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Reviews
Adv Clin Exp Med 2011, 20, 6, 771–778
ISSN 1230-025X
© Copyright by Wroclaw Medical University
Lidia Usnarska-Zubkiewicz1, Jadwiga Hołojda2, Kazimierz Kuliczkowski1
AL Amyloidosis (Amyloidosis Antibody Light).
Part 2 – Epidemiology, Clinical Symptoms, Diagnosis
and Treatment of Amyloidosis AL
Amyloidoza AL (amyloidosis antibody light). Część II – epidemiologia,
objawy kliniczne, rozpoznanie i leczenie amyloidozy AL
Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University,
Poland
2
Hematology Department of District Specialist Hospital of Legnica, Poland
1
Abstract
Studies have shown that 10–20% of patients with multiple myeloma develop AL amyloidosis. AL amyloidosis
can affect the kidney and the heart, as well as cause peripheral polyneuropathy and CNS impairment. The main
diagnostic test to confirm amyloidosis is the staining of the adipose tissue from abdominal fat with Congo red,
which demonstrates green birefringence when polarized light is used, or reveals nonbranching fibril structures
with a diameter of 10 nm under an electron microscope. Oral melphalan and prednisone have been the leading
drugs in the therapy of AL amyloidosis for 30 years. The patients qualified for megachemotherapy and stem cells
transplantation had to be free from severe, burdening diseases and had to have less than three involved organs (Adv
Clin Exp Med 2011, 20, 6, 771–788).
Key words: amyloidosis AL, epidemiology, clinical symptoms, diagnosis, treatment.
Streszczenie
Badania wykazały, że u 10–20% pacjentów chorych na szpiczaka mnogiego rozwija się amyloidoza AL. W przebiegu tej postaci skrobiawicy najczęściej dochodzi do zajęcia nerek i serca oraz rozwoju polineuropatii obwodowej
i uszkodzenia o.u.n. Podstawowym testem diagnostycznym potwierdzającym amyloidozę jest barwienie czerwienią
Kongo tkanki tłuszczowej z fałdu brzusznego i wykazanie charakterystycznego zielonego, dwułomnego świecenia
w świetle spolaryzowanym lub nierozgałęzionych włóknistych struktur o średnicy 10 nm w mikroskopie elektronowym. Od 30 lat wiodącymi lekami w terapii amyloidozy AL są melfalan i prednison. Podobnie jak w leczeniu
szpiczaka mnogiego, w terapii amyloidozy zaproponowano stosowanie talidomidu, lenalidomidu i bortezomibu,
w monoterapii lub w połączeniu z deksametazonem. Do megachemioterapii i przeszczepienia komórek macierzystych byli kwalifikowani chorzy bez poważnych, obciążających chorób, którzy mieli zajęte przez amyloidozę mniej
niż trzy narządy (Adv Clin Exp Med 2011, 20, 6, 771–788).
Słowa kluczowe: amyloidoza AL, epidemiologia, objawy kliniczne, rozpoznanie, leczenie.
Epidemiology
The prevalence of amyloidosis is difficult to estimate, as the disease often remains undiagnosed or
misdiagnosed. In AL amyloidosis, the estimations
more often include mortality due to this complication, while estimations of the prevalence of the AA
type are based on post mortem examinations [1].
In order to evaluate the incidence of AL amyloidosis, Kyle and colleagues analyzed the number of
cases in one Minnesota county from 1952 to 1992.
They found that the annual morbidity rate was
8.9 cases per million of the county residents [2, 3].
This was used as the basis for an estimation according to which there are 1275–3200 new AL amyloidosis cases diagnosed annually in the USA, which
constitutes 5.1–12.8 cases per million residents.
The studies have shown that systemic AL amyloidosis is a more common form among residents of
the USA and western Europe. The incidence of this
772
disease is 0.8–1/100000 cases/year, with patients at
the age of 50–70 [4].
In Europe, there are no centers that would keep
a register of amyloidosis cases. Data reported from
individual countries only provides information on
the incidence of amyloidosis in a given region [5].
Studies have shown that 10–20% of patients
with myeloma develop AL amyloidosis [6]. Vela-Ojeda et al. analyzed 201 newly diagnosed MM
patients and found that 68 of them (34%) had
amyloidosis AL and poorer disease prognosis [7].
Primary AL amyloidosis also affects 7% of patients
suffering from non-hematologic malignancies [8].
Amyloidosis rarely occurs before the age of 40,
patients aged 50–70 constitute 60% of cases, and it
more often affects men (50–65%) [4].
Clinical Symptoms
The most common clinical symptoms associated with amyloidosis include: weight loss, ankle oedema, hoarseness, paraesthesia, tiredness, orthostatic hypotension, heart failure, enlargement of the
liver and the tongue, and carpal tunnel syndrome
[9]. The amyloidosis can also affect the kidney and
the heart as well as cause peripheral polyneuropathy and CNS impairment [10]. According to Müller et al., kidney damage in the form of nephritic
syndrome affects 28% of patients, heart failure and
polyneuropathy 17%, carpal tunnel syndrome 21%,
orthostatic hypotension 11%, and orbital purpura
15% of the subjects [11].
The Kidney
Studies have shown that in a group of 211
newly dialyzed patients, 2% developed systemic
amyloidosis [12]. Kyle et al., analyzing 474 AL patients, revealed the presence of proteinuria in 73%
of the subjects, out of which 28% met the criteria
of nephritic syndrome and 50% developed renal
failure [13]. Other authors reported Bence-Jones
proteinuria in 60% of amyloidosis patients, while
10% of patients had amyloidosis without typical
proteinuria. In these patients, proteinuria was replaced by fatigue and ankle oedema [14].
The Heart
17% of amyloidosis patients develop amyloid
cardiomyopathy in the type of restrictive cardiomyopathy with the symptoms of right ventricular
insufficiency. The low ejection fraction observed
in 13% of patients may evolve into orthostatic hypotension [11]. Congestive heart failure is associated with shorter median survival and exertional
L. Usnarska-Zubkiewicz et al.
syncope is a predictor of early death [15]. ECG
(echocardiography) tracing shows low voltage QRS
complex in standard leads, or traces corresponding
to myocardial infarction, but without evidence of
ischaemic disease. The deposits of amyloid in coronary vessels may also lead to arrhythmia, conduction blocks, angina pectoris, or myocardial infarction [16]. Unlike ECG, troponin I and N-terminal
pro-brain natriuretic peptide (NT-proBNP) are
objective parameters of cardiac involvement. According to these measurements, three stages of cardiac amyloidosis have been proposed. In patients
with stage I of cardiac amyloidosis, troponin T,
troponin I and NT-proBNP must be within normal values, while in stage II, one of them, and in
stage III both of them, exceed normal values [17].
At the Mayo Clinic, the serum troponin T level was
introduced as a criterion of the inclusion for stem
cell transplantation (SCT) [18].
The Haematopoietic System
In AL amyloidosis, 18% of patients reveal
above 20% plasmocytes in the bone marrow, and
60% – below 10% [19]. According to Merlini et al.,
the majority of patients with amyloidosis AL do
not meet the criteria for myeloma [9]. A tendency
to bleeding, ecchymoses, and periorbital extravasations in the type of “raccoon eyes” results from
amyloid deposition in the blood vessels, which increases their fragility. Moreover, the bleeding tendency is associated with the binding of the X factor by the amyloid, which leads to the formation of
a faulty clot [20].
The spleen is involved in 10% of amyloidosis patients. Amyloid may be present in the white
splenic pulp and less commonly in the red pulp
[13]. Hyposplenism resulting from amyloid infiltration may cause thrombocythemia, and the
presence of Howell-Jolly bodies has also been observed.
The Liver
Hepatomegaly is secondary to amyloid cardiomyopathy, or results from the accumulation
of amyloid fibrils. Liver involvement is observed
in 50% of amyloidosis patients. Laboratory studies reveal significantly elevated levels of alkaline
phosphatase and slightly elevated levels of aminotransferases.
The Skin
Skin involvement affects 30–40% of patients
and 10–15% of them develop spontaneous petechiae. Skin nodules in the form of flat, waxy, shiny,
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AL Amyloidosis (Amyloidosis Antibody Light) – Part 2
scaling infiltrations are common. Mucous membranes present a similar picture. The sensation of
dryness in the mouth (xerostomia) results from
amyloid infiltration of the salivary glands. An evident balding tendency occurs.
The Musculo-Skeletal System
Amyloid accumulation in the muscles leads
to pseudohypertrophy, such as enlargement of the
tongue. Macroglossia affects up to 10% of amyloidosis patients. Arthropathy results from amyloid
depositions in the joints.
The Nervous System
20% of patients with nervous system involvement develop polyneuropathy. Its peripheral form
is associated with peripheral sensation disturbances, such as numbness, paraesthesia and piercing
pains. The symptoms result from pressure exerted
by the amyloid deposits on peripheral nerves, like
in carpal tunnel syndrome in the course of AL amyloidosis. Orthostatic hypotension, impotence and
digestive tract motor disturbances are associated
with autonomic neuropathy.
Diagnosis of Amyloidosis
The main diagnostic test to confirm amyloidosis is the staining of adipose tissue from abdominal
fat with Congo red, which demonstrates green birefringence when polarized light is used, or reveals
nonbranching fibril structures with a diameter of
10 nm under an electron microscope. If the test is
negative, it may be followed by a salivary gland,
rectal mucosa, gingival, or bone marrow biopsy, or
a biopsy from an organ which is assumed to contain accumulated amyloid fibrils [21]. The efficacy
of amyloid identification in various loci varies: kidney, spleen and liver biopsies are positive in about
90% of cases, abdominal adipose tissue aspirates
in 60–80%, rectal biopsy in 50–70%, bone marrow
biopsy in 50–55%, and skin biopsy in 50–80% [22,
23]. The amyloid deposits may also be visualized
by means of radioisotope methods with the use of
Tc99m technetium, which is especially useful in
the case of cardiac amyloidosis [24]. It is effective
in very advanced cardiomyopathy, which, together
with echocardiography, constitutes the basic diagnostic test.
Amyloid deposits may be diagnosed by means
of another diagnostic method – scintigraphy,
which is based on the coexistence of amyloid deposits with normal serum SAP protein, which may
be tagged with technetium or iodine (I123). Scintig-
raphy using the radioisotope combined with SAP
is able to determine the locations of amyloid deposits and amyloid fibril load in a very short time.
This examination is especially useful in secondary
amyloidosis and may be positive despite a negative
tissue biopsy. Spleen scintigraphy may be positive
in 100%, kidney in 80%, adrenals in 50% and liver
in 25–50% of cases [25]. The method is of no use
in cardiac amyloidosis due to the large amount of
blood flowing through the organ, which may cause
100% false results [26]. In AL amyloidosis, a bone
marrow aspiration biopsy is performed in order
to demonstrate plasma cell infiltration. The clonal
character of the plasma cells may be demonstrated
by means of the immunohistochemical method
with the use of anti-κ or anti-λ antibodies.
The use of electrophoresis and immunofixation of serum and urine proteins may help reveal
the presence of light chains and monoclonal immunoglobulin in 90% of amyloidosis patients [6].
The serum level of free light chains (FLCs) is determined with the immunonephelometric method with the use of antibodies specific for κ and
λ chains, which do not recognize light chains linked
with heavy chains. The sFLCs test is more sensitive
than protein electrophoresis and at least 500 times
more sensitive that immunofixation [27]. With
the immunofixation method, while the presence
of light chains may be determined when their level
is 100–500 mg/l, the immunonephelometric method revealed the presence of sFLCs at the level of
3–4 mg/l. According to Katzmann, a combination
of 2 parameters, i.e. the kappa/lambda ratio and
serum immunofixation, gives the highest sensitivity (99%) in diagnosed AL patients [28].
DNA examinations used in sequencing of the
amino acids in the amyloid fibrils are indicated in
patients who reveal the presence of monoclonal
protein, and who at the same time present clinical symptoms of inborn amyloidosis [29]. In other
forms of fibrilosis than AL amyloidosis, apart from
a histological demonstration of amyloid deposits,
other examinations are performed in order to
identify the amyloid protein, immunohistochemical evaluation with the use of an electron microscope, or spectrophotometric examinations [30].
Treatment of Amyloidosis
All therapies for amyloidosis AL have focused
on lowering clonal plasma cells and reduction of
the synthesis of monoclonal FLC. There are: high
dose chemotherapy with autologous hematopoietic stem cell transplantation, standard therapy
with melphalan and prednisone Vel/dex, thalidomide, lenalidomide and bortezomib [31]. Therapy
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L. Usnarska-Zubkiewicz et al.
for solubilizing the amyloid fibril is not known at
the moment. The response criteria in patients with
amyloidosis AL meet both the monoclonal protein, measured as a serum free light chains level,
and an objective improvement in organ function
[5]. The current study conducted by Kumar et al.
supports the notion that FLC response is a more
useful measure of hematological response than Mprotein and achieving at least a 90% reduction in
the FLC to improve the outcome of patients with
light-chain AL [32]. According to Lachmann et al.,
there is a positive correlation between a hematologic as well as organ response to therapy and survival
[33]. The hematologic response has been defined
as a 50% reduction in the precursor monoclonal
protein level (PR, partial response), and survival is
better in patients who have at least 50% reduction
of FLC compared with those who do not fulfill this
criterion. The best outcomes were observed in patients with normalization of these parameters and
negative immunofixation of the serum and urine
(CR, complete hematologic response) [34]. An organ response has been defined as a 50% reduction
in urinary albumin loss in patients with renal amyloidosis, a decrease in liver size (or a 50% lowering
of alkaline phosphatase in serum) in persons with
hepatic amyloidosis, and echocardiographic improvement (or a 30% abatement in the BNP level)
in cardiac amyloidosis [35].
Megachemotherapy
and Stem Cells
Transplantation
In the Mayo Clinic, the patients who were
qualified for megachemotherapy and stem cells
transplantation had to be free from severe, burdening diseases and had to have less than three
involved organs [35]. The conditioning therapy
involved administration of high doses of melphalan. A multi-center study performed in the
years 1998–2006 demonstrated that 25–67% of
patients treated this way achieved remission of the
disease, however the transplant-related mortality
was high and ranged from 15 to 40% [36]. Bone
marrow transplantation in patients with amyloidosis differs from the procedure performed in
other plasma cell dyscrasias. Multi-organ dysfunction occurs more commonly in amyloidosis. This
leads to post-transplantation complications, such
as kidney failure requiring dialysis, as well as liver
and heart failure. Studies have shown that the success of transplantation is affected by the high level
of expertise of the transplantation center, with
significantly better outcomes achieved in centers
with over 5 years’ experience [37].
Stem cell transplantation is not a routine management in amyloidosis, despite the reported fact
that remission of organ involvement was achieved
in up to 50% of patients [38]. Studies performed
by a multi-center French group involving 100 patients treated with melphalan and dexamethasone
at standard doses, or megachemotherapy, revealed
that the median survival for group I was 57 months,
and in patients after transplantation – 49 months,
and the therapeutic response was achieved in 64%
and 65% of patients respectively [39]. However,
according to the authors, the rejection of megachemotherapy as a therapeutic modality in amyloidosis seems premature.
Treatment of Patients
not Qualified
for Transplantation
Oral melphalan has been the leading drug in
the therapy of AL amyloidosis for 30 years. The
drug is administered in 4-day cycles every 28 days
at a daily dose of 0.22 mg/kg, in combination with
prednisone. In the study by Kyle et al. involving
219 patients, the median survival was demonstrated to reach 17 months, twice as much as in
the case of colchicine-treated patients [40]. Promising outcomes were also achieved in 93 patients
treated with dexamethasone with or without interferon: a complete hematological remission was
achieved in 24% of patients, improved organ function in 45% of patients, and median survival was
31 months [41]. The above outcomes were confirmed in the study by Palladini et al. [42].
Thalidomide, Lenalidomide
and Bortezomib
for Amyloidosis AL
Like in myeloma therapy, amyloidosis is also
treated with thalidomide, lenalidomide and bortezomib, in monotherapy or in combination with
dexamethasone.
According to data provided by Palladini et al.,
thalidomide as a single agent is toxic and ineffective, but used with dexamethasone showed hematologic response in 48% patients with 19% CR and
the organ response rate was 26% [43]. The results
of the second phase of two trials that tested the efficacy of lenalidomide +/– dexamethasone therapy
showed that 10 of 23 patients and 16 of 24 evaluable patients achieved the hematologic response.
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AL Amyloidosis (Amyloidosis Antibody Light) – Part 2
Adverse events of grade 3 and 4, possibly related
to lenalidomide, were neutropenia, thrombocytopenia and fatigue [44, 45].
In 2008, the National Amyloidosis Center in
Great Britain presented data of a study conducted
on 18 patients treated with bortezomib that had previously received thalidomide-based therapy [46].
Hematologic and organ response was observed in
77% and 27% of patients, respectively. Kastritis et
al. reported on AL patients, who relapsed or progressed after previous therapy and persons with
renal dysfunction, treated with bortezomib. This
data as well as a study conducted by Lamm et al.
in previously untreated patients has shown significant benefits in overall and progression-free survival [47, 48].
New Therapeutic Options
New drugs, the main aim of which is to inhibit
amyloid fibril formation, are being investigated
and tested clinically. They include:
1. Drugs diminishing the aggregation of fibrils and stimulating the resorption of amyloid.
The effect is achieved by 4-iodo-4-deoxydoxorubicin (IDOX). Clinical trials have shown that a dose
of 15 mg/m2 is able to evoke a clinical response in
15% of patients [49].
2. R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylicacid causes the
elimination of SAP protein from the circulation
and its secondary resorption from amyloid deposits [50].
3. Etanercept – a TNF blocker, the use of which
is associated with TNF-alpha activity in the development of amyloidosis [51].
4. Eprodisate (sulfated glycosaminoglycan),
the use of which in the therapy for secondary amyloidosis is tested in ongoing phase II–III clinical
trials [52].
Supportive Care of Organ
Involvement in the Course
of Amyloidosis
Cardiac Amyloidosis
The therapy for cardiac amyloidosis has two
aims: it is directed against light chains, and it is
aimed to protect the heart. Maintaining balance
between the function of the amyloidosis-affected
heart muscle and the volume of the vascular bed
plays a key role, thus administration of diuretics,
e.g. spironolactone and metholasone, as well as
a sodium regime are important measures [53]. Such
management may be limited if there is coexisting
orthostatic hypotension or nephritic syndrome.
In case of recurrent fainting, the patients should
be qualified for pacemaker implantation [54].
In patients with paroxysmal ventricular arrhythmias, defibrillator implantation is advisable. The
use of angiotensin inhibitors is hampered due to
large differences in blood pressure. Patients with
low ejection fraction may use ICE, however with
extreme caution, starting from low doses. Calcium-channel blockers are also advocated. Orthostatic hypotension is an important problem in patients with amyloid heart disease. In such cases, the
use of compression stockings and midodrine may
prove useful. In cases of extreme heart failure, trials were undertaken to transplant the heart, which
gave a symptom-free survival rate of 32 months
[55]. According to recommendations of the National Amyloidosis Center in Great Britain, and
the Spanish Register for Heart Transplantation,
heart transplantation should follow bone marrow
transplantation and be reserved for patients with
or without mild systemic AL [55, 56].
Kidney Amyloidosis
A crucial role in the therapy for kidney dysfunction in the course of amyloidosis is played by
diuretics and a sodium regime. However this management proves insufficient in the case of nephritic syndrome and high loss of protein with urine.
In these patients, in the terminal stage of kidney
failure, ramipril remains the drug of choice [57].
The mean time lapse between the diagnosis of kidney amyloidosis to the onset of dialysis therapy is
14 months, and the mean survival rate of patients on renal replacement therapy is assessed at
9 months. Simultaneously coexisting cardiac amyloidosis significantly hampers the dialysis therapy.
Researchers from the Mayo Clinic found out that
institution of chemotherapy prior to renal transplantation ensures better tolerance of the transplant,
however it requires the use of immunosuppressive
drugs since the very onset. It was established that
a positive therapeutic response to decreased doses
of melphalan constitutes an indication to kidney
transplantation in amyloidosis patients.
To summarize: In the past decade, significant
progress in the diagnosis and treatment of patients
with amyloidosis AL has been made. However,
there still is an urgent need for education in order
to promote the earlier diagnosis and proper therapy of this disease. The aim of the therapy of amyloidosis AL is to suppress the monoclonal plasma
cell clone that produces the amyloidogenic FLC.
The most important clinical endpoint of this treat-
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L. Usnarska-Zubkiewicz et al.
ment is the improvement of organ response. For
this reason, the definition of an organ response
(PR, CR) was developed.
The introduction of thalidomide, lenalidomide
and bortezomib, the new agents for the manage-
ment of AL, have significantly expanded the possibilities of treatment of amyloidosis AL. Reduction
of FLC level is associated with survival benefits, irrespective of the chemotherapy regimen used.
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Address for correspondence:
Lidia Usnarska-Zubkiewicz
Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation
Wroclaw Medical University
Pasteura 4
50-367 Wrocław
Poland
Tel.: +48 71 784 25 96, +48 600 642 881
E-mail: [email protected]
Conflict of interest: None declared
Received: 2.08.2011
Revised: 21.09.2011
Accepted: 7.12.2011