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LYMPHOPROLIFERATIVE DISORDERS
AL amyloidosisMajid Kazmi
AbstractAmyloidosis is a rare group of disorders with protean manifestations char-
acterized by the deposition in tissue of misfolded protein. The body’s ca-
pacity to remove such deposits is poor, resulting in progressive
accumulation of amyloid deposits and disruption of organ function.
Among patients with systemic amyloidosis, AL type is more common
than AA type (secondary amyloidosis), which is caused by a chronic infec-
tion or chronic inflammatory disease.
The familial types of amyloidoses are rare, with an estimated incidence
of less than 1 per 100,000. They are autosomal dominant inherited dis-
eases with manifestations of amyloid deposition not developing until
mid-life. The most common form is caused by mutations in the transthyr-
etin (TTR) protein.
This chapter will focus on AL amyloidosis, formerly known as primary
amyloidosis, which most frequently affects the kidneys, heart, liver and
peripheral nervous system. Fatigue and weight loss are common but
the diagnosis is rarely made until symptoms referable to a particular
organ appear. Untreated, it is progressive and fatal within two years in
about 80% of patients. There is a three-step approach to diagnosis and
investigation of AL amyloid, which involves establishing the diagnosis;
assessing the extent of organ involvement; and excluding a plasma cell
dyscrasia or lymphoma. Treatment is directed towards reducing the pro-
duction of amyloidogenic light chains and stabilizing organ function.
New drugs such as bortezomib show real promise in rapidly reducing
light chain burden whilst being well tolerated. Future developments will
focus on reducing the amyloid load by interfering with the misfolding
of the proteins or interaction with serum amyloid P protein.
Keywords AL amyloid; amyloidosis; chemotherapy; SAP scan; stem cell
transplantation
Introduction
Amyloidosis is a rare group of disorders with protean manifes-
tations characterized by the deposition in tissue of misfolded
protein. The body’s capacity to remove such deposits is poor
resulting in a progressive accumulation of amyloid deposits and
disruption of organ function.
Awareness of amyloidosis has increased in recent years but
most diagnoses are still made at an advanced stage of disease. It
is important to differentiate the different types of amyloidosis as
their treatments are very different. There are over 20 different
types of amyloid in man. Among patients with systemic
amyloidosis, AL type is most common, followed by AA type;
hereditary amyloidosis accounts for about 10% of cases.
Majid Kazmi FRCP FRCPath is a Consultant Haematologist at Guy’s and ST
Thomas’ NHS Foundation Trust, UK. Competing interests: none
declared.
MEDICINE 41:5 299
AL amyloidosis
Systemic AL amyloidosis occurs where there is extracellular
accumulation of amyloidogenic monoclonal immunoglobulin
light chain fragments1 in association with the normal plasma
protein serum amyloid P (SAP). AL amyloidosis affects most
frequently the kidneys, heart, liver and peripheral nervous sys-
tem.2 Untreated, it is progressive and fatal within 2 years in
about 80% of patients.3 The age-adjusted incidence of AL
amyloidosis in the USA is estimated to be between 5.1 and
12.8 per million persons per year4; 60% of patients are between
50 and 70 years old at diagnosis and only 10% are aged under
50 years.2 There is equal male:female incidence. AL amyloidosis
may be associated with myeloma or other B-cell malignancy, but
in most cases the underlying plasma cell dyscrasia is subtle.
Clinical features
Fatigue and weight loss are common but the diagnosis is rarely
made until symptoms referable to a particular organ appear.
The most common clinical features at diagnosis are listed in
Table 1.2 It is important to recognize however that AL
amyloidosis can affect almost any organ or tissue in the body
other than the brain.
Diagnosis and investigation
The approach to diagnosis and investigation is a three-stage
process. In the UK it is recommended that all cases of amy-
loid are referred to, or at least discussed with, the National
Amyloidosis Centre (www.ucl.ac.uk/medicine/amyloidosis/
nac)
1. Establish the diagnosis of AL amyloid. Amyloid deposits
stained with Congo red produce red-green birefringence
when viewed under cross-polarized light. Amyloid is usually
diagnosed by biopsy of an affected organ, although less
invasive alternatives may be considered (e.g. subcutaneous
fat aspirate).6 Bone marrow involvement with amyloid is
strongly suggestive of AL amyloid [Figures 1 and 2]. Owing
to poor sensitivity of immunohistochemical staining for light
chains (60%), AL amyloidosis is often diagnosed after
exclusion of AA and hereditary types by immunohisto-
chemistry and genetic sequencing, respectively.7 In cases of
doubt, amyloid fibril gene sequencing or mass spectrometry
should be undertaken.8,9
2. Search for evidence for involvement by amyloid within other
organs. (Table 2).
3. Evaluation of plasma cell dyscrasia/lymphoma.
It is important to exclude a diagnosis of myeloma or other
lymphoid malignancy.
Prognostic factors
Patient survival has steadily improved from a median of
1e2 years in the 1980s to more than 5 years in recent se-
ries,2,11,12 probably reflecting a combination of better sup-
portive care and more successful treatment strategies. A poor
prognosis has been associated with symptomatic cardiac
disease.13
� 2013 Elsevier Ltd. All rights reserved.
Most common organ-specific manifestations of AL amyloid
Affected organ Approximate incidence Clinical features
Renal amyloid 33% Proteinuria and nephrotic syndrome with or without renal insufficiency.
Orthostatic hypotension
Cardiac involvement 20% Reduced QRS complexes on ECG.
Restrictive cardiomyopathy, orthostatic hypotension
Neurological involvement 20% C Sensory most commonly symmetrical
C Motor rare
C Carpal tunnel syndrome
C Autonomic peripheral neuropathy with gastrointestinal dysmotility, severe
orthostatic hypotension, weight loss, sexual dysfunction, bladder
dysfunction, abnormal sweating
Organ enlargement 25%
10%
Hepatomegaly
Macroglossia
Haemostatic involvement 50%
(5 Mumford et al 2000.)
Abnormal clotting screen
Bleeding diathesis including peri-orbital purpura (‘raccoon eyes’)
Table 1
LYMPHOPROLIFERATIVE DISORDERS
Treatment
Localized AL amyloid (non-vital organ)
The course of the disease is relatively benign in most patients. In
some cases local surgical intervention is appropriate.
Systemic AL amyloid including vital organ involvement
No treatment is yet available that removes specifically amy-
loid deposits, and therapy is aimed at suppressing the pro-
duction of clonal light chains to slow or halt ongoing amyloid
deposition, along with supportive measures for organ
function.
Numerous case series have shown that patients who achieve
complete or near-complete clonal responses have better out-
comes in terms of both patient survival14,15 and improvement in
amyloidotic organ dysfunction.16,17
Figure 1 AL amyloid in the bone marrow (interstitial).
MEDICINE 41:5 300
Myeloma-based conventional chemotherapy has been used
to treat AL amyloidosis.18 Relatively low rates of response and
delayed time to response prompted use of high dose melphalan
and autologous peripheral blood stem cell transplantation
(HDM and PBSCT).19 The risk of such a procedure in patients
with AL amyloid is significantly higher than in patients with
myeloma, with mortality rates running as high as 21% often
due to poor patient selection. Such treatments are now confined
to low-risk patients (defined by low-risk of transplant-related
mortality).
The advent of novel agents in myeloma treatment has seen
significant suppression of light-chain production and higher
complete response rates compared to conventional chemotherapy.
Although there are no prospective comparative trials, the
emerging data from the USA and Europe suggest that bortezomib-
containing regimens achieve rapid and deep clonal responses and
Figure 2 AL amyloid in the bone marrow (vessel wall).
� 2013 Elsevier Ltd. All rights reserved.
Evaluation of organ involvement with AL amyloid
Organ involved Tests
Generic Full blood count, clotting screen, skeletal
survey, chest X-ray, SAP scana
Renal Renal function tests, Quantification of
proteinuria e 24-hour urine collection or
protein/creatinine ratio calculation.
Liver Liver function tests
Cardiac ECG/echocardiogram/NT-proBNP and cardiac
troponin, cardiac MRI.
Respiratory Pulmonary function tests
Neurological Nerve conduction studies and autonomic
function tests
BNP, brain natriuretic peptide; ECG, electrocardiography; MRI, magnetic reso-
nance imaging; SAP, serum amyloid P.a SAP scintigraphy. This investigation is available only at the NHS National
Amyloidosis Centre, allows diagnosis and quantification of deposits,10 and
is useful in assessing the extent and distribution of organ involvement and
for evaluating the effects of treatment.
Table 2
LYMPHOPROLIFERATIVE DISORDERS
are generally well tolerated.20, 21 Such regimens may become the
first-line treatment of choice in AL amyloidosis. A
REFERENCES
1 Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J
Med 1997; 337: 898e909.
2 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and labo-
ratory features in 474 cases. Semin Hematol 1995; 32: 45e59.
3 Kyle RA, Gertz MA, Greipp PR, et al. Long-term survival (10 years
or more) in 30 patients with primary amyloidosis. Blood 1999; 93:
1062e6.
4 Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of
primary systemic amyloidosis in Olmsted County, Minnesota, 1950
through 1989. Blood 1992; 79: 1817e22.
5 Mumford AD, O’Donnell J, Gillmore JD, et al. Bleeding symptoms and
coagulation abnormalities in 337 patients with AL amyloidosis. Br J
Haematol 2000; 110: 454e60.
6 Libby CA, Skinner M, Cohen AS. Use of abdominal fat tissue aspirate
in the diagnosis of systemic amyloidosis. Arch Intern Med 1983; 143:
1549e52.
7 Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary
amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002; 346:
1786e91.
MEDICINE 41:5 301
8 Rodriguez FJ, Gamez JD, Vrana JA, et al. Immunoglobulin derived
depositions in the nervous system: novel mass spectrometry appli-
cation for protein characterization in formalin-fixed tissues. Lab
Invest 2008; 88: 1024e37.
9 Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by
laser microdissection and mass spectrometry-based proteomic
analysis in clinical biopsy specimens. Blood 2009; 114: 4957e9.
10 Hawkins PN. Serum amyloid P component scintigraphy for diagnosis
and monitoring amyloidosis. Curr Opin Nephrol Hypertens 2002; 11:
649e55.
11 Skinner M, Sanchorawala V, Seldin DC, et al. High-dose melphalan
and autologous stem-cell transplantation in patients with AL
amyloidosis: an 8-year study. Ann Intern Med 2004; 140: 85e93.
12 Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment
of AL amyloidosis. Br J Haematol 2008; 140: 365e77.
13 Kyle RA, Greipp PR, O’Fallon WM. Primary systemic amyloidosis:
multivariate analysis for prognostic factors in 168 cases. Blood 1986;
68: 220e4.
14 Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of
immunoglobulin free light chains are prognostic in patients with
primary systemic amyloidosis undergoing peripheral blood stem cell
transplantation. Blood 2006; 107: 3378e83.
15 Sanchorawala V, Seldin DC, Magnani B, et al. Serum free light-chain
responses after high-dose intravenous melphalan and autologous
stem cell transplantation for AL (primary) amyloidosis. Bone Marrow
Transplant 2005; 36: 597e600.
16 Palladini G, Perfetti V, Obici L, et al. Association of melphalan and
high-dose dexamethasone is effective and well tolerated in patients
with AL (primary) amyloidosis who are ineligible for stem cell
transplantation. Blood 2004; 103: 2936e8.
17 Pinney JH, Lachmann HJ, Bansi L, et al. Outcome in renal AL
amyloidosis following chemotherapy. J Clin Oncol 2011; 29:
674e81.
18 Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for
primary amyloidosis: colchicine alone, melphalan and prednisone,
and melphalan, prednisone, and colchicine. N Engl J Med ; 336:
1202e7.
19 Comenzo RL, Vosburgh E, Falk RH, et al. Dose-intensive melphalan
with blood stem-cell support for the treatment of AL (amyloid light-
chain) amyloidosis: survival and responses in 25 patients. Blood
1998; 91: 3662e70.
20 Kastritis E, Wechalekar AD, Dimopoulos MA, et al. Bortezomib with or
without dexamethasone in primary systemic (light chain) amyloid-
osis. J Clin Oncol 2010; 28: 1031e7.
21 Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib,
and dexamethasone therapy in AL amyloidosis is associated with
high clonal response rates and prolonged progression-free survival.
Blood 2012; 119: 4387e90.
� 2013 Elsevier Ltd. All rights reserved.