Amyloidosis Diagnosis and Management

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08 Clinical Lymphoma & Myeloma November 2005

IntroductionAmyloidosis is a generic term for hyaline eosinophilic

extracellular material deposited in various tissues, which shows

polarization birefringence after Congo red staining.1 The

extracellular deposits produce diverse clinical syndromes

depending on the site of organ deposition. Amyloid of all types

shares the same physical properties, including apple-green

birefringence after Congo red staining,2 characteristic fibrillar

appearance by electron microscopy, and -pleated sheet

conformation. Not all normal proteins have an -helical

secondary structure, and not all the -conformation proteins arepathologic (eg, keratin).3 Despite these similar physical

properties, the chemical composition of amyloid has been

shown to include 22 different proteins (Table 1). Virchow in

Berlin thought amyloid was a starch (amyloid), and Rokitansky

in Vienna thought it was fat (lardaceous). Both were incorrect.

Amyloidosis is a nonspecific term because it includes all

forms of systemic and localized amyloidosis. In the 19th

century, the most common form was the secondary systemic

form caused by chronic respiratory and bone infections,

tuberculosis, and leprosy. In the 20th century, inherited forms

of amyloidosis were recognized. The most common form of

systemic amyloidosis in the United States, however, is theimmunoglobulin light chain form (AL). Primary, or

immunoglobulin light chain, amyloidosis is structurally

unrelated to all other forms of amyloidosis, including

Alzheimers disease.4 Light chain amyloidosis is the systemic

amyloidosis with the shortest patient survival.

The structural subunit of primary amyloid fibrils is the

monoclonal light chain or fragment or monoclonal heavy chain

(very rare). It would be unusual for the entire immunoglobulin

light chain molecule to be found in an amyloid deposit. The

light chain found in amyloid is produced by a clonal population

of plasma cells in the bone marrow.5

Symptoms Associated with AmyloidosisSymptoms of amyloidosis include weight loss, edema, andfatigue. They are so nonspecific that amyloidosis would not

appear in the differential diagnosis of these symptoms.6 Patients

are referred to hematologists because they have been found to

have a monoclonal gammopathy or are thought to have

premyeloma,with symptoms not easily explained and bone

marrow with 10% plasma cells.7 Fluid retention, weight loss,

and fatiguerare in newly diagnosed myeloma but common in

amyloidosisshould be important clues to clinicians. However,

no single blood test, radiograph, or scan can diagnose

amyloidosis. Finding Howell-Jolly bodies in a peripheral blood

film of a nonsplenectomized patient is an important but

uncommon clue. Thus, maintaining a high index of suspicion is

essential for recognizing this disease.

The clinical presentation is broad. Patients with renal

amyloidosis generally develop nephrotic-range proteinuria and

may be treated empirically with prednisone before the diagnosis

is confirmed with renal biopsy findings. Before biopsy, common

diagnoses include membranous or membranoproliferative

glomerulonephropathy and minimal change glomerulonephritis.8

Amyloidosis: Diagnosis and Management

Morie A. Gertz, Martha Q. Lacy, Angela Dispenzieri, Suzanne R. Hayman

Amyloidosis is a rare plasma cell proliferative disorder. The annual incidence in Olmsted County, Minnesota, is 8 in 1,000,000 patients.

This is a difficult disorder to diagnose, because the symptoms at presentation are vague and include dyspnea, paresthesias, edema,

weight loss, and fatigue. The clinical syndromes at the time of presentation include nephrotic-range proteinuria with or without renal fail-

ure, cardiomyopathy, atypical multiple myeloma,hepatomegaly, and autonomic or peripheral neuropathy. The serum immunoglobulin

free light chain assay has been an important step forward in classifying systemic amyloidosis as an immunoglobulin light chain form and

in monitoring therapy. Recently, the importance of serum cardiac biomarkers in assessing outcome has been recognized. New therapies

developed over the past 5 years include high-dose chemotherapy with stem cell reconstitution, combinations of alkylating agents with

dexamethasone, and, most recently, thalidomide.

Clinical Lymphoma & Myeloma, Vol. 6, No. 3, 208-219, 2005

Key words:Amyloid, Monoclonal gammopathy, Multiple myeloma, Stem cell transplantation

Abstract

ComprehensiveReview

Address for correspondence: Morie A. Gertz, MD, Division of Hematology,Mayo Clinic, 200 First St SW, Rochester, MN 55905E-mail: [email protected]

Submitted: Apr 8, 2005; Revised: Jun 2, 2005; Accepted: Jun 27, 2005

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group,ISSN #1526-9655, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.


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Clinical Lymphoma & Myeloma November 2005 20

Hematologists who evaluate

patients with suspected

myeloma and light chain

proteinuria should be

attentive to dramatic increases

in serum cholesterol

concentration or marked

hypoalbuminemia, features of

nephrotic syndrome not seen

in light chain multiple

myeloma in which lipid levels

are normal and the serum

albumin level is usually only

mildly decreased.

Frequently, patients with

amyloid cardiomyopathy do

not develop cardiomegaly or

classic signs of pulmonary

edema because of the

restrictive nature of cardiac

involvement. The normal sizeof the heart and the normal

left ventricular ejection

fraction (LVEF) determined

echocardiographically often

make it difficult to decide

whether the patients fatigue

and dyspnea have a cardiac

basis.9 Many patients with cardiac amyloidosis are referred by

pulmonologists who initially evaluate the patient for

noncardiac dyspnea.Often, amyloid peripheral neuropathy is diagnosed initially as

chronic inflammatory demyelinating polyneuropathy or, moreimportantly, as peripheral neuropathy associated with

monoclonal gammopathy of undetermined significance

(MGUS) because diagnostic testing was not sufficient to

exclude amyloidosis as the underlying disease.10 The median

duration of neuropathic symptoms before the diagnosis of AL

amyloidosis is 2 years.11

Patients with amyloidosis presenting with hepatomegaly are

generally thought to have malignancy and undergo liver biopsy.

In amyloidosis, liver biopsy has a small risk of bleeding, and

rupture of the liver has been reported.12 By recognizing

amyloidosis and obtaining tissue at a lower risk site, this

potentially rare but catastrophic complication can be avoided.13

Physical findings in amyloidosis include the following:

enlargement of the tongue, periorbital purpura, and, rarely, extra-

articular deposits producing skeletal pseudohypertrophy (shoulder

pad sign). These physical findings are highly specific for

amyloidosis but are relatively insensitive because only 15% of

patients have them. The clinician needs to focus on organs that

become involved with amyloid and the nature of their

dysfunction. Amyloidosis should be in the differential diagnosis

for any adult patient with nephrotic-range proteinuria. Ten

percent of nondiabetic patients aged 44 years with nephrotic

syndrome have amyloidosis.14 Slightly more than one-half of

patients with amyloidosis have changes of infiltrative

cardiomyopathy as defined with echocardiography.15

Cardiac symptoms can range from minimal (eg, easy

fatigability or unexplained lower extremity edema) to frank

congestive symptoms. Electrocardiography demonstrates low-voltage QRS complexes in the limb leads or an infarction

pattern that is related to myocardial infiltration and unrelated to

coronary artery disease.16 The most common echocardiographic

finding is not a granular sparkling appearance, as frequently

assumed; instead, the ventricular wall is thickened, which is

usually misinterpreted as hypertrophy rather than infiltration.15

If a patient has echocardiographic evidence of wall thickening

but does not have a history of hypertension or cardiac valvular

disease, amyloidosis must be considered in the differential

diagnosis. Occasionally, patients with heart dysfunction

undergo catheterization and coronary angiography; however,

the evaluation is terminated when the angiographic findings are

found to be normal despite high right-sided filling pressures that

suggest the need for endomyocardial biopsy, a test that is 100%

sensitive. The complication rate is 3%, with none of the

complications being fatal or long term.17 All patients with an

unexplained heart problem or unexplained proteinuria should

have studies for possible light chain AL.

Approximately 15% of patients with amyloidosis have

clinically important liver involvement.13 Serum amyloid P

scanning component quite frequently identifies patients who

have liver involvement that has not produced biochemical

changes or hepatomegaly. The most common liver presentation

Primary; may be associated with myeloma

Primary; may be associated with myeloma

Secondary and familial; mediterranean fever

Native in senile systemic amyloid; mutant in familial amyloidosis

Inherited renal amyloidosis

Inherited hepatic amyloidosis

Familial amyloid neuropathy

Dialysis associated

Alzheimers disease

Diabetes; islet cells

Isolated atrial amyloidosis

Finnish familial amyloidosis

Hereditary cerebral hemorrhage with amyloidosis, Iceland

Creutzfeldt-Jakob disease

Medullary thyroid cancerIslet amyloidosis (degu)

Prolactinoma

Corneal dystrophy

Spongiform encephalopathies

Abbreviation Protein

Immunoglobulin light chain or fragment

Immunoglobulin heavy chain or fragment

Amyloid A

Transthyretin

Fibrinogen chain

Lysozyme

Apolipoprotein AI or AII

2-Microglobulin

-Protein precursor

Islet amyloid polypeptide

Atrial natriuretic factor

Gelsolin

Cystatin C

Scrapie protein

(Pro) CalcitoninInsulin

Prolactin

Lactoferrin

Prion

Clinical Phenotype

AL

AH

AA

ATTR

AFib

ALys

AApoA

A2M

A

AIAPP

AANF

AGel

ACys

ASCR

ACal

AINS

APro

Alact

APrPSC

Amyloid NomenclatureTable 1


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Amyloidosis

is an unexplained increase in alkaline phosphatase (ALP) level orunexplained hepatomegaly. Typical liver symptoms of early

satiety, anorexia, and right upper quadrant fullness are generally

present but not specific. Radionuclide liver scans, computerized

tomographic scans, and magnetic resonance imaging do not

show any abnormality other than physical enlargement. These

patients are the most likely to have a hyposplenic peripheral

blood film. When evaluating patients who have unexplained

liver dysfunction, it is important to screen for infiltrative liver

disease with studies to detect monoclonal light chain

abnormalities in addition to performing studies to detect

hepatitis, cirrhosis, and biliary obstruction.

Peripheral neuropathy is present in 15% of patients with ALamyloidosis.11 Sensory changes precede motor changes, and the

lower extremities are affected before the upper extremities are.

Clues to recognizing amyloid neuropathy include the presence

of carpal tunnel syndrome (present in half the patients) in

association with autonomic neuropathy. Autonomic neuropathy

can be the presenting manifestation of amyloidosis. Clinical

manifestations of amyloid autonomic neuropathy include

gastrointestinal tract involvement, which can be manifest in the

upper gastrointestinal tract as nausea, vomiting, delayed gastric

emptying, and pseudo-obstruction, and in the lower

gastrointestinal tract as alternating diarrhea and constipation,

often to the point of incontinence. Autonomic failure of the

urinary tract includes delayed emptying, inability to void, and

spontaneous overflow incontinence. Autonomic failure may also

produce orthostatic hypotension with orthostatic syncope and

failure of a compensatory increase in heart rate when the patient

changes from a supine to standing position. Amyloid

neuropathy is typically dysesthetic, and the pain requires

treatment with analgesics, amitriptyline, and gabapentin as well

as narcotics. Without sufficient evaluation to exclude

amyloidosis, amyloid neuropathy may be misdiagnosed as

monoclonal gammopathyassociated peripheral neuropathy or

Waldenstrms macroglobulinemiaassociated neuropathy.18

Any patient with nephrotic-range proteinuria, nonischemic

cardiomyopathy, hepatomegaly, or peripheral neuropathy or

with an atypical myeloma presentation needs to have screeningtests for amyloidosis.19

Screening for AmyloidosisLight chain amyloid is composed of immunoglobulin light chain

or heavy chain fragments.20 Thus, by definition, AL amyloidosis is

a plasma cell dyscrasia. Virtually all patients have a clonal

population of plasma cells detectable in the bone marrow.7 Also,

most patients have a detectable immunoglobulin abnormality

defined as positive serum immunofixation for light chain,

positive urine immunofixation for light chain, or abnormal

serum immunoglobulin free light chain nephelometric assay.21

Screening with serum protein electrophoresis is inadequatebecause 50% of patients do not have an intact

immunoglobulin protein in the serum or have light chain

proteinemia, which will not produce a discrete band on the

electrophoretic pattern (Figure 1). Urine immunofixation is

important and complementary to serum immunofixation

(Figure 2). In a Mayo Clinic study of 110 consecutive patients

with light chain AL, serum immunofixation results were

positive in 69%, and urine immunofixation results were positive

in 74%. When immunofixation was used to screen serum and

urine, a monoclonal protein was found in 104 of the 110

patients (95%). The immunoglobulin free light chain assay was

abnormal in 100 patients (91%). When all 3 screening studies

were combined, 109 of the patients with AL amyloidosis were

identified correctly, a sensitivity of 99%. Conversely, when the

serum immunoglobulin free light chain assay was used in 52

patients with non-AL amyloidosis, all had a normal :ratio,

including 23 patients with localized, 16 with familial, 6 with

senile, and 3 with secondary amyloidosis, a specificity of

100%.22 Overall, serum and urine immunofixation and the serum

immunoglobulin free light chain assay constitute the best

noninvasive screening tests for patients who potentially have AL. A

positive finding justifies performing biopsy to confirm the

diagnosis. Serum amyloid P scanning also detects amyloid deposits

Serum Monoclonal Protein (g/dL)

Percentof

Patients

0 0.01-0.50 0.51-1.50 > 1.5

60

40

20

0

: = 1:3.1

G

D

o

M

AG

Biclonal

Results of serum protein electrophoresis and serum immunofixation in 219 patients with AL orlight-chain amyloidosis. A, G, M, D, immunoglobulin heavy chain; K, L, or

immunoglobulin light chain.

Serum Protein Electrophoresis and Immunofixationin Patients with Amyloidosis

Figure 1

Results of urine immunofixation and 24-hour urine total protein in 219 patients with AL or light-chain amyloidosis.

Urine Protein per Day

Numbe

rofPatients

< 1.0 1.0-2.9 3.0-5.9 > 6.0

80

60

40

0

21%

68%

Median3.5 per day

0

Biclonal

20

1%10%

Urine Immunofixation in Patients with AmyloidosisFigure 2


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with a high level of sensitivity,23 but it is not widely available.

The possibility of nonlight chain AL in a patient with an

unrelated MGUS must be considered. Patients with MGUS can

have an abnormal serum free light chain ratio.24 Therefore,

amyloidosis with an immunoglobulin light chain must be

confirmed immunohistochemically for type to avoid the rare

patient with amyloid A (AA) or an inherited form of

amyloidosis, the transthyretin (TTR) type or fibrinogen (AFib)

type, with a low-level monoclonal gammopathy.

The 2 types of hereditary amyloidosis that are most likely to

be misdiagnosed as AL type are variants TTR and AFib because

of the frequent lack of family history. Important clues to the

possibility are the predominant neuropathic or cardiac

phenotype of variant TTR and the lack of extrarenal

involvement in AFib. Renal biopsies in patients with AFib show

massive glomerular amyloid deposition without interstitial or

vascular amyloid deposits.

How Is the Diagnosis of AmyloidosisConfirmed?

If a patient has a compatible clinical syndrome andimmunofixation or nephelometric testing subsequently

demonstrates an immunoglobulin light chain abnormality, the

diagnosis must be confirmed by biopsy. In patients with nephrotic

syndrome, cardiomyopathy, hepatomegaly, or neuropathy, amyloid

deposits can be demonstrated histologically in biopsy specimens

from kidney (Figure 3), heart, liver, or nerve, but this is generally

not required. In patients with amyloidosis, kidney and liver biopsies

have a risk of bleeding; rarely, catastrophic rupture of the liver or

spleen can occur.25 It is easier and safer to obtain a bone marrow

sample or a subcutaneous fat aspirate. In 220 consecutive patients

receiving high-dose therapy at Mayo Clinic, the bone marrow was

positive for amyloid deposits when stained with Congo red in 156of 213 patients (73%; 3 equivocal), and the subcutaneous fat

aspirate results were positive in 137 of 190 (72%; 7 equivocal).

Either the bone marrow sample or the fat aspirate results were

positive in 181 of 218 patients (83%). Obtaining the fat aspirate or

the bone marrow sample is convenient and less invasive and does

not cause any bleeding complication (in the absence of factor X

deficiency). Bone marrow biopsy is required for every patient with

AL amyloidosis to exclude overt multiple myeloma. Other centers

have reported the efficacy of biopsy of the minor salivary glands,26

gingiva, rectum, and skin, with all the biopsies causing minimal

morbidity. Amyloidosis has a very low prevalence in the general

population and, as a screening tool, fat aspiration has a very low

yield. It would be expected to produce more false-positive than

true-positive results if the prevalence of amyloidosis in the

population studied is expected to be low.27 False-positive results

from overstaining, thick fat particles trapping Congo red stain, and

nonspecific staining of elastin or collagen fibers in the fat.

Immunohistochemical verification of the type of amyloid

with and antisera is essential.28 Nonimmunoglobulin

amyloidosis and incidental MGUS are possibilities.29 Clinically,

distinguishing among AL, AA (secondary), AF (familial), and

SSA (senile systemic) types of amyloidosis is difficult. In our

experience, half of the patients with AF amyloidosis do not have

a positive family history. Patients with AA amyloidosis present

with renal amyloid nephrotic syndrome or gastrointestinal

involvement indistinguishable from AL amyloidosis.30 Patientswith AF amyloidosis can present with kidney involvement,

cardiomyopathy, or neuropathy31 indistinguishable from AL

amyloidosis. Senile systemic amyloidosis presents with amyloid

cardiomyopathy, and the clinical and echocardiographic features

are indistinguishable from those of AL amyloidosis.32

Immunohistochemical staining of tissues with commercially

available antisera is helpful. All forms of amyloid contain

amyloid P component, a glycoprotein representing 10% of the

fibril by weight. Positive immunochemical staining with P

component is a useful positive control.33 Transthyretin

antiserum that stains AF is highly reliable, and its absence should

make AF amyloidosis (as a result of TTR) unlikely. The sameapplies to the use of AA antiserum purchased commercially.

When and immunostaining is positive, it can be quite

specific, but it lacks sensitivity. Commercial antisera may not

recognize immunoglobulin light chain amyloid deposits because

the fibrils consist only of the N terminus of the light chain, thus

lacking the epitopes recognized by commercial antisera, or the

epitopes are hidden when the light chains fold into the -pleated

sheet conformation.34 Immunoelectron microscopy has been

used with immunogold to characterize the amyloid fibril.35

A specific form of inherited amyloidosis should be mentioned.

A mutation of the TTR molecule, isoleucine 122, results in

autosomally dominant inherited cardiac amyloidosis. This allele is

carried in 63 of 3376 (2%) of black Americans, or 700,000 black

Americans in the United States (2003 census data). Amyloid

cardiomyopathy in a black patient aged 70 years should

automatically be screened for this isoleucine 122 variant.36

Mutations in fibrinogen-A cause renal amyloidosis. The

fibrinogen origin of the amyloid deposit can be detected

immunochemically.37 In a landmark study, 10% of patients

referred to an amyloidosis center with the diagnosis of the AL

type had another form of amyloidosis, including 5% with AFib

and 4% with unrecognized mutations of TTR.28 Excluding

familial amyloidosis before therapy is initiated is important.

Sulfated alcian blue stain; 1000.

Vascular Amyloid Deposits in KidneyFigure 3

Morie A. Gertz et al


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Amyloidosis

PrognosisThe most common cause of death of patients with AL

amyloidosis is cardiac failure or arrhythmia. The mechanism can

be progressive congestive cardiomyopathy or arrhythmic

death.38 The overall response rate and clinical outcome are

determined by the extent of cardiac involvement at diagnosis.

The method for accurately assessing the extent of cardiac

amyloidosis has evolved over the past 4 decades. In the early1960s, cardiac involvement was defined by clinical criteria such

as the presence of overt congestive heart failure. With these

clinical criteria alone, it is possible to detect a population of

patients whose median survival is only 3 months.39 In the 1970s

and 1980s, these clinical criteria were replaced by

echocardiographic criteria.

Echocardiography with Doppler studies, which assist in

measuring diastolic compliance, is useful in assessing all patients

with newly diagnosed AL amyloidosis. One-fourth of patients

without obvious heart symptoms have echocardiographically

detected cardiac amyloidosis.40 With echocardiography, the

LVEF and mean thickness of the ventricular septum can be

quantified. Left ventricular ejection fraction and septalthickness are important measures, although depression of the

LVEF is a very late phenomenon in amyloidosis because systolic

function is preserved until late in the disease. Doppler

echocardiography,9 however, allows measurement and

qualitative assessment of diastolic function with grades from I to

IV. These are accurate measures of ventricular diastolic

compliance. The stiffer the ventricle, the slower the relaxation

and the longer it takes blood to flow across the mitral valve. This

is measured by the deceleration time, which provides

information that correlates well with survival.40

Since the 1990s, cardiac biomarkers have supplemented

echocardiography in measuring sensitive changes in myocardialfunction. Serum biomarker studies are more reproducible and less

subject to interobserver variability than is echocardiography.

Serum troponin levels are more sensitive measures of ischemic

myocardial injury than the creatine kinase-MB fraction. Troponin

has been shown to be a powerful predictor of survival in patients

with AL amyloidosis, including those receiving conventional

treatment41 and those receiving high-dose therapy with stem cell

transplantation. Serum troponin T levels can be used to separate

patients into 3 subgroups of equal size with markedly different

survival rates: < 0.03 ng/mL, 0.03-0.1 ng/mL, and > 0.1 ng/mL.

The cardiac biomarkers N-terminal probrain natriuretic peptide

(NT-proBNP), which can be measured in stored frozen serum,

and brain natriuretic peptide (BNP) increase with atrial dilatation.

Increased NT-proBNP levels have been shown to predict survival

after the diagnosis of amyloidosis. A normal NT-proBNP level

excludes involvement of the heart with amyloid.42 The

combination of serum troponin T and NT-proBNP levels can be

used to classify patients into 3 groups43: those in whom troponin

T and NT-proBNP levels are increased (stage 3); both levels are

normal (stage 1); and the level of only 1 of the 2 markers is

increased (stage 2).44

Others have shown that serum 2-microglobulin is

prognostically important in AL amyloidosis45,46 and the

number of organs involved with amyloid appears to predict

outcome after stem cell transplantation.

For all patients with AL amyloidosis, our routine is to measure

serum troponin T, NT-proBNP, BNP, and 2-microglobulin

levels, count the number of organs involved, and perform

echocardiography.

Assessing the Therapeutic EffectOftentimes, assessing the response to therapy can be difficult.

Unlike multiple myeloma, in which the majority of patients

have a quantifiable monoclonal protein that can be used as a

surrogate for reduction in tumor mass, interpreting the response

of patients with amyloidosis is more complex. The majority of

patients with AL amyloidosis do not have a measurable

monoclonal protein (Figure 1). Because so many of the patients

have only light chain proteinemia, quantification has been

difficult until recently. Only 10% of patients with amyloidosis

have a serum monoclonal protein level > 1.5 g/dL.

Quantification of the urinary light chain is equally difficult

because a high proportion of patients have marked albuminuria

that overwhelms the monoclonal protein peak (Figure 2).Patients with AL amyloidosis have an average of 5% plasma cells

in the bone marrow. This degree of plasmacytosis is recognized

as abnormal. Amyloid can often be identified in bone marrow

biopsy samples. To convincingly demonstrate a reduction in

bone marrow plasmacytosis is difficult because of interobserver

variability and sampling variation.

Despite these limitations, a hematologic response for

amyloidosis has been defined by a 50% reduction in the

precursor monoclonal protein.47 The effect of a 50% decrease in

the monoclonal protein level in a cohort of patients receiving

high-dose therapy followed by stem cell transplantation is

shown in Figure 4. The nephelometric serum immunoglobulinfree light chain assay has become important in quantifying

hematologic responses in patients with amyloidosis. As

mentioned earlier, the light chain assay was used as a sensitive

and specific marker for AL amyloidosis. In addition to

classifying of the type of amyloid, this test provides a new

quantification method for confirming hematologic responses.48

The most important clinical endpoint in amyloidosis is organ

response. It has been assumed that the amyloid in organs cannot

resolve until production of the precursor light chain has been

interrupted. After this interruption occurs, the amyloid

deposits, as determined by serum amyloid P component

scintigraphy, will slowly resolve if the organ has not been

damaged irrevocably by the deposits or toxic intermediates.

Biopsy verification of amyloid resolution is rare. A hematologic

response to therapy correlates well with subsequent organ

response49 and survival (Figure 4). Therefore, a 50% reduction

in the serum or urine (or both) monoclonal protein or the

nephelometric serum free light chain assay is a reasonable

surrogate for response and will ultimately lead to functional

organ improvement, defined as reduction in urinary protein in

patients with renal amyloidosis, echocardiographic

improvement in patients with cardiac amyloidosis, and decrease

in liver span and serum ALP level in patients with hepatic


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amyloidosis if irrevocable organ damage has not occurred. The

immunoglobulin serum free light chain level and light chain

ratio are measured in all patients who are receiving therapy andare monitored serially. A 50% decrease is accepted as a

hematologic response. Eradication of the monoclonal protein

from the serum and urine by immunofixation and normalization

of the serum free light chain ratio would be considered a

complete hematologic response. A diagnostic pathway for

considering, recognizing, and confirming AL amyloidosis and

assessing the prognosis of patients is given in Table 2. Remember

that therapy is not to be initiated until it is certain that the

amyloid is of light chain origin.

Nonsystemic Amyloidosis

Patients may be referred with localized forms of amyloidosis.These patients generally do not require systemic therapy, and

management can be supportive or localized. The location of the

amyloid deposits can be a clue to its localized nature. When

amyloid is detected in the ureter, bladder, urethra, or prostate, it is

generally localized.50,51 Most forms of cutaneous amyloidosis are

also localized, and macular amyloidosis is virtually always

localized.52 Nodular amyloidosis may be a component of systemic

AL amyloidosis.53 Tracheobronchial amyloidosis54 and nodular

pulmonary amyloidosis are localized and generally not associated

with a plasma cell dyscrasia.55,56 Soft tissue deposits of amyloid

and amyloid lymphadenopathy may not be associated with

systemic disease.57 Patients who present with localized amyloidosis

do not have a demonstrable monoclonal protein in the serum or

urine nor do they have bone marrow plasmacytosis.

A therapeutic strategy designed to dissolve the amyloid deposits

or to prevent their accumulation would be optimal. If the amyloid

deposits could be solubilized, the patients would not sustain brain

damage. No effective means is known for solubilizing amyloid

deposits. The approach has been to reduce precursor protein

production by cytotoxic chemotherapy. All therapies have been

derived from the treatment of multiple myeloma and are directed

at the small clonal population of plasma cells responsible for the

synthesis of the amyloidogenic light chain.

TherapyConventional TherapyThe first reports on cytotoxic chemotherapy for AL

amyloidosis are > 30 years old.58 Melphalan/prednisone is

effective treatment.59,60 A difficulty with this regimen is the

difficulty distinguishing between patients in whom therapy will

fail and those in whom the response will be delayed. Reports

have indicated that nearly a year is needed to detect a response

to melphalan/prednisone therapy. In addition to a low response

rate, oral melphalan can cause late myelodysplasia or acute

leukemia, and myelodysplasia can develop in nearly 7% of

exposed patients.61,62 The response rate to melphalan/

prednisone does not exceed 30%. However, this therapy issuitable for even the most severe disease and can be an option if

other regimens are considered excessively toxic.

The best responses to melphalan/prednisone occur in

patients with single-organ nephrotic syndrome without renal

insufficiency. The response rate for all patients treated with

melphalan/prednisone is 18%.47 If the ALP level is > 4 times

normal or the serum creatinine level is > 3 mg/dL, responses to

melphalan/prednisone are rare. Responses have been seen in

patients with advanced cardiomyopathy, and modest

prolongation of survival has been seen in patients with amyloid

congestive heart failure. Of 153 patients treated with

melphalan/prednisone, the 5-year survival rate of responders

was 78%. For 810 patients, the 10-year survival rate was 4.7%,

and all 10-year survivors received melphalan/prednisone.63 Of

the 10-year survivors, 14 of 30 exhibited a complete

hematologic response. Prospective randomized studies have

shown that melphalan/prednisone is superior to colchicine.64,65

In one study, survival in the melphalan/prednisone group was

17 months, and, in another study, it was 12.2 months.

Continuous oral daily melphalan has been used as single-agent

therapy for cardiac amyloidosis. In 30 such treated patients, 7

of the 13 evaluable after 3-4 months of therapy exhibited a

partial hematologic response, and 3 exhibited a complete

Survival Months

Nonresponders (n = 68)Responders (n = 151)

Survival(%)

100 20 30 40 50 60 70 80 90 100 110

100

80

40

60

20P< 0.001

Survival After Stem Cell Transplantation in Amyloidosis:Comparing Hematologic Responders with Nonresponders(N = 219)

Figure 4

1.Consider AL amyloidosis in differential if patient has:

Nondiabetic nephrotic syndrome

Nonischemic cardiomyopathyechocardiography shows leftventricular hypertrophy

Hepatomegaly with no scan defects

Chronic inflammatory demyelinating polyneuropathy

Atypical myelomaurine monoclonal light-chainpositive and bonemarrow plasmacytosis

2.Perform immunofixation serum, urine, and immunoglobulin serum- free light-chain assay; if results are positive, AL is a likely explanation

3.Biopsy bone marrow and subcutaneous fat, and stain with Congo red;kidney or liver biopsy is usually not required; electron microscopydemonstrates fibrils

4.Assess prognosisechocardiography with Doppler, serum troponin,NT-proBNP or BNP, 2-microglobulin

5.Initiate therapy

Diagnostic Pathway for AL AmyloidosisTable 2



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Amyloidosis

hematologic response.66 Reports of improvement in organ

function after treatment of AL with colchicine are rare.67

Dexamethasone-Based RegimensOf the first 4 patients who received treatment with

vincristine/doxorubicin/dexamethasone (VAD), 2 had a 50%

decrease in serum monoclonal protein. Vincristine is not a good

choice for patients with amyloid peripheral neuropathy, and

doxorubicin should be avoided if patients have severe

cardiomyopathy. Three of 4 patients with amyloid nephrotic

syndrome treated with VAD exhibited a partial response and were

alive and in remission for 4-9 years.68 VAD has been used in an

induction scheme to reduce the amyloid burden and to enhance

stem cell transplantation outcome.69 According to one study,

clinical improvement after VAD did not reduce transplantation-

related mortality.70

Among 92 patients treated at the AmyloidosisCenter in Great Britain, 4 cycles of VAD led to an organ response

in 39 patients (42%), with a treatment-related mortality rate of

7%.48 In the first report on dexamethasone therapy for

amyloidosis, 9 patients received dexamethasone 40 mg on days

1-4, 9-12, and 17-20, every 5 weeks. Improvement in AL organ

involvement was seen in 8 of these patients. Of 7 patients with

nephrotic syndrome, 6 had a 50% reduction in proteinuria.71 In 2

separate studies, we have reported on 44 patients with

amyloidosis.72,73A large proportion of these patients had cardiac

amyloidosis, and this may have affected outcome. The survival of

this cohort is shown in Figure 5.

Dexamethasone toxicity is substantial. Fluid retention occurs in

patients with nephrotic syndrome and heart failure. Dose

reductions are common. In the largest study (92 patients in the

Southwest Oncology Group study), 24% of patients had

hematologic complete remissions, and 45% had improvement in

amyloid-related organ dysfunction.74 Median survival for the

group was 31 months, and the overall 2-year survival rate was

60%. Heart failure and an increased 2-microglobulin level

predicted adverse outcome. Patients with cardiomyopathy had a

low response rate. The median time to hematologic response was

103 days. Improved survival was reported for patients with organ

response. Toxicity was linked to the number of organs involved.

However, according to the statistical analysis, only heart failure

predicted excessive toxicity. Patients in the Southwest Oncology

Group study received maintenance interferon therapy, but its

effect on outcome could not be determined.

The Italian Amyloidosis Group also reported on

dexamethasone therapy.49 The same group has also combined

dexamethasone with melphalan. The hematologic response rate

was 67% at a median of 4.5 months, with a 33% complete

response rate and a 48% organ response rate. Treatment-related

mortality was 4%, and one-half the patients had improved

organ function. Heart failure resolved in 19% of patients. The

use of oral melphalan and dexamethasone is viable alterative

therapy for patients with amyloidosis.75

In a report from Boston University Medical Center, pulsed low-

dose melphalan was administered intravenously to patients

ineligible for stem cell transplantation because of severe cardiac

involvement or poor performance status.76 The dose of melphalan

ranged from 17.5 mg/m2 to 25 mg/m2 every 4-6 weeks for 3-4

cycles. All patients received growth factor support, and the

melphalan dose was adjusted for granulocytopenia and

thrombocytopenia. Fifteen patients (median age, 55 years)received a median of 3 cycles of low-dose melphalan. Eight of 10

evaluable patients had more than a 50% decrease in serum free

light chain levels, and 2 exhibited normal serum free light chain

levels. Of the 15 patients treated, 2 survived 6 months and 24

months after treatment and 13 died. Median survival was 2

months. Ten patients died within 35 days after starting treatment.

Myelosuppression was the major toxic effect, suggesting that

the dose of 17.5 mg/m2 to 25 mg/m2 may have been excessive.

Pulsed low-dose melphalan given intravenously induced

hematologic responses, but long-term survival was poor, which

is typical of patients with advanced cardiac amyloidosis.

For 144 patients, the National Amyloidosis Treatment Centercombined the intermediate dose of melphalan at 25 mg/m2with

dexamethasone 20 mg for 4 days every 21-28 days.77 The median

follow-up was 13 months. Median number of cycles was 3. Fifty-

one patients did not receive dexamethasone. The treatment-related

mortality rate was 2%. Of the patients, 23% had normalization of

the serum free light chain, 31% had a 50% decrease in serum free

light chain, and 46% were thought to be nonresponders. The

response rate was higher among melphalan-treated patients who

also received dexamethasone. Clinical responses were evident

within 2 cycles in almost all the patients who eventually had a

response. Median survival for responders was 44 months

compared with 18 months for nonresponders. Amyloid organ

dysfunction improved in 14% of patients and was stable in 51%.

Parenteral melphalan and oral dexamethasone is a reasonable

therapeutic strategy, but, in our opinion, the initial dose of

parenteral melphalan should be approximately 16 mg/m2.

Thalidomide

For 16 patients enrolled in a thalidomide study, the median

maximum tolerated dose was 300 mg. Fifty percent of the

patients experienced grade 3/4 toxicity, 25% had to discontinue

taking the drug, and 25% had a reduction in light chain

proteinuria but not in total urinary protein.78 In a Mayo Clinic

Months

Surviv

al(%)

100 20 30 40 50 60 70 80 90 100 110

100

80

40

60

20

Survival of 44 Amyloidosis Patients Treated withDexamethasone at Mayo Clinic

Figure 5


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report on 12 patients treated with thalidomide, 75% of patients

had a drug-related toxic effect.79 Progressive renal insufficiency

developed in 5 patients, and deep venous thrombosis and

syncope developed in 2 patients. The median time of

thalidomide treatment was 72 days; patients were intolerant of

the drug. The Italian Amyloidosis Group reported on

thalidomide and dexamethasone therapy in 31 patients.80 Only

11 patients tolerated 400 mg per day for a median of 5.7 months.

Twenty patients experienced severe grade 3 or greater toxicity. The

National Amyloidosis Treatment Center administered

thalidomide81 at a median dose of 100 mg per day. Although this

treatment had to be discontinued for 31% of patients, the

hematologic response rate was 55%. Thalidomide and

dexamethasone warrant further investigation in the treatment of

AL amyloidosis, but the thalidomide dose likely should be limited

to 100 mg per day. Irreversible peripheral neuropathy and skin

rash are common side effects of thalidomide.

Stem Cell Transplantation

Although no prospective randomized studies have compared

stem cell therapy with conventional therapy, many centers aroundthe world are using stem cell therapy for AL patients who are

thought to be sufficiently robust to withstand its toxic effects.82 In

a case-matched control series matching patients for age, organ

involvement, and extent of cardiac involvement, patients who

received high-dose therapy had a survival advantage.83 The

rationale for high-dose therapy is derived from data on multiple

myeloma that unequivocally demonstrate a survival advantage for

patients given high-dose therapy. Currently, most patients are not

eligible for stem cell transplantation. In our experience,

approximately one-fourth of patients are candidates. The mortality

rate of 12% is high compared with that of autologous stem cell

transplantation for hematologic neoplasia.82

There is selectionbias. Patients eligible for stem cell transplantation have better

cardiac function and do not have advanced liver or kidney

failure.84 Patients with marked organ dysfunction are at higher risk

for complications, including sudden cardiac death and

gastrointestinal tract bleeding.85

We have completed stem cell transplantation in 219 patients.86

The ratio of -to-amyloid was 1:3.1 (Figure 1). The kidney was

involved in 67% of patients, the heart in 50%, and the liver in

20%, and 15% of patients had peripheral neuropathy.

Conditioning used at Mayo Clinic is risk adjusted. Patients with

advanced cardiac amyloidosis receive a melphalan dose of 140

mg/m2, as do elderly patients or those who have a marked decrease

in creatinine clearance.87 Twenty percent of our patients had an

LVEF < 0.60 when they received a stem cell transplant.

Another group has used a similar risk-adapted approach to

dosing and has added dexamethasone and thalidomide as

posttransplantation therapy.88 Patients at high risk were given 2

cycles of melphalan 40 mg/m2without stem cell replacement. If

patients did not exhibit a complete response, they received 9

months of dexamethasone/thalidomide therapy. Also, 31

patients who had stem cell transplantation received melphalan

at the following doses: 5 patients at 100 mg/m2, 16 at 140

mg/m2, and 10 at 200 mg/m2. The treatment-related mortality

rate was only 7.4%. Six patients died of progressive disease at a

median of 5.5 months. Fifty-nine percent of patients had a

response to treatment. Seven patients had objective

improvement in amyloid-related organ function. There was an

association between a persistently abnormal serum free light

chain ratio and an increased risk of death. Risk-adapted dosing

of melphalan can decrease the treatment-related mortality rate.

There may be a role for maintenance dexamethasone therapy

following high-dose therapy.

In our experience, a hematologic response has a profound

effect on outcome. Our response rate is 68%,86 and responders

do exceedingly well (Figure 4). (Organ responses are defined in

the section on assessing therapeutic effect.) Nonresponders have

a median survival of 12.6 months. Although we frequently

reduce the dose of melphalan, we have not found a survival

difference among responders on the basis of the conditioning

dose; however, higher doses appear to produce higher response

rates. Treatment-related mortality is directly associated with the

number of organs involved as well as the serum creatinine level

before transplantation. Recently, we have recognized that weight

gain during growth factorprimed mobilization is a powerfulpredictor of treatment-related mortality. Patients who, during

mobilization, gain > 3% of their pretransplantation body weight

appear to have a higher treatment-related mortality rate even if

measures are taken to return their weight to the

pretransplantation level before conditioning chemotherapy is

initiated.89 The median survival for patients with > 2 organs

involved at the time of transplantation is 21.5 months. The

most common cause of death was sudden cardiac death, but we

have also observed fatal liver failure, exsanguinating

gastrointestinal tract hemorrhage, and postconditioning renal

insufficiency with multiorgan failure.90

We have not administered cytoreductive chemotherapybefore stem cell transplantation because patients have only

5%-10% plasma cells. The value of preconditioning

cytoreductive therapy has not been proven. According to a

report from Boston University, 2 cycles of melphalan and

prednisone before transplantation did not provide survival

benefit, and the delay often led to progression.91 For 312

patients treated at Boston University, the median survival was

4.6 years.92 A complete hematologic response was seen in

40% of patients, and this led to prolonged survival. Their

reported treatment-related mortality rate was 13%, with

mortality greatest among patients with cardiomyopathy. The

criteria for administering melphalan 200 mg/m2 were the

following: age, < 65 years; LVEF by echocardiography, > 0.45;

and > 2.5 million stem cells. At Mayo Clinic, the current goal

for stem cells is 4 million, but transplantation is performed if

the yield is only 2 million, with median time to 500 neutrophils

on day 13 and 20,000 platelets on day 13.

The group at Princess Margaret Hospital has emphasized how

selection criteria affect outcome. Of 80 patients referred to

Princess Margaret Hospital, 48 had AL amyloidosis without

myeloma. Twenty-six of these patients were thought to be

candidates for stem cell transplantation, and 20 underwent the

procedure.93 Over 5 years, treatment-related mortality has



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Amyloidosis

decreased from 50% to 20%. Intent-to-treat organ responses

were kidney 46%, heart 25%, and liver 50%. The 3-year

survival rate was 56%. Improved outcome was predicted by

performance status, ALP level, nephrotic syndrome, and the

absence of hypotension. For patients with marked hypotension

or poor performance status, treatment-related mortality was

high. These patients should not receive a stem cell transplant.

The German Myeloma Group evaluated VAD induction

chemotherapy before stem cell mobilization with high-dose

melphalan.94 The VAD regimen produced grade 3/4 toxicity in

25% of patients, with a mortality rate of 7%. Stem cell

transplantation was performed in 86% of patients. An additional

benefit of pretransplantation induction therapy increasing the

posttransplantation hematologic response rate was not shown.

The mortality rate after stem cell transplantation was 13%. At the

time the results were reported, the 1-year survival rate from the

time of diagnosis was 75%, and the 3-year survival rate was 71%.

The survival rate was lower for patients with involvement of > 2

organs (60%) and was lower still for those with cardiac

involvement (40%). In the cohort of 24 patients who received

high-dose melphalan, a complete hematologic response wasobserved in 11. There were 3 treatment-related deaths (13%) and

1 death from progressive disease (4%).

The optimal conditioning regimen for amyloidosis has not

been studied. Most centers use melphalan alone. The use of total

body irradiation has been reported, but it did not appear to lower

treatment-related mortality.95 Tandem transplantation has been

attempted, but only a few patients, on an intent-to-treat basis,

completed a second planned transplantation. However, for those

who had the second procedure, the response rate increased.96

One of the worst complications we have observed is

postconditioning renal insufficiency. The serum creatinine level

increased in 19% of 80 patients. The risk factors were age,hypoalbuminemia, proteinuria, diuretic use, and increased

urine sediment score. Patients who develop postconditioning

renal insufficiency often require dialysis and have a low 12-

month survival rate. The renal insufficiency appears temporally

related to the infusion of melphalan.89 Ongoing tubular injury

may be a prerequisite for the development of postconditioning

renal insufficiency.

After stem cell transplantation, clonal responses range

between 50% and 60%, twice that reported with the use of

melphalan and prednisone.83,93 The selection bias inherent in

administering high-dose therapy may contribute partly to this

improved outcome. Eligibility for stem cell transplantation is a

predictor of improved survival.84 Stem cell transplantation does

produce kidney, heart, and liver responses. Currently, a

prospective randomized French trial is comparing stem cell

transplantation with oral melphalan/dexamethasone therapy. A

randomized trial begins in the United States in 2005.

Solid organ transplantation has been performed to manage

amyloidosis.25,97We have performed kidney transplantation in

patients with AL amyloidosis. Two strategies have been used. In

the first strategy, patients received high-dose therapy while on

dialysis in an effort to eliminate precursor light chain

production, followed by renal transplantation. The disadvantage

of this strategy was that patients on dialysis received a reduced

dose of melphalan, only 140 mg/m2, which may have

compromised the hematologic response rate. The complexities

of performing stem cell transplantation in patients on dialysis

are also increased. In the second strategy, high-dose therapy was

attempted within 6 months after patients received an allograft

kidney. Complication rates are high because these patients were

receiving long-term immunosuppressive therapy with

cyclosporine, prednisone, and tacrolimus and were at higher risk

for infection because of their chronically low CD4 cell counts.

Of our 8 patients, 5 of whom had end-stage renal disease by the

time of kidney transplantation, 1 died shortly after kidney

transplantation from causes unrelated to the procedure, and 1

has delayed stem cell transplantation. Of the 6 patients who

received stem cell transplantation, 1 died after transplantation,

but 5 are alive, and 3 have exhibited a complete hematologic

response. One patient developed a posttransplantation

monoclonal gammopathy. Immunosuppression did not

interfere with engraftment. Renal allograft function did not

decline with high-dose therapy.

Investigational Therapies

Etanercept has been used to treat advanced amyloidosis in 16

patients.98 The median duration of treatment was 42 weeks, and

objective improvement was noted in 50% of patients. The

estimated median survival was 24.2 months. Etanercept

warrants further study in the management of AL amyloidosis.

Dendritic cell idiotype vaccines have been attempted for

managing AL amyloidosis. Dendritic cell precursors were

purified from peripheral blood mononuclear cells and incubated

ex vivo with the patients serum containing the amyloid protein

precursors adjusted to a concentration of 10 g/mL. After 2

days of ex vivo expansion, the antigen-sensitized dendritic cellswere infused at 2, 4, and 16 weeks. No toxic effects were

observed. One patient had a reduction in proteinuria from 1400

mg to 60 mg per day. One patients neuropathy improved. Two

patients have died. The patients who had a clinical response had

a specific T-cell proliferative response to idiotype.99

An attempt to destabilize the amyloid fibril by interfering with

its sulfated glycosaminoglycan structure has been attempted.

Phase II trials with NC-531 were under way in October 2002.

Because all forms of amyloid have a high content of

glycosaminoglycans, particularly heparan sulfate proteoglycan,

such an agent could hold promise as a treatment.100A murine

antihuman light chain monoclonal antibody has been developed

that recognizes an epitope common to all AL fibrils. One

antibody, 11-1F4, was given to mice bearing AL amyloidomas

induced by the subcutaneous injection of human AL extracts.

Their tumor masses rapidly decreased. The antibody is now

being chimerized into a human form. Administration of the

chimerized reagent in mice bearing human AL tumors has

produced a marked reduction in amyloid burden with no

toxicity. Phase I trials of 11-1F4 are expected to begin.101,102

All forms of amyloid contain P component, and inhibitors of

P component have been developed in an attempt to destabilize

the amyloid fibril.103A compound has been shown to deplete P


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component from the serum and, according to scanning results,

is capable of depleting P component from amyloid deposits.

The cross-linked P component is removed by liver clearance. It

is hoped that the amyloid fibril will be destabilized.

ConclusionAmyloidosis should be considered in any patient with nephrotic

syndrome, cardiomyopathy, unexplained hepatomegaly,

peripheral neuropathy, or atypical myeloma.Initial evaluation

includes immunofixation of serum and urine and a serum

immunoglobulin free light chain nephelometric assay. Biopsy is

required to substantiate the diagnosis, but examination of a

subcutaneous fat aspirate and bone marrow will lead to the

diagnosis in 80% of patients. Biopsy of the heart, kidney, or

liver is rarely required. Prognosis of amyloidosis can be

accurately assessed with troponin T and NT-proBNP.

Echocardiography is helpful in all cases.

No optimal treatment has been established for AL amyloidosis.

The most commonly used is cytotoxic chemotherapy, oral

melphalan, low-dose parenteral melphalan, or high-dose

melphalan with stem cell reconstitution. Dexamethasone isfrequently given in combination with oral and intermediate-dose

melphalan and has been used alone successfully. Thalidomide

and the new analogue lenalidomide are being studied. A phase

III trial by the French Myeloma Study Group is expected to

answer the question of whether high-dose therapy provides

survival benefit for patients with amyloidosis.

AcknowledgementThis work was supported in part by the Hematologic

Malignancies Fund, Mayo Clinic.

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