Download Light chain amyloidosis in the era of novel agents

4
Review Hematology
Light chain amyloidosis in the era of
novel agents
K. Beel, MD, PhD1
The development of new immunomodulatory therapies and their implementation in the treatment of multiple myeloma in the past years, offer new perspectives for the treatment of other plasma cell dyscrasias.
Light chain amyloidosis is historically associated with a very poor prognosis, despite the small size of the
monoclonal plasma cell population, due to progressive amyloid deposition in vital organs. Hence, advances
in treatment are eagerly awaited. Luckily, myeloma patients are paving the way for light chain amyloidosis
treatment, clearly demonstrating that immunomodulatory drugs and proteasome inhibitors are capable
of controlling plasma cell proliferation. Two recently published trials have shown a remarkable survival
benefit with CyBorD, a bortezomib containing regimen in light chain amyloidosis, possibly setting a new
standard for the treatment of this disease. In this article, we review current insights in the pathogenesis,
diagnostic challenges, prognostic markers and available treatments for light chain amyloidosis.
(Belg J Hematol 2013;4(4):120-126)
Introduction
Systemic light chain amyloidosis (AL) is caused by a
small clone of plasma cells, synthesising immunoglobulin light chain polypeptides, which are prone to misfolding and interstitial deposition as insoluble β-sheet
fibrils. Without treatment, the associated proteotoxicity
inevitably leads to progressive organ failure and death.
AL occurs in approximately one case per 100 000 persons in western countries, similar to chronic myeloid
leukaemia, with a mean age of 63 years at diagnosis.
Historically, AL had a very poor prognosis, with a median survival of thirteen months.1 Although AL is the
most common type of systemic amyloidosis; hereditary,
senile and secondary forms exist and should not be
confused with AL because of the different therapies
indicated. An overlap with multiple myeloma (MM)
exists, as 20% of AL patients meet the criteria for
myeloma and up to 30% of myeloma patients have
minor amyloid deposition.2 As opposed to other plasma
cell disorders, a 1:3 κ:λ ratio is found in AL, which
supports the concept that λ light chains are intrinsically
more amyloi-dogenic than κ.3 Some cytogenetic abnor-
malities occur both in MM and in AL. The translocation
t(11;14) is more frequent in AL (40-50%), but in contrast
to MM, it is associated with a worse prognosis, as is
the presence of cyclin D1 overexpression. Of interest,
marrow plasma cells of amyloidosis patients exert an
intermediate gene expression profile between a normal
and a myeloma signature.4
Pathogenesis
The process of amyloid formation is not completely
understood. Like Parkinson’s disease and Alzheimer’s,
AL is a proteopathy, meaning that changes in protein
conformation induce toxicity through highly ordered
amyloid β-sheet depositions. AL amyloidosis is inherently linked to the adoptive immune response in jawed
vertebrates. Immunoglobulin formation in the plasma
cell relies on recombination and somatic gene mutations.
However, genetic plasticity has its downside and amyloid formation could be considered the price for the
acquisition of a sophisticated adoptive immune system.
It is assumed that the amyloid deposition process was
Department of Haematology, Ziekenhuisnetwerk Antwerpen (ZNA), Antwerp, Belgium.
1
Please send all correspondence to: K. Beel, MD, PhD, Ziekenhuisnetwerk Antwerpen (ZNA), Department of Haematology, Middelheim,
Lindendreef 1, 2020 Antwerp, Belgium, tel: +32 3 230 34 95, email: [email protected].
Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest.
Key words: diagnosis and treatment of AL amyloidosis, novel agents in AL amyloidosis, systemic immunoglobulin light chain amyloidosis.
Belgian Journal of Hematology
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clinical: high index of suspicion
nephrotic range proteinuria, non-ischemic cardiomyopathy, peripheral
neuropathy, autonomic neuropathy with weight loss, unexplained hepatomegaly
histological: obtain biopsy
fine needle aspiration of abdominal fat: noninvasive, fast, cheap (sensitivity 88%, specificity 97%)9
or minor labial salivary gland (sensitivity 50%), or bone marrow biopsy (sensitivity 60%,)7,8 or rectum, liver or renal biopsy
Congo red staining and red-green birefringence under polarized light microscopy or 10 nm fibrils on electron microscopy
possible future gold standard with amyloid typing capacity: laser dissection with mass spectrometry9
laboratory: demonstrate monoclonal gammopathy
serum electrophoresis + serum immunophenotyping + serum FLC + urine EP/IFE = 98% sensitivity
bone marrow biopsy with plasma cell count (median plasma cell precentage is 7%)
-
+
organ distribution: determine extent of disease (no uniform scoring criteria)
molecular: typing of non AL amyloidosis
-screen the heart with biomarkers troponin T and NT-proBNP <-> low sensitivity for EKG
hereditary mutations in amyloid proteins (TTR)
(voltage loss), echocardio (atrial septum thickening), or cardiac MRI
or direct amyloid fibril sequencing ($)
-screen the kidneys with serum creatinine and 24h urine collection
-screen other organs guided by signs & symptoms: EMG, pulmonary function, liver biopsy
full body scan: SAP scintigraphy (only abroad, does not detect cardiac involvement)11
Figure 1. Diagnostic algorithm for light chain amyloidosis.
selected during evolution, as a last resort to prevent
misfolded peptides from interaction with physiological
processes, by concentrating them in certain tissues.5
Some mutations in the genes, encoding the variable
domain of the light chains, can cause thermodynamic,
hydrophobic or electrostatic instability, giving rise to
an amyloidogenic light chain. Up to 28 different amyloidogenic proteins have been recognised in humans,
but only a few are common.6 Once the secondary
structure of an α-helix-rich peptide, typical of most
proteins, refolds and forms more β-sheet structures,
peptides start to associate in an antiparallel way, allowing continued amyloid polymerisation. Besides immunoglobulin light chains, many stabilising proteins are
present in amyloid fibrils, such as the serum amyloid
protein (SAP) and apolipoproteins. Specific tissue characteristics (‘tropism’), e.g. matrix components glycosaminoglycans and proteoglycans in the target organ,
play a role in the amyloid deposition. As an example, the
6a λ light chain is classically mentioned as preferentially
associated with kidney involvement. However, later
studies have shown that some cases involve the heart.7
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121
Diagnosis
The diagnosis of AL can be challenging and a high
index of suspicion is required by all physicians, since
AL is a systemic disease with a variable phenotype.
A diagnostic delay results in more organ impairment,
which jeopardises treatment tolerability, which in turn
has a negative impact on prognosis. A diagnostic algorithm is presented in Figure 1.
The four most frequent presentations of AL are nephrotic
syndrome with preserved glomerular filtration rate, nonischemic cardiomyopathy, autonomic (orthostatism) or
peripheral neuropathy (carpal tunnel) and hepatomegaly
with cholestasis.8 Kidney involvement is most frequent,
but cardiac involvement is most dangerous. Fatigue (in
68%), peripheral oedema (in 62%) and weight loss (in
43%) are the most common systemic symptoms. Diarrhoea, due to gastro-intestinal amyloid deposition, occurs
in 9%. Macroglossia (in 14%) or periorbital ecchymosis
(raccoon eye) (in 11%) are rare, but pathognomonic for
AL, as is the shoulder-pad-sign (in 15%), caused by
periarticular amyloid infiltration. Factor X absorption
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4
of amyloid deposits and capillary fragility increase the
risk of bleeding.3 A biopsy needs to be obtained to confirm a clinical suspicion of amyloidosis. Fine needle
aspiration of abdominal fat is the preferred diagnostic
test, as it is non-invasive, fast and cheap with a high
sensitivity (88%) and specificity (97%).3 Confirmation
of AL by the demonstration of a monoclonal gammopathy and/or exclusion of other types of amyloidosis is
important, to spare patients unnecessary chemotherapy.
Common types of amyloidosis besides AL are senile,
hereditary transthyretin (ATTR) and serum amyloid A
(AA) secondary to chronic inflammation. Senile amyloidosis classically occurs in old men with isolated cardiac
involvement and the treatment is merely supportive.
Hereditary ATTR amyloidosis, particularly common in
African-Americans (3%), is a contra-indication for chemotherapy and requires liver transplantation. Molecular
analysis of hereditary mutations in amyloid proteins and
direct amyloid fibril sequencing can be performed, at a
considerable expense, at the NHS amyloidosis Centre
in London. Hereditary amyloidosis has a low penetrance
and a variable presentation in different family members,
further confounding the diagnosis.9 The mere presence
of a serum or urine monoclonal protein leads to misdiagnosis in 10%, as a coincidental monoclonal gammopathy
of unknown significance (MGUS) is not uncommon in
patients with other types of amyloidosis.6 Moreover, the
absence of a detectable serum monoclonal protein does
not exclude systemic amyloidosis. The last step in the
diagnostic process is defining the extent of the disease.
Localised amyloidosis is first suspected on the basis of
its location. It usually presents in the skin, larynx, brain,
bladder or as solitary pulmonary nodules. Life expectancy is normal and these patients should be referred
for laser therapy. A systematic clinical exam, followed
by directed organ screening helps to establish the extent
of the disease. Iodinated serum amyloid P scintigraphy
(SAP-scan) is a diagnostic tool for imaging organ distribution at diagnosis or follow-up. However, its availability
is limited and cardiac involvement cannot be detected.10
Response monitoring and prognosis
Hematologic response to therapy and the presence and
the extent of cardiac involvement are significant independent prognostic factors in AL.3 Hematologic response
predicts and precedes organ response by a median of
twelve months and is the goal of treatment. Before the
advent of serum free light chain (FLC) nephelometry,
measurement of hematologic response was difficult.7
The serum FLC assay now represents a powerful tool
Belgian Journal of Hematology
for monitoring response in the vast majority of patients
and normalisation of the serum FLC ratio is a strong
predictor of survival. Classically, the more organs involved the worse the prognosis, but cardiac involvement
has the greatest impact on survival with >70% of AL
patients dying of amyloid cardiomyopathy. Dispenzieri
et al. developed the Mayo cardiac staging system, based
on Troponin T and NT-pro-BNP levels, both sensitive
and reliable markers of cardiac function. Troponin T
correlates with cardiac damage and NT-pro-BNP with
wall strain.8 Prognosis and survival differ significantly
between patients with 0 (stage I), 1 (stage II) or 2 (stage
III) elevated markers.11 A reduction of 30% of NT-proBNP with treatment qualifies as response and normalisation of NT-pro-BNP correlates with improved survival.
These biomarkers are less reliable for cardiac monitoring
in the presence of renal failure, but in this case, they
provide a composite view on both organ systems.12 With
treatment, cardiac function starts to improve before the
resorption of amyloid deposits, indicating that circulating amyloid precursors exert reversible organ toxicity.
Therefore monitoring these biomarkers of cardiac function is more useful for follow-up than echocardiographic
measurement of wall thickening.13 The haematological
disorder and organ damage are currently measured by
the combination of serum FLC and cardiac biomarkers
troponin T and NT-pro-BNP, which are easy and powerful tools for evaluation of prognosis and response to
therapy.14 Some authors recommend annual measurement of NTpro-BNP and urinary albumin in all MGUS
patients with an abnormal FLC ratio.15 Other prognostic factors are the number of organs involved, the level
of FLC at diagnosis, serum uric acid, male gender,
weight loss and beta2-microglobulin, but these are not
validated.7
Treatment
The goal of treatment is rapid reduction of the plasma
cell clone and elimination of circulating free light chains,
in order to rescue organ function before irreversible
damage has occurred, while supporting organ function
in a multidisciplinary way and to extend survival. There
is a clear relationship between hematologic response,
organ response and survival.16 Ideally, future treatments
should also contain fibril directed therapies, to prevent
fibril formation and promote resorption of amyloid
deposits.
The paucity of randomised trials and the heterogeneity
of the disease challenge treatment recommendations. Myeloma treatments seem to provoke a higher toxicity in AL
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Table 1. Selected therapeutic trials in light chain amyloidosis
Regimen
Patients (pretreated)
Hematologic Response
Complete Response
Reference
Dex
25 (0)
40%
16%
Gertz et al. 199924
Mel - Dex
89 (0)
68%
33%
Palladini et al. 200418,
Jaccard et al. 200722
ASCT 200 Mel
275 (0)
76%
33%
Gertz et al. 200419
ASCT 100-140 Mel
173 (0)
53%
18%
Gertz et al. 200419
Thal - Dex
31 (31)
48%
19%
Palladini et al. 200525
Cy - Thal - Dex
75 (44)
74%
21%
Wechalekar et al. 200726
Len - Dex
34 (31)
47%
21%
Sanchorawala et al. 200727
Mel - Len - Dex
26 (0)
58%
23%
Moreau et al. 201028
Cy - Len - Dex
35 (11)
60%
11%
Kumar et al. 201229
Pom - Dex
33 (29)
47%
0%
Dispenzieri et al. 201230
Bortezomib
70 (70)
69%
38%
Reece et al. 201131
Bor - Dex
18 (7)
94%
44%
Kastritis et al. 200732
Bor - Mel - Pred
16 (0)
94%
56%
Gasparetto et al. 201033
Cy - Bor - Dex
17 (7)
94%
71%
Mikhael et al. 201234
Cy - Bor - Dex
43 (23)
81%
40%
Venner et al. 201235
Dex=dexamethasone, Mel=melphalan, ASCT=autologous stem cell transplantation, Thal=thalidomide, Cy=cyclophosphamide,
Len=lenalidomide, Pom=pomalidomide, Bor=bortezomib
patients and treatment should be individualised based
on age, frailty, organ dysfunction and treatment toxicities.
Chemotherapy and stem cell transplantation
The first randomised trial in amyloidosis was melphalan
plus prednisone versus placebo in 1978.17 This combination induced complete remission (CR) rates of 30%.
Replacing prednisone with dexamethasone improved
response rates and survival (33% CR, 48% organ response, 5.1 years overall survival (OS)).18 However, in
patients with cardiac amyloidosis Mel-Dex is clearly
ineffective. High dose melphalan (200 mg/m2) followed
by autologous stem cell transplantation has improved
outcome in a proportion of eligible patients. A pilot study
with autologous stem cell transplantation (ASCT) was
performed in 1996.18 The high treatment related mortality in this fragile population (especially with cardiac
involvement) was reduced by attenuating the melphalan
conditioning dose (100-140 mg/m2) in frail patients
but at the price of lower response and survival rates.19
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Deaths have been reported during stem cell mobilisation
in AL patients with cardiac disease. To minimise the
risk of toxicity, granulocyte-colony stimulating factor
(G-CSF) alone is recommended for mobilisation.20 Median time to organ response after ASCT is twelve months.
In experienced centres, where strict selection criteria
are implemented, median survival in AL after ASCT is
eight years.21 However, the use of ASCT in AL remains
controversial, as the only randomised trial in amyloidosis treatment was a French multicentre trial on melphalan plus dexamethasone and ASCT, which showed
no superiority of Mel-Dex/ASCT over Mel-Dex alone.22
Yet this trial was hampered by low patient numbers,
the inclusion of patients with severe organ damage,
low experience with ASCT for AL at investigation sites
and lack of randomisation for cardiac involvement.23
Novel agents
Mel-Dex has a low CR rate and ASCT is limited to a
minority of patients. Therefore, the search for therapies
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for AL continues. A selection of trials in treatment-naïve
and relapsed AL patients is listed in Table 1.
The results of the addition of an imid to the steroid and
alkylating agent backbone are promising, but renal and
cardiac toxicity, as well as the risk of venous thromboembolism are cause for concern. For lenalidomide, higher doses than 15 mg per day are poorly tolerated in
patients with systemic AL.
Since the first investigations with bortezomib, it’s became
clear that this agent could represent a major breakthrough in the treatment of AL, as bortezomib induces
rapid reduction of monoclonal light chains with potent
hematologic and organ (especially cardiac) responses and
is well tolerated. However, dose reductions are required
in certain patients, especially in cases with neuropathy
or cardiac symptoms.
After impressive response rates in myeloma, CyBorD
(the combination of cyclophosphamide, bortezomib and
dexamethasone) has been explored in light chain amyloidosis. In May 2012, two independent groups reported
on this therapy scheme. Mikhael et al. (Mayo clinic,
Toronto) reported on a retrospective analysis of seventeen patients with AL amyloidosis, ten of which were
treatment naive, who were treated with two to six cycles
of bortezomib 1.5 mg/m2 weekly or 1.3 mg/m2 on days
1,4,8,11, cyclophosphamide 300 mg orally weekly and
dexamethasone 40 mg weekly, before autologous stem
cell transplantation in eligible patients, as an alternative to those ineligible and as salvage therapy for relapsed patients.34 They report unprecedented results,
with 94% hematologic responses and a 71% CR rate.
Renal response was observed in half of the patients.
Median duration of response was 22 months. Three
ineligible patients became eligible after CyBorD. Low
grade neuropathy was the major side effect, which
could be managed by changing to weekly bortezomib.
Venner et al. (London National amyloidosis Centre)
reported on 43 patients, of which 20 were treatment
naive, who were treated with biweekly bortezomib,
dexamethasone and cyclophosphamide. Hematologic
response rate was 81.4% with a CR rate of 39.5%. Stem
cell collection remained successful after eight cycles of
bortezomib 1.3 mg/m2 (1,4,8,11), dexamethasone 20 mg
(1,2,4,5,8,9,11,12) and cyclophosphamide 350 mg/m2
orally (d1,8,15). In the 20 patients with Mayo stage III
cardiac disease, the OS at two years was 94.4%, improving the ten month median survival with melphalan
Belgian Journal of Hematology
and dexamethasone.35 Larger phase III studies are currently underway.
Both studies are retrospective, have a limited number
of patients and a short follow-up. Despite these limitations, these studies show that CyBorD has the potential to change the natural course of the disease, through
rapid and durable reduction of the culprit plasma cell
clone, and to reverse the poor outcome in patients with
cardiac involvement. The use of bortezomib as induction therapy renders some originally ineligible patients
eligible for transplantation. An important question to
be answered in future prospective trials (as in myeloma)
is whether ASCT is still mandatory for AL patients in
stable CR after treatment with a bortezomib containing
regimen. A European phase II trial is being developed
for patients with Mayo stage III cardiac disease, with
attenuated bortezomib doses. CyBorD can be administered in Belgium, if bortezomib is obtained in compassionate use. The pharmaceutical company provides
twelve compassionate use administrations per doctor
per year. However, patient registration in a data survey
would be highly recommendable, as this would at least
allow a retrospective study. International collaboration
is required to accrue enough patients in prospective
clinical trials. A Hovon trial opened in 2012, comparing
dexamethasone plus bortezomib versus dexamethasone
alone as an induction therapy before ASCT. However,
we believe that most treating physicians do not feel comfortable about withholding bortezomib from patients
with AL amyloidosis.
Future treatments will probably involve antibodies
against Serum Amyloid Protein (SAP) or the tertiary
structure of amyloid.36 SAP stabilises amyloid fibrils
and promotes fibrillogenesis. Humanised monoclonal
anti-SAP antibodies have been developed and are currently being tested in phase I/II trials. Antibodies against
light chain fibril compounds are also being tested in a
phase I/II trial.
Supportive organ care
Organ function starts to improve several months after
the achievement of a hematologic CR, but continues
to improve over time. Meanwhile, a multidisciplinary
approach is important for providing optimal individualised supportive treatment.
Patients with diastolic dysfunction are best treated with
a combination of loop diuretics and spironolactone.
Angiotensin converting enzyme (ACE) inhibitors can
worsen cardiac symptoms, unless used to treat hypertension. Anticoagulation should be considered to prevent
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Key messages for clinical practice
• A fast and accurate diagnosis of light chain amyloidosis requires a high index of suspicion and is
crucial to prevent end-stage organ failure.
• Cardiac involvement and response to treatment are the most important prognostic factors in light
chain amyloidosis.
• Serum FLC and cardiac biomarkers troponin T and NT-pro-BNP are elegant and powerful tools
for the evaluation of prognosis and response to therapy in light chain amyloidosis.
• CyBorD looks promising as standard treatment for light chain amyloidosis. The role of autologous
stem cell transplantation in the era of novel agents remains to be determined.
atrial thrombosis, but bleeding is a risk. Digoxin is
contra-indicated for atrial fibrillation in AL patients, as
this seems to bind to amyloid deposits with increased
toxicity. Calcium channel blockers can aggravate congestive heart failure and beta-blockers have shown to
increase mortality in cardiac AL. Amiodarone is best
tolerated. For severe nephrotic syndrome, diuretics are
the mainstay of therapy. ACE inhibitors can be considered to reduce proteinuria, but caution is warranted in
the case of poor cardiac output or hypotension. Octreotide is effective for the treatment of diarrhoea. Renal
transplantation can be considered after ASCT and
results in prolonged survival. Heart transplantation
has been carried out before and after ASCT with acceptable outcomes in small series.7
achieved by a combination of cytotoxic chemotherapy,
targeted and immunologic approaches to prevent amyloid deposition and promote fibril resorption.8
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Conclusion
Systemic AL is a life-threatening disease and prompt
diagnosis is required to allow intensive treatment in
order to preserve organ, especially cardiac, function.
The expanding myeloma armamentarium is improving
AL treatment, but specific large randomised trials in
amyloidosis are urgently needed. To date there are no
approved drugs for the treatment of light chain amyloidosis. Because of the rarity and the heterogeneity of
the disease, internationally joint efforts will be required
for prospective AL studies. The field is now mature for
large scale international collaborations. Such a network
of amyloidosis referral centres is currently working on
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May 2012, Groningen). One important task for future
trials will be to determine the role of ASCT in AL.
With the advent of novel agents, the field of amyloidosis
has entered an exciting era. A real prospect of cure
emerges on the horizon and this will probably be
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