidosis). There are also a number of rare hereditary amyloid
disorders. All forms of amyloidosis involve the deposition in the tissues of
protein in the form of characteristic fibrillar aggregates. Amyloid fibrils can
be derived from many different types of protein, but the particular protein is
always deposited in combination with the glycoprotein serum amyloid P
component (SAP), which is a normal plasma protein. Amyloid can be
identified if a tissue biopsy is stained with specific chemicals such as the
dye Congo red (Figure 1). Amyloid in tissue stained with Congo red
possesses a unique property as its colour changes from orange-pink to
`apple-green' when viewed microscopically with polarised light. Amyloid
also has a distinctive morphology or structure when viewed with an
electron microscope, forming linear non-branching fibrils with a width of
approximately 9.5 nanometers (Figure 2). In AL amyloidosis the amyloid
fibrils are derived from monoclonal immunoglobulin (Ig) light chains, which
are deposited in the tissues in association with SAP. Amyloid fibrils are
more commonly derived from l than from k light chains. The reason that
some light chains are amyloidogenic is not clearly understood, but they
seem to contain hydrophobic residues which promote aggregation
(Schormann et al, 1995).
Figure 1: Congo red staining
Amyloidosis:
tissue biopsy and
Congo red staining
Figure 2: Electron microscopy
C. EM
3
AL amyloidosis can complicate most clonal B-cell dyscrasias. It occurs in
10% - 15% of patients with multiple myeloma (MM), and more rarely in
Waldenstrom's macroglobulinaemia and other lymphoid malignancies.
However most cases of AL amyloidosis are associated with more subtle
B-cell dyscrasias, analogous to monoclonal gammopathy of undetermined
significance (MGUS). Thus serum and/or urinary paraprotein is typically
present at low levels with fewer than 10% plasma cells in the bone marrow,
and in approximately 5-10% of patients with AL amyloid no paraprotein is
detectable in either serum or urine. The term primary systemic amyloidoisis
is usually used to mean AL amyloidosis not associated with myeloma or
other malignant B-cell disorder.
AL amyloidosis is a rare disorder with an estimated annual incidence of
about 3000 cases in the United States (Gertz et al, 1999) and about
300-600 cases in the UK. Although in the majority of cases the underlying
B-cell clone is not malignant, survival is poor due to progressive organ
failure. Without treatment, the majority of AL patients die within two years of
diagnosis. The presence or absence of symptomatic amyloid cardiac
involvement is the most important prognostic factor with respect to survival.
Treatment can range from expectant observation to oral chemotherapy to
stem cell transplantation, but recently the poor prognosis of AL amyloidosis
has led to the use of the more intensive treatment regimens, such as
would be used in myeloma. Using such regimens, it has become evident
that if the production of the amyloidogenic protein can be halted, the
amyloid can regress. However the morbidity of treatment is significantly
greater than in myeloma patients and selecting the appropriate treatment
approach for a patient with AL amyloidosis remains a difficult problem.
4
Clinical Features
of AL Amyloidosis
The organs most commonly involved are the kidneys and the heart, and so
nephrotic syndrome and/or congestive cardiac failure are common modes
of presentation. However, almost any other organ except the brain may be
involved (Gillmore et al, 1997; Falk et al, 1997; Gertz and Kyle, 1997; Gertz
et al, 1999) and AL amyloidosis can present in a wide variety of ways, often
causing diagnostic difficulty until the possibility of the disorder is considered.
Neuropathies, both peripheral and autonomic, occur in 10-20% of patients.
The lungs, liver, gut, spleen, joints and skin may also be affected.
Macroglossia is rare but characteristic of AL amyloidosis, and involvement of
nerves, skin muscles and the gastro-intestinal tract are more common than
in AA amyloid. The vast majority of AL amyloidosis patients report fatigue,
weakness and decreased libido at diagnosis. Criteria for defining
amyloid-related organ involvement are provided in Table 1.
Table 1
Clinical and non-invasive criteria for determining
amyloid-related major organ involvement*
HEART
Echocardiogram showing increased ventricular wall thickness and
thickened valves with no history of hypertension or valvular heart disease
Electrocardiogram showing unexplained low voltage
NYHA Functional Capacity Class 2 or higher without ischaemic
heart disease
KIDNEYS
Twenty-four hour proteinuria greater than 500mg
LIVER
RUQ discomfort
Early satiety
Hepatomegaly
- With normal alkaline phosphatase
- With normal C-reactive protein
PERIPHERAL NERVOUS SYSTEM
Orthostatic hypotension
Lower extremity sensory or polyneuropathy
Impotence, diarrhoea or constipation
*In all instances, a positive biopsy remains the gold standard
6
Sixty percent of patients with AL amyloidosis are between fifty and seventy
years of age at diagnosis; and only 10% are younger than fifty. Historically,
the time from onset of symptoms to the diagnosis of AL has varied
depending on the dominant symptomatic organ system. In patients
presenting with congestive heart failure or nephrotic syndrome, symptoms
usually have been present for a median of three months. Patients with
neuropathy or slowly progressive hepatomegaly may be symptomatic for a
year prior to diagnosis.
Cardiac Involvement
About 20% of AL patients have dominant symptomatic cardiac amyloid at
diagnosis. Symptoms and signs of congestive heart failure often reflect
right-sided dysfunction with relatively preserved left ventricular function
despite thickening of the ventricular walls due to deposits of amyloid.
Patients may complain of breathlessness with exertion, prominent neck
veins and lower extremity oedema. Increased jugular venous distension,
a right-sided third heart sound and congestive hepatomegaly is often seen.
Heart failure due to amyloid is due to a restrictive cardiomyopathy, resulting
in diminished cardiac output. This is exacerbated by any increase in the
heart rate, since the main problem is diastolic dysfunction. In addition to
causing heart failure, cardiac amyloid can lead to conduction disturbances
and arrhythmias. Premature ventricular contractions are the most common
arrhythmias,but supraventricular arrhythmias are also frequent and may
have life-threatening haemodynamic consequences. Other manifestations
include sinus arrest and various conduction defects, including
atrioventricular block. Electrocardiographic findings frequently include low
voltage and a pseudoinfarct pattern with Q waves in the anterior chest
leads. The most common echocardiographic finding is ventricular
hypertrophy, with thickening of the posterior wall and septum.
Renal Involvement
Nearly a third of AL amyloid patients have dominant renal amyloid at
diagnosis. Typically amyloid is deposited in the glomeruli leading to
proteinuria and nephrotic syndrome. AL amyloid patients rarely present with
advanced renal failure, though renal failure frequently develops during the
course of the disease. Symptoms and signs of nephrotic syndrome include
peripheral oedema, "frothy" urine, low serum albumin and elevated
cholesterol. The fatigue and loss of energy associated with nephrotic
syndrome can be debilitating; in addition, the presence of pleural or occult
pericardial effusions can give a picture of heart failure. Patients may be
salt-avid and yet volume-depleted at times, causing nausea and vomiting,
and complicating attempts at diuresis. Volume-depletion can also cause
7
orthostatic hypotension in the absence of autonomic neuropathy.
A significant number of patients with dominant renal amyloidosis are,
however, asymptomatic and are diagnosed after proteinuria is revealed as
part of a routine examination.
Peripheral Neuropathy
A peripheral sensorimotor neuropathy occurs in 20% of patients.
There may be exquisitely painful sensory symptoms. Examination typically
reveals a symmetrical lower extremity neuropathy, as opposed to chronic
inflammatory demyelinating syndromes that can present with an
asymmetric picture. Involvement of the autonomic nerves is common,
resulting in a variety of symptoms including orthostatic hypotension,
chronic nausea, and constipation or diarrhoea. In neuropathic male patients
impotence is a common finding. Orthostasis may involve profound postural
hypotension without a corresponding increase in heart rate, since the heart
may suffer dysautonomia and not respond appropriately.
Hepatic and Gastro-intestinal Involvement
Symptomatic hepatic or gastrointestinal involvement with amyloid can
occur simultaneously or separately. Symptoms of hepatic involvement may
include early satiety, weight loss, chronic nausea, dyspepsia, and right
upper quadrant fullness or discomfort. Gastrointestinal involvement can
present with frank rectal bleeding as well as symptoms of nausea, food
intolerance, and weight loss. It is important to bear in mind that many
gastrointestinal symptoms may be a function of autonomic neuropathy
interfering with gastric motility. Involvement of the gastrointestinal tract can
be focal or diffuse and symptoms usually are linked to the location and
extent of AL amyloid deposits. The entire length of the gastrointestinal tract
may be involved; macroglossia, which occurs in about 10% of patients,
can be massive and produce inability to eat or drink normally, airway
obstruction and sleep apnoea. Achalasia, haematemesis, gastroparesis,
and pseudo-obstruction are among the many possible manifestations of
gastrointestinal amyloid. Rarely, duodenal or bowel perforation due to
amyloid occurs; the decision to allow surgical management of such
problems should be based on the presence or absence of co-morbid
organ involvement. If symptomatic heart or renal amyloid disease is also
present, conservative non-surgical management is preferred.
Involvement of Other Organs
Many other organ systems can be involved with amyloid including
connective tissue, skin and muscles, and the respiratory tract and
genitourinary system. An erosive arthritis may occur. Carpal tunnel
8
syndrome occurs in about 40% of patients. Macroglossia or periorbital
ecchymoses ("racoon or panda eyes") occur in about one fifth of AL
amyloidosis patients and are pathognomonic for AL disease. In some cases
the process is truly localised in association with a very localised infiltrate of
monoclonal plasma cells. Localised AL amyloidosis usually does not
progress to systemic disease and generally carries a favourable prognosis.
9
Diagnosis
The diagnosis of AL amyloidosis should be considered in patients who
present with congestive heart failure without ischemic heart disease or with
nephrotic syndrome, peripheral polyneuropathy, or unexplained
hepatomegaly.
Histology
The diagnosis of amyloidosis usually requires histological confirmation.
A tissue diagnosis of amyloid can usually be established by performing
amyloid stains (Congo red) on biopsies of involved organs, or less
invasively on biopsy of subcutaneous abdominal fat or rectal biopsy.
Sub-cutaneous fat biopsy has a higher pick-up rate than rectal biopsy but
is dependent on operator experience. Having established the diagnosis of
amyloid, immunochemistry should then be performed to determine the type
of amyloid. Although antibodies to AA fibrils are sensitive and specific,
using standard Ig light chain antisera to stain AL fibrils is less satisfactory,
and gives potentially useful results in only 50% of AL cases. The histological
diagnosis of AL amyloidosis therefore usually rests on the presence of
amyloid on Congo red but with negative immunochemistry for AA amyloid;
antibodies to other types of amyloid fibrils are also available, and can help
exclude the rarer forms of amyloidosis.
Investigation for B-Cell Dyscrasia
The diagnostic work-up should always include electrophoresis and
immunofixation of serum and urine to look for a monoclonal paraprotein.
It is important to perform immunofixation even if routine protein
electrophoresis is negative, because the paraprotein in AL amyloidosis is
often present at very low level. In 5-10% of patients the causative
paraprotein cannot be detected in serum or urine, even using
immunofixation, so a negative result does not exclude the diagnosis of
AL amyloidosis. A bone marrow aspirate and biopsy should also be
performed with staining for kappa and lambda to detect a clonal plasma
cell population. In 60% of patients the proportion of plasma cells is 10% or
less. Thus the majority of patients have a monoclonal protein identified on
immunofixation of either serum or urine, and a bone marrow biopsy
showing a small clonal population of kappa or lambda staining plasma
cells. It is of value to stain the trephine biopsy for amyloid as bone marrow
involvement characteristically occurs in AL amyloidosis.
11
SAP Scintigraphy
SAP is a normal serum protein that binds to amyloid fibrils of any origin,
and which when labelled with I123 can be used for whole body
scintigraphic imaging (Gillmore et al, 1997). A positive SAP scan can
confirm the presence of amyloid, and the pattern of distribution can provide
some evidence as to the type of amyloid; as noted above, bone marrow
involvement is characteristic of AL amyloid and the pattern of visceral
involvement generally is much more heterogeneous in AL amyloid than in
other types. The SAP scan is of particular value in determining the extent of
organ involvement and in monitoring disease progression and response to
therapy. Note that it is not possible to assess cardiac involvement with the
SAP scan because of background signal from the blood pool and cardiac
movement. Involvement of the heart is best identified and assessed by
echocardiography.
Further Investigation
Laboratory and non-invasive testing in all patients should include a full blood
count, coagulation screen, renal and hepatic blood chemistries, a 24 hour
urine for total protein, chest X-Ray, electrocardiogram and echocardiogram.
In patients with relevant symptoms or signs, a gastric emptying scan, nerve
conduction studies, and pulmonary function tests may be useful.
The peripheral blood picture is usually normal. Anaemia is rare; if present, it
is usually due to unless the amyloidosis is associated with myeloma,
gastrointestinal bleeding and consequent iron loss, massive marrow
deposits of amyloid, or advanced renal dysfunction causing low levels of
erythropoietin. Coagulation tests may reveal abnormalities of the INR or the
partial thromboplastin test (APTT) and, when they do, should be further
evaluated for the presence of thrombin inhibitors (about 30% of patients)
and factor X deficiency (about 5% of patients).
Proteinuria is common; levels that exceed 150 mg/day are abnormal and
those that exceed 3 g/day are considered nephrotic. In nephrotic syndrome
serum cholesterol level may be elevated, and the serum albumin level
decreased. Abnormalities of liver function tests related to hepatic amyloid
are often limited to an elevated alkaline phosphatase; a rising bilirubin level is
a poor prognostic sign and usually a terminal event.
The most common echocardiographic finding is ventricular hypertrophy with
thickening of the posterior wall and septum. Other findings include low
voltage and a pseudoinfarct pattern. Chest X-ray may show prominent
vascular markings and pleural effusions, although the latter are more often
associated with left-heart failure or nephrotic syndrome with
hypoalbuminaemia.
12
Differential Diagnosis
A diagnostic service for amyloid including SAP scanning is available in the
UK at the National Amyloidosis Centre (Royal Free Hospital, London) the
contact details for which can be found at the back of this book. A full
evaluation can assist in confirming the diagnosis of AL amyloid. This is
important because, as noted above, it is often not possible to make a
definitive diagnosis of AL amyloidosis on histology. Thus a patient with
non-AA amyloidosis but no evidence of a monoclonal B-cell disorder may
indeed have AL amyloidosis, while a patient with non-AA amyloidosis and a
paraprotein may not in fact have AL amyloid but have a rare familial form of
amyloid together with an incidental MGUS. DNA analysis may be
necessary to make the latter distinction.
13
Investigation of
Organ Involvement
Once the diagnosis has been confirmed, further investigations are needed
to define the pattern of organ involvement and the degree of functional
impairment of the involved organs. The majority of patients will have an
obvious dominant involved organ system. Some will have evidence of
several involved systems but symptoms relating to the dominant system,
while others will have more than two major systems involved, often
associated with a picture of progressive deterioration both in terms of
symptomatology and non-invasive measures of organ function.
Cardiac Involvement
Investigations should include echocardiogram to estimate mean left
ventricular wall thickness (average of posterior wall and septum) and
assess diastolic and systolic function and evidence of restrictive
physiologic changes, or MUGA for left ventricular ejection fraction;
electrocardiogram for voltage abnormalities; PA and lateral chest x-ray;
pulmonary function tests including DLCO, and oxygen saturation by pulse
oximetry. Cardiac involvement is defined as the presence of a mean left
ventricular wall thickness on echocardiogram greater than 11 mm in the
absence of a history of hypertension or valvular heart disease, or of
unexplained low voltage (< 0.5 mV) on the electrocardiogram (Falk et al,
1997). Clinical status is based on history, physical exam and New York
Heart Association (NYHA) heart failure class (see Appendix A). Patients who
are New York Heart Association (NYHA) class 1 with evidence of cardiac
amyloid by echocardiogram or electrocardiogram are categorized as having
asymptomatic cardiac involvement. Patients who are New York Heart
Association (NYHA) class 2 or higher with evidence of cardiac involvement
are categorized as having dominant cardiac involvement (amyloid
cardiomyopathy).
Renal Involvement
Investigations should include urea and creatinine, 24hour urinary protein
and creatinine clearance. Renal involvement is defined as proteinuria > 0.5
g/day. There is frequently deterioration in renal function over time, so it is
important to monitor urea and creatinine. Creatinine clearance will provide a
more accurate measure of renal function than serum creatinine.
Neurological Involvement
Investigations should include: Orthostatic signs, full neurological
examination, gastric emptying scan (if symptoms of gastroparesis); EMG
(if neuropathy present). Neuropathic involvement is defined based on
clinical history, autonomic dysfunction with orthostasis, and abnormal
sensory and/or motor findings on neurological examination.
15
Hepatic and Gastro-intestinal Involvement
Gastrointestinal involvement is defined by symptoms of nausea or early
satiety, gastric atony by gastric emptying scan, or gastrointestinal bleeding
with confirmation by tissue biopsy. Hepatic involvement is defined as
hepatomegaly with an alkaline phosphatase > 200 U/L (upper limit of
normal 130 U/L).
Other Organ Involvement
Soft tissue and lymphatic involvement are defined based on classic
physical examination findings (macroglossia, shoulder pad sign,
raccoon/panda eyes, carpal tunnel syndrome, arthritis and swollen joints
due to amyloid deposition in the synovium) and biopsy.
16
Prognosis
Because of the protean manifestations and rarity of this disorder,
AL amyloidosis sometimes goes undiagnosed until the patient has become
gravely ill due to failure of several major organ systems. The median
survival of patients with AL amyloidosis is around 12 months, but prognosis
is correlated with the dominant organ involvement. In patients with
dominant or symptomatic cardiac involvement, the progression of restrictive
disease, bi-ventricular failure and arrhythmias, goes hand in hand with a
decline in performance status. Survival is negatively influenced by
diminished left ventricular ejection fraction and by increased mean left
ventricular wall thickness. In patients with dominant cardiac involvement,
median survival is about 6 months from the onset of symptoms, although
in patients with asymptomatic cardiac involvement, treatment with
chemotherapy may prevent the progression of disease.
For patients with symptomatic polyneuropathy in association with
orthostasis, gastroparesis, nausea and chronic diarrhoea, performance
status and survival are also severely compromised. Peripheral neuropathy
rarely improves with treatment and is an indicator of poor prognosis
(Rajkumar et al, 1998). Of note, the performance status of patients with
dominant renal involvement (i.e., nephrotic syndrome) often improves after
treatment with gentle use of diuretics and salt restriction (<1500mg/day);
however, patients with nephrotic syndrome remain at high risk for
developing renal failure and becoming dialysis dependent, a situation that
occurs in nearly one-fifth of AL amyloidosis patients.
Although the median survival of patients with AL amyloidosis is only 1-2
years, approximately 5% of patients treated with alkylating agents survive
for 10 years or more (Kyle et al, 1999). These long-term survivors are
predominantly patients without symptomatic cardiac involvement or
peripheral neuropathy and with relatively normal renal function.
18
Treating AL
amyloidosis
The approach to management is to reduce the production of the
amyloidogenic light chain by chemotherapy directed against the plasma
cell population. The same therapeutic approaches are therefore used to
treat AL amyloidosis as are used in multiple myeloma. These include
low-dose oral chemotherapy regimens (e.g. melphalan and prednisolone),
intravenous chemotherapy (e.g. vincristine, adriamycin and
dexamethasone) and, in selected patients, high-dose chemotherapy with
autologous transplantation. The choice between these approaches is
particularly difficult in AL amyloidosis. Although the plasma cell dyscrasia is
generally subtle, a treatment that works only gradually may be ineffective
because death may occur before there is time for the amyloid deposition to
regress. Because deposits in key viscera such as the heart or liver may
progress rapidly, AL amyloid can be an acutely fatal disease with death
occurring soon after diagnosis, although most patients do not succumb
quite so quickly. There is therefore an argument that patients with a higher
amyloid load would benefit from more aggressive treatment; however these
same patients are at highest risk of treatment related complications, which
are a far greater problem in patients with AL amyloidosis than those with
multiple myeloma. To add to the difficulty of selecting appropriate
treatment, there have been very few randomised controlled trials in
AL amyloidosis. Most available data comes from non-randomised studies
that are based on selected patients; moreover the criteria for selection are
not always entirely clear. Outcome has variably been described in terms of
response rate, i.e. proportion of patients with improved performance status
and organ function and/or prolongation of survival.
Melphalan and Prednisolone
Oral MP was the first effective treatment for amyloidosis and has been
shown in randomised, controlled trials to improve the outlook for patients
with AL amyloidosis as compared with placebo (Kyle and Greipp, 1978;
Kyle et al; 1985; Kyle et al, 1997). Approximately 30% of patients show a
benefit in terms of improved organ function and median survival is
prolonged from 12 to 18 months. Patients with nephrotic syndrome fare
better than those with cardiac involvement, of whom only 15 -20%
respond. This partly reflects the fact that MP takes approximately a year to
produce maximum benefit. The side effects of melphalan include
myelotoxicity and in patients who survive for some years there is a small
risk of secondary leukaemia.
Alkylator-based Combination Chemotherapy
A prospective randomised trial of MP versus the VBMCP combination
chemotherapy regimen (vincristine, BCNU, melphalan, cyclophosphamide
and prednisolone) showed no difference in response rate or survival (Gertz
et al, 1999).
20
Vincristine, Adriamycin and Dexamethasone (VAD)
This regimen induces remission in over 80% of patients with myeloma and
the response is very rapid, with maximum response reached after 2 or 3
months in most patients. This rapidity of response could prove particularly
advantageous in treating AL amyloidosis. There are several anecdotal
reports showing improved organ function and reduction of amyloid load in
patients treated with VAD (Persey et al; 1996; Wardley et al, Sezer et al,
2000) but there have been no formal clinical trials. It is important to note that
patients with amyloid are more vulnerable than myeloma patients to some of
the side effects of this regimen including neuropathy, fluid retention and
cardiac toxicity. Dexamethasone alone appears to produce responses in
occasional patients (Gertz et al 1999b, 1999c)
High-dose Therapy and Transplantation
As in myeloma, neither complete elimination of the clonal plasma cell
disease nor complete resolution of amyloid related organ dysfunction is
observed with any frequency in patients treated with oral melphalan and
prednisolone. Neither dexamethasone nor combination chemotherapy
significantly improves such outcomes or prolongs survival beyond that seen
with oral melphalan and prednisolone. However, with high-dose melphalan
and autologous stem cell transplantation, durable complete responses of
the plasma cell disorder, improvements of amyloid-related organ disease
and prolonged survival have been observed (Comenzo et al 1998, 1999;
Patriaca et al, 1999; Sezer et al, 1999; Gertz et al, 2000b).
In the series published to date there has been a significant (20%) risk of
transplant-related death (Comenzo et al, 1998, Comenzo, 2000; Gertz et al,
2000a). Patients with more than 2 major organ systems involved and
evidence of worsening function have a higher transplant-related mortality, as
do patients with symptomatic cardiac involvement. Unpublished data from
the UK again indicate that patients may do well with high-dose therapy but
indicate a high treatment-related mortality (TRM) in patients with a high
amyloid load on SAP scan as well as in those with cardiac involvement,
autonomic neuropathy or gastro-intestinal disease associated with
haemorrhage (Gillmore et al, in preparation).
As with high-dose therapy for other diseases, it is likely that the best results
will be obtained in patients transplanted early in the course of their disease
and without significant organ dysfunction. Patients who have dominant
nephrotic syndrome, with up to two organ systems involved and without
symptomatic cardiac involvement are excellent candidates for aggressive
therapy with stem cell transplant and are likely to benefit from it. Patients
with dominant cardiac amyloid and no other organ involvement should be
21
considered for cardiac transplant followed by stem cell transplant. Those
with dominant cardiac amyloid and one other system involved should be
considered high-risk candidates for stem cell transplant but may still be
offered transplant unless they have histories of syncope or symptomatic
arrhythmias or recurrent pleural effusions. Patients with dominant cardiac
amyloid and any of those complicating features are unlikely to survive
attempts to collect stem cells or to treat them with high-dose chemotherapy.
Supportive care
Supportive care measures such as salt-restriction, gentle use of diuretics,
albumin infusions, use of anti-diarrhoeals, and the use of agents such as
midodrine or fludrocortisone (to treat postural hypotension) may contribute
significantly to the improved well-being of AL patients.
A global approach to diagnosing and treating patients with AL is provided in
Figure 3.
Figure 3
An approach to diagnosis and treatment of AL amyloidosis
Unexplained congestive heart failure
Nephrotic syndrome
Hepatomegaly
Orthostatic hypotension
Peripheral neuropathy
Consider AL amyloidosis
Immunofixation of serum and urine
Bone marrow biopsy with kappa/lambda and Congo red staining
Abdominal fat pad aspirate for Congo red staining
Biopsy of involved organ
Diagnosis confirmed
Stratify
Less than 3 major organ
Three or more major organ systems
systems involved
involved
Less than 50 years of age
And more than 50 years of age
NYHA cardiac functional
NYHA cardiac functional capacity
capacity class 1
class 2 or greater
Consider oral chemotherapy
Consider stem cell transplantation
Consider solid organ transplant
Consider emerging therapies
followed by stem cell transplantation
post-transplant
Consider emerging therapies
22
Conclusions
There are few acquired diseases that possess the troubling and ominous
overtones imported by the diagnosis of AL amyloidosis. It is a rare disorder
and most family and friends will never have heard of it. The mechanism of
disease is hard to comprehend, although in the UK the availability of
amyloid scans helps make the concept of deposition disease more
accessible to patients and their families. The literature on AL amyloid is
fatalistic, and the first encounters with nurses and physicians may reflect
this fatalism. Nevertheless, the increasing availability of effective treatments
for AL amyloidosis and the heightened patient and physician awareness of
the disease and of the progress that has been made at the end of the
20th century are hopeful signs for present and future patients.
24
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26
Appendix
Appendix A:
New York Heart Association Classification of Functional Capacity and Objective Assessment of
Patients with Diseases of the Heart
Functional Capacity
Class 1. Patients with cardiac disease but without resulting limitation of physical activity.
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea, or anginal pain.
Class 2. Patients with cardiac disease resulting in slight limitation of physical activity. They are
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea, or anginal pain.
Class 3. Patients with cardiac disease resulting in marked limitation of physical activity. They are
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnoea, or anginal pain.
Class 4. Patients with cardiac disease resulting in an inability to carry on any physical activity
without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at
rest. If any physical activity is undertaken, discomfort increases.
Objective Assessment
A. No objective evidence of cardiovascular disease.
B. Objective evidence of minimal cardiovascular disease.
C. Objective evidence of moderately severe cardiovascular disease.
D. Objective evidence of severe cardiovascular disease.
Examples
* A patient with minimal or no symptoms but a large pressure gradient across the aortic valve or
severe obstruction of the left main coronary artery is classified:
Function Capacity 1, Objective Assessment D
* A patient with severe anginal syndrome but angiographically normal coronary arteries is
classified:
Functional Capacity 4, Objective Assessment A
Appendix B:
Response Criteria for amyloid-related organ disease
Consensus of investigators may be needed in rare cases; usually, however, the patient's
presenting symptomatology indicates the dominant involved organ-system. At study entry the
extent of amyloid-related organ involvement is evaluated in each patient. On follow-up evaluation,
amyloid-related organ involvement is assessed as improved, stable or worsened. Responses are
defined in terms of objective measures of function. New organ disease at a follow-up visit is
always graded as worsened amyloid disease.
Specifically
For patients with cardiac involvement, an improvement or response to therapy is defined as a
decrease of > 2 mm in mean left ventricular wall thickness in patients with baseline wall
thickness > 11 mm, or a decrease in 2 classes in NYHA class (i.e., from 3 to 1). Stable disease
is defined as no evidence of clinical response and no progressive disease by clinical,
electrocardiographic and echocardiographic evaluation. Progression of cardiac involvement post-
therapy is defined by worsening clinical signs or symptoms, worsening NYHA class (i.e., from 1
27
to 3), or by an increase of > 2 mm in mean left ventricular wall thickness in a patient with
baseline wall thickness < 11 mm.
For patients with renal involvement, an improvement or response to therapy is defined as a 50%
decrease in daily proteinuria without progressive renal insufficiency.
For those with hepatic involvement, improvement is defined as a decrease in liver span of > 2
cm with a concomitant decrease of alkaline phosphatase by 50%.
For patients with neuropathic involvement, improvement is defined as normalization of orthostatic
vital signs and symptoms, and resolution of gastric atony and of abnormal findings on
neurological examination. Stabilization or worsening of renal, hepatic and neuropathic
involvement is defined by consensus based upon clinical evaluation and appropriate non-
invasive tests.
Appendix C:
Criteria for response of the plasma cell disease
The clonal plasma cell disease is assessed by electrophoresis and immunofixation of serum and
urine, by quantitative Bence Jones proteinuria and by percentage and preponderance of plasma
cells in the immunostained bone marrow biopsy as noted above.
Patients whose clonal plasma disease becomes undetectable after treatment are considered
complete responders. They must have NO previously identified clonal M-component bands on
immunofixation and NORMAL bone marrow biopsies in order to be considered complete
responders. Patients not achieving this category of response will be considered to have
persistent clonal disease, although those achieving at least a 75% reduction in baseline
measures of plasma cell activity may be considered partial responders. Patients who achieve
complete response but who show evidence of recurrence of their clonal plasma cell disease are
considered in relapse.
28
Contact
information
NHS Amyloidosis Centre
Mayo Clinic Rochester
Royal Free Hospital
200 First St. S.W.
Pond Street
Rochester, MN 55905
London NW3 2QG
USA
Tel: 020 7794 0500
Tel: 001 507-284-2511
Fax: 020 7830 2468
Fax: 001 507-284-0161
http://www.royalfree.org.uk/index.htm
www.mayo.edu:80/MayoHome.html
International Myeloma Foundation (UK)
Amyloid Treatment and Research Programme
9 Gayfield Square
Boston University School of Medicine
Edinburgh EH1 3NT
715 Albany Street, EB33
Tel: 0131 557 3332
Boston MA 02118
Fax: 0131 556 9280
USA
www.myeloma.org.uk
Tel: 001 617 638 4317
www.medicine.bu.edu/amyloid/amyloid1.htm
International Myeloma Foundation
International Headquarters
Dr Diana Samson
12650 Riverside Drive
Senior Lecturer in Haematology
Suite 206
Faculty of Medicine
North Hollywood
Imperial College, London
CA 91607
Contact address
Tel: 001 818 487 7455
Dept Haematology
Fax: 001 818 487 7454
Hammersmith Hospital
www.myeloma.org
London W12 0NN
UK Myeloma Forum
Raymond Comenzo, MD
An organisation of health professionals
Director, Cytotherapy Laboratory
engaged in the field of myeloma and
Memorial Sloan-Kettering Cancer Center
amyloidosis.
1275 York Avenue
www.ukmf.org.uk
New York,
New York 10021
Leukaemia Research Fund
43 Great Ormond Street
London WC1N 3JJ
Tel: 020 7405 0101
Fax: 020 7405 1488
e-mail: lrf@leukaemia.demon.co.uk
29
www.myeloma.org.uk
Helpline 0800 980 3332
Published by the International Myeloma Foundation (UK) November 2001
9 Gayfield Square
Edinburgh
EH1 3NT
Tel (Admin): (44) 0131 557 3332
Freephone Support Line: 0800 980 3332
Fax: (44) 0131 556 9720
E-mail: TheIMF@myeloma.org.uk
Website: www.myeloma.org.uk
Charity Registration Number: SC 026116
Company Number: 190563