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What do I need to know about immunoglobulin light chain (AL) amyloidosis?
Blood Reviews, 4, 26, pages 137 - 154
Immunoglobulin light chain (AL) amyloidosis is the most common acquired systemic amyloidoses. Its presentation is often insidious and progressive, which may delay diagnosis. The interval between first symptoms and actual diagnosis along the intrinsic heterogeneity of tissue tropism create a wide spectrum of presentations, both in terms of scope and depth of symptoms and signs and functional status of patients. In this review, the authors review the pathogenesis, diagnosis and differential diagnosis of AL amyloidosis along with the prognosis and state-of-the-art management for patients with this affliction.
Keywords: Amyloidosis, Multisystem disease, Monoclonal gammopathy, Prognosis, Transplantation.
Immunoglobulin light chain amyloidosis (AL) is a low tumor burden plasma cell disorder characterized by deposition of insoluble fibrils composed of immunoglobulin light chains. Without treatment, AL has an inexorable progressive course due to uncontrolled tissue damage ( Fig. 1 A). Although AL is the most common form of systemic amyloidosis, with an incidence of approximately 1 case per 100,000 person-years in Western countries, 1 there are other forms of systemic amyloidosis ( Table 1 ). 2 Typing the amyloid is imperative since treatment strategies are different depending on the source of precursor protein. 3 In the case of AL amyloidosis, the precursor protein is bone marrow plasma cell derived immunoglobulin light chains, which is quite different from the case of ATTR, wherein the precursor protein—transthyretin—is made in the liver.
|Type of amyloidosis||Precursor protein component||Clinical presentation|
|AL amyloidosis a (previously referred to as primary amyloidosis)||κ or λ immunoglobulin light chain||Systemic or localized|
|AH amyloidosis||γ, μ, α immunoglobulin heavy chain||Systemic or localized|
|AA amyloidosis (previously referred to as secondary amyloidosis)||Serum amyloid A protein||Renal presentation most common; associated with chronic inflammatory conditions; typically acquired, but hereditary in case of familial periodic fever syndromes|
|LECT2||Leukocyte chemotactic factor 2||Renal presentation; acquired|
|b Mutated transthyretin (commonly referred to as familial amyloid polyneuropathy)||Mutant TTR||Hereditary; peripheral neuropathy, autonomic neuropathy, vitreous opacities, and/or cardiomyopathy|
|Wild-type TTR b (senile amyloidosis)||Normal transthyretin||Restrictive cardiomyopathy; carpal tunnel syndrome|
|β2-microglobulin amyloidosis (associated with long-term dialysis)||β2-microglobulin||Carpal tunnel syndrome, arthropathy large joints|
|Aβ amyloidosis||Aβ protein precursor||Alzheimer disease|
|Other hereditary amyloidosis|
|A fibrinogen (also called familial renal amyloidosis)||Fibrinogen α-chain||Renal presentation|
|Lysozyme||Lysozyme||Renal presentation most common|
|Apolipoprotein A-I||A-I Apolipoprotein||Renal presentation most common|
a AL amyloidosis is the only form of amyloidosis that is secondary to a clonal plasma cell disorder. AL amyloidosis can be associated with multiple myeloma in approximately 10% of patients.
b TTR refers to transthyretin, which is commonly referred to as prealbumin.
The mechanism of amyloid formation is not completely understood, but amyloid is formed when the structure of a native protein is converted into a predominantly antiparallel β-sheet secondary structure which is conducive to aggregation in tissues in the form of fibrils that we recognize as amyloid on electron microscopy and on light microscopy with stains like Congo Red. In the case of AL, not all immunoglobulin light chains are equally amyloidogenic since only 10 to 15% of patients with myeloma have co-existing amyloidosis at diagnosis, 4 and only 1% of patients with active myeloma go on to develop AL. 5 The intrinsic property of the B-cell and plasma cell niches to generate immunoglobulin diversity through a large immunoglobulin variable gene repertoire, programmed recombination, and somatic mutation make immunoglobulins very suitable amyloid precursor proteins. The distribution of immunoglobulin light chain variable gene usage by bone marrow plasma cells is expected to be 3:1 κ to λ in the normal population. Despite this, the number of AL cases favors λ to κ by 2:1, which supports the concept that germline λ is intrinsically more amyloidogenic than κ ( Table 2 ). Moreover, certain immunoglobulin variable genes (IGLV and IGKV) appear to be more amyloidogenic than others given their frequency of usage in the general population as compared to patients with AL.6 and 7 For example, IGLV6 family usage is rare among other B-cells and B-cell neoplasms, but comprises approximately 30% of λ restricted AL cases. IGLV3-1 gene usage is higher than expected and usage of genes from the IGKV2 family is less common in AL than expected. 8 Risk factors for amyloid formation have included specific modifications to the immunoglobulin light chain.9, 10, 11, 12, and 13
|Ref||N||λ cases||% of λ cases||κ cases||% of κ cases|
|Expected6 and 7||26||24||40||2||4||64||18||9||9|
IGKV refers to a family of immunoglobulin kappa variable genes.
IGLV refers to a family of immunoglobulin lambda variable genes.
Not all rows add up to 100% due to an occasional patient with IGLV family not included in the table.
It is believed that AL immunoglobulin light chain internalizes into cells and traffics into lysosomes. Macrophages and their lysosomes are implicated in amyloid formation at target tissues14, 15, and 16 For example, human mesangial cells exposed to AL immunoglobulin light chain not only form amyloid fibrils in vitro but they become transformed to a macrophage-like phenotype including the acquisition of lysosomes. 17 Amyloid fibrils found in human tissues are not merely comprised of pure amyloid precursor protein. Other proteins are found in the amyloid deposits, most commonly serum amyloid protein (SAP), apolipoprotein E (ApoE), apolipoprotein A1 (ApoA1), and apolipoprotein A4 (ApoA4). 18
Little is known about why amyloid targets specific tissues in one patient versus another. There are a few relatively small series evaluating whether a specific IGKV and IGLV gene used pre-determines tissue tropism ( Fig. 2 ),6, 19, 20, 21, 22, and 23 but these have produced inconsistent results, potentially due to the small number of sequences included, differences in technique including primer selection, patient populations, and analyses performed. It had been dogma that IGLV6 always involved the kidneys, but later studies have shown that IGLV6 cases can involve the heart.19, 20, and 23
There are four essential steps in diagnosing amyloidosis: 1) consider the diagnosis; 2) make the diagnosis by tissue biopsy; 3) determine the precursor protein; and 4) define the extent of involvement. One of the biggest challenges for patients with AL is having the diagnosis considered in timely fashion. Often it is a physician other than a hematologist/oncologist who is charged with contemplating the diagnosis. Although features like periorbital purpura and macroglossia are pathognomonic, they are rare and cannot be relied upon to be the sole triggers for considering a diagnosis of AL. Hematologists should not be misled by a stable monoclonal protein in a patient followed for monoclonal gammopathy of undetermined significance or smoldering myeloma, who reports increased fatigue, into believing that the clonal plasma disorder is not the source of the patient's status without seriously considering the possibility of AL.
The most commonly affected organs resulting in symptoms are the heart, kidneys, skin, peripheral nerves, autonomic nerves, and liver and their respective means of presentation are: 1) normal ejection fraction with diastolic dysfunction, left ventricular hypertrophy with low voltage electrocardiogram; 2) nephrotic syndrome with preserved glomerular filtration rate; 3) purpura most notably around the eyes and neck; 4) small fiber peripheral neuropathy characterized by dysesthesia; 5) orthostatic hypotension; 6) hepatomegaly often with a cholestatic rise in liver function tests Although the gastrointestinal tract is commonly biopsy positive, it is relatively uncommon for patients to have symptoms referable to it. A diagnosis of pulmonary involvement is rare since no formal criteria exist. Amyloid arthropathy occurs in about 2% of patients, whereas carpal tunnel syndrome is quite common, occurring in 25%. 24 The dominant symptomatic organ system involved varies among different practices ( Fig. 3 ). 25
Once a diagnosis of AL is suspected, a monoclonal protein in the serum and the urine should be sought and a tissue biopsy performed. Screening for a monoclonal protein is done by serum immunoglobulin free light chain measurement and immunofixation studies of the serum and urine. 26 Although an important part of the work-up, serum and 24-hour urine protein electrophoresis alone are insufficient as screening tools. Among patients with AL amyloidosis, the sensitivity of serum protein electrophoresis for detecting a monoclonal protein is only 66%, whereas the sensitivity of serum immunofixation is 74%, and serum immunoglobulin free light chain assay is 88%. The sensitivity for detecting a monoclonal protein further increases to 94% if one combines all three serum tests and rises to 98% if urine immunofixation is added. 26 The diagnostic biopsy may be of the tissue causing symptoms—e.g. heart or kidney—or of a more accessible tissue, like fat or bone marrow. The sensitivity of a biopsy of a symptomatic organ is higher than that of the more accessible tissues, i.e. more than 95% for symptomatic tissue, 75–80% for fat, and 50–65% for bone marrow. 27 A diagnosis of amyloidosis is not made by hematoxylin and eosin staining alone; special stains like Congo Red, Thioflavin T or sulfated Alcian blue are required. Congo Red avidity is not sufficient; apple-green birefringence under polarized light is essential for a diagnosis. Electron microscopy is also helpful to identify the 8–11 nanometer non-branching fibrils. Once a diagnosis of amyloidosis is made, typing is required by subjecting the amyloid to direct sequencing, immunogold, immunofluorescence or immunohistochemistry. The presence of a serum or urine monoclonal protein does not assure a diagnosis of AL and may lead to misdiagnosis in as many as 10% of cases.28 and 29 In the 21st century, the preferred method of typing the amyloid protein from tissues is mass spectrometry.30 and 31
4. Defining disease extent
A thorough assessment of extent of involvement is required in order to develop a treatment plan. 32 It is at this time that the distinction between localized and systemic AL is made. The designation ‘localized’ applies to those cases of AL in which the precursor protein (the immunoglobulin light chain) is made at the site of amyloid deposition33, 34, and 35 and is typically not associated with a detectable circulating monoclonal protein in the serum or urine. The mere absence of a monoclonal protein does not mean that a patient has a localized form of amyloid. The classic examples of localized amyloidosis are tracheobronchial, urinary tract, cutaneous, lymph node, and nodular cutaneous involvement. At the Mayo Clinic 7% of amyloidosis cases falls into one of these classic distributions.
Establishing the extent of disease in systemic AL is achieved by a thorough review of systems and physical examination and by performing the tests in Table 3 . An amyloid review of system includes ascertaining whether any of the following exists: fatigue, weight loss, peri-orbital purpura, peri-orbital edema, jaw claudication, xerostomia, swollen submandibular nodes, macroglossia, orthostasis, change in bowel habit, dyspnea on exertion, paroxysmal nocturnal dyspnea, palpitations, chest pain, syncope, leg or hip claudication, paresthesias or dysesthesias in the hands or feet, bleeding, or spooning or splitting of nail beds. Physical exam mirrors the review of systems. The definitions of organ involvement are listed in Table 4 . Once clarifications about disease extent are made, one can embark on a treatment and follow-up plan.
|Congo red stain with apple green birefringence|
|Type amyloid protein|
|Alkaline phosphatase, bilirubin, creatinine, albumin, uric acid|
|Troponin, N-terminal brain natriuretic peptide (or brain natriuretic peptide)|
|Immunoglobulin free light chain, serum protein electrophoresis with immunofixation|
|Factor X level|
|24 hour urine|
|Protein electrophoresis with immunofixation|
|Echocardiogram with tissue Doppler imaging to assess for heart size and diastolic dysfunction|
|As clinically indicated|
|Diagnostic imaging of liver and spleen|
|Fecal fat measurements|
|Serum carotene levels|
|Nerve conduction studies|
|Serum amyloid P scan|
|Response type||Abbreviation||Criteria||Difference between 2005 and 2011 criteria b|
|Complete response||CR||Negative serum and urine IFE and
Normal serum immunoglobulin κ/λ FLC ratio
|Mandatory bone marrow removed from response criteria|
|Very good partial response||VGPR||dFLC < 40 mg/L b||New response criterion|
|Partial response||PR||dFLC decrease of greater than equal to 50% b||Serum M-spike relegated to secondary status and used only if no measurable involved serum free light chain|
|No response||NR||Less than a partial response||No change|
|Progression||Prog||From CR, any detectable monoclonal protein or abnormal free light chain ratio (light chain must double)
From PR, serum immunoglobulin free light chain increase of 50% which also must be to a level of greater than 100 mg/L,
Or a 50% increase in serum M protein which must also be to a level greater than 5 g/L,
Or a 50% increase in urine M protein which also must be to a level greater than 200 mg/day (a visible peak must be present)
a The final version of the latest International Consensus Response criteria have not been finalized.
b A difference between the involved and uninvolved FLC (dFLC) of 50 mg/L was defined as assessable or measurable for response.
dFLC, difference between involved and uninvolved serum immunoglobulin free light chain, which means that if patient has a lambda FLC of 300 mg/L and a kappa of 20 mg/L, the dFLC would equal 280 mg/L.
As will be discussed in the section on prognosis, understanding the extent of cardiac involvement is paramount for risk stratification and deciding about the therapeutic window of a given therapy. The echocardiogram had been one of the most important tests among patients with amyloidosis. As the amyloid community gains experience with soluble cardiac markers like troponin and NT-proBNP, the relatively low sensitivity of echocardiographic changes becomes more evident.36 and 37 The earliest echocardiographic finding is diastolic, 38 but a variety of cardiac abnormalities may be seen in these patients including left ventricular hypertrophy, 39 left ventricular outflow obstruction, 40 right ventricular dysfunction,41 and 42 right ventricular dilatation, 43 atrial dysfunction., 44 abnormal strain imaging and strain rate imaging,45, 46, and 47 reduced ejection time, 48 late gadolinium enhancement and abnormal gadolinium kinetics on cardiac magnetic resonance imaging,49 and 50 and rhythm and conduction abnormalities. 51 As the disease progresses, progressive left ventricular wall thickening with myocardial hyperechogenicity, biatrial enlargement, thickened atrial septum and valve leaflets, and pericardial effusion can be seen. Doppler myocardial images can detect early systolic dysfunction even among those amyloid patients who have no evidence of cardiac amyloid by standard echocardiography. 46 The mean of either systolic strain rate or systolic strain from 6 middle segments can detect early cardiac involvement and further cull out patients with more advanced cardiomyopathy. 47
The role of cardiac MRI is not yet established in terms of prognosis, but the presence of delayed gadolinium enhancement seen on T1-weighted images—predominantly subendocardially—is relatively sensitive for amyloid involvement and is frequently becoming the test prompting suspicion of a diagnosis of amyloidosis.49 and 50
The specific organs and the extent of organ involvement vary considerably in patients with AL so identification of prognostic factors is important. The major prognostic factors can be categorized into five major categories: 1) referral bias; 2) cardiac factors; 3) factors directly related to the clone; 4) number of organs involved; and 5) other factors.
5.1. Referral bias and cardiac parameters as prognostic factors
Referral bias and the ability to survive for at least a year are two under recognized prognostic factors in this patient population. In 1995, Kyle reported that the median overall survival was nearly double for those patients seen at Mayo Clinic more than 30 days after their diagnosis as compared to those seen within 30 days (24 months versus 13 months) 27 and that risk factors for death were different during the first year and after the first year. 52 More recent data from our institution ( Fig. 4 A) illustrate what the magnitude of the early mortality problem in this disease is. 53 Over the past 40 years, the proportion of patients dying within 6 months of diagnosis remains fixed at about 35%, with the least improvement over time for these sickest patients ( Fig. 4 B). Patients with AL can be parsed into prognostic groups based on cardiac biomarkers, most notably troponin T and NT-proBNP.54, 55, 56, and 57 When outcomes are examined based on both period of diagnosis and on Mayo Stage,54 and 55 one can see that marked improvements have occurred among patients with stage I disease. 53 Among the lowest risk AL patients, the median OS was not reached for the two most recently diagnosed cohorts in contrast to a median overall survival of 2.3 years (95% confidence interval, 1.4–3.3) for those diagnosed between 1987 and 1996 ( Fig. 4 C). Among patients with stage II disease, the median OS was not reached for the most recent group and was 2.4 years for the 1996–2004 and 0.9 year for the 1987–1996 ( Fig. 4 D). Finally, among stage III patients, the most recent group had a median OS of 1.0 year compared with 0.4 year for the two other periods ( Fig. 4 E). More refined ways of predicting early death have been developed. 53 Using receiver operator curves, a system using the following cut points: troponin T greater than 0.01 mcg/L; NT-proBNP greater than 4200 ng/L; and uric acid greater than 7.8 mg/dL has been developed. For each test over the threshold a point is assigned, resulting in 4 groups (0, 1, 2, or 3 risk factors) with 1 year mortality rates of 19%, 37%, 61%, and 80% ( Fig. 4 F).
The potential advantage of blood tests for assessing cardiac status includes the reproducibility of the assays in contrast to the inter-observer variability of echocardiography, their ease of testing, and their relatively low cost. Disadvantages of the soluble biomarkers include the number of reagents available. For example, some facilities do not offer NT-proBNP or troponin T but rather only offer BNP and troponin I. A touted disadvantage of cardiac biomarkers in general is that they rise in the setting of renal failure, which may be a problem for serial measurements in the context of fluctuating glomerular filtration rates. We would argue that this ‘susceptibility’ is an asset in terms of prognostication since these markers provide a composite view of the patient providing information about two organ systems.
Aside from troponin T and NT-proBNP, there are data supporting the prognostic value of troponin I, BNP, and high-sensitivity troponin T.23, 36, 50, 54, 55, 58, 59, and 60 There may be a role for using high-sensitivity troponin T alone in lieu of the troponin T and the NT-proBNP as a prognostic marker in the future. 61 General disadvantages of the different assays include a relative lack of sensitivity of troponin I, no current widespread clinical availability of high sensitivity troponin T in the U.S., a lack of standardization of the various BNP assays, and inferior performance of NT-proBNP as compared to BNP in the setting of renal dysfunction.62, 63, and 64
Aside from blood tests, the clinical history is an important prognosticator. AL patients presenting with florid CHF or syncope have median survivals of 4–6 months.65 and 66 Cardiovascular magnetic resonance (CMR) is also proving to be of use in diagnosing and predicting prognosis in patients with AL amyloidosis, but it is an early science. Two small studies have evaluated the prognostic value of CMR and found that gadolinium kinetics, 49 but not late gadolinium enhancement,49 and 50 predict for overall survival. 49 The 2 minute post-gadolinium intramyocardial T1 difference between subepicardium and subendocardium predicts mortality with 85% accuracy at a threshold value of 23 ms (the lower the difference the worse the prognosis). 49 Late gadolinium enhancement volume was positively correlated with serum level of B-type natriuretic peptide (BNP; R = 0.64, p < or = 0.001), and in multivariate analysis, late gadolinium enhancement volume proved the strongest independent predictor of BNP. 50
5.2. Plasma cell clone and prognosis
The observation that the size of the underlying plasma cell clone was prognostic was made in 1975. 67 Patients with coexisting multiple myeloma, which was largely defined based on bone marrow plasmacytosis, had inferior overall survival rates; the respective median survival rates with and without coexisting multiple myeloma were: at 1 year, 26% and 54%; and at 5 years, 3% and 17%. This observation has withstood the test of time.65 and 66 Bone marrow plasmacytosis, the proliferative rate of the bone marrow plasma cells, and the presence of circulating plasma cells are all adverse prognostic markers for overall survival.56, 57, and 68
The presence of light chains in the urine was also noted to be an adverse prognostic factor for patients with AL.69 and 70 Whether this is a function of “tumor burden” or renal damage is not clear. The absolute level of serum immunoglobulin free light chains has also been reported to be prognostic.71, 72, and 73
The presence of translocation 11;14 appears to be an adverse prognostic factor in one small series. 74 If validated this is an important observation since the translocation 11;14 is found in 40–50% of patients with AL amyloidosis.74 and 75 Preliminary work assessing for elevated levels of cyclin D1 would support this finding. 76
Attempts at analyzing overall survival based on IGKV and IGLV usage have given disparate results. In one series, overall survival was better in patients whose amyloid contained product from IGVL6 compared to those with IGLV1 + IGLV2 + IGLV3. 19 In contrast, in another series, overall survival was better in patients with IGVK1 or IGVL1 gene usage than patients with IGLV2–3 or IGLV6 gene usage. 23 These observations were limited by small sample size and a lack of multivariate analyses.54, 55, 56, 57, 58, and 77
5.3. Number of organs involved are prognostic
It has been long recognized that the more organs involved, the worse the prognosis for the patient regardless of the treatment.78 and 79 Fig. 5 illustrates the impact that the number of organs involved by amyloidosis based on clinical parameters has on overall survival in 270 patients undergoing ASCT. Whereas median survival had not been reached at 6 years in those patients with one affected organ, the respective median survival rates for patients with two and three affected organs, respectively, were 55 months and 25.5 months. 80 In a proportional hazards model, overall survival is associated with the number of organs involved and the free immunoglobulin light-chain protein level before treatment. 71
Delineation of the extent of organ involvement rather than merely the presence or absence or organ involvement is supplanting the current system of counting organs. The cardiac biomarker system offers a viable alternative since elevations reflect not only cardiac dysfunction, but also renal dysfunction.54, 55, and 56 Another motivation for migrating away from merely counting the number of organs involved is that outcomes vary not only due to extent of involvement, but also based on organ type.27 and 69 In a cohort of 474 patients with AL seen at the Mayo Clinic between 1981 and 1992 within 30 days of diagnosis, the respective median overall survival for patients with congestive heart failure, orthostatic hypotension, nephrotic syndrome, and peripheral neuropathy was 4, 12, 16, and 28 months, while the median survival of the entire group was 13.1 months and the 5-year survival was 7% ( Fig. 6 ).
5.4. Other prognostic factors
Several other important prognostic factors include weight loss, 69 male gender, 24 Howell–Jolly bodies, 81 beta-2 microglobulin,82 and 83 123I-labeled serum amyloid P component extravascular retention,84 and 85 and uric acid. 86 Serum amyloid P (SAP) component binds to amyloid. SAP scintigraphy is used to evaluate the extent and distribution of amyloid. Two studies demonstrate the prognostic utility of the extravascular retention of 123-I-SAP after 24 h in patients with AL.84 and 85 Hachulla and colleagues studied 24 patients with AL amyloidosis and found that 24 hour tissue retention was elevated in all patients. In addition, the mean survival in patients with tissue retention greater than 50% was 11.3 months versus 24.5 months in patients with levels less or equal to 50%. 85 Similarly, Hazenberg and colleagues studied the extravascular retention of 123-I-SAP at 24 h in 80 patients with AL amyloidosis. 84 They found that the extravascular retention of 123-I-SAP after 24 h was strongly associated with the number of organs involved. On multivariate analysis, both cardiac involvement (hazard ratio, 3.9; 95% CI, 2.0–7.8) and extravascular retention of 123-I-SAP after 24 h of greater than 50% (hazard ratio, 2.0; 95% CI, 1.1–3.9) were independent predictors of survival. The authors concluded that although this measurement is prognostic, its sensitivity is only 61%.
6. Assessing response to treatment
The first International consensus opinion for the definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis was published in 2005 and has served the amyloid community well. 87 A revision is in progress, and the current status of hematologic and organ response are shown in Table 4 and Table 5. Quantifying “response” in patients with AL is a major challenge. Since most patients have “low tumor burden,” with bone marrows and serum and urine M-proteins more akin to monoclonal gammopathy of undetermined significance than myeloma, 24 meaningful hematologic response assessment had not been feasible in the majority of patients until the advent of the serum immunoglobulin free light chain assay.71, 88, and 89 Moreover, since these patients do not typically die due to bone marrow crowding from high “tumor-burden,” the major focus for response had been improvement in organ function rather than hematologic response ( Fig. 1 B), despite the recognition that hematologic response predicts for organ response.79 and 90 Organ response is a time dependent factor with the median time to organ response of 1 year in the era of alkylator therapy with organ response continuing long after cessation of chemotherapy among those fortunate enough to respond. 91 Organ responses may occur more rapidly using proteasome inhibitors, 92 but the paradigm gearing initial treatment to achieve hematologic response rather than organ response is still important. In addition, quantifying organ response is an imperfect science. There are amyloid abnormalities including macroglossia, purpura, intestinal and pulmonary involvement for which no response criteria exist, and for those where criteria do exist, especially cardiac, measurement was not always reproducible. The emerging use of the soluble cardiac biomarker, N-terminal-pro B-type natriuretic peptide (NT-proBNP) has proved to be a helpful gage of cardiac response.58 and 92
|Organ system||Involvement b||Improvement||Worsening|
|Kidney||24-hour urine protein > 0.5 g/day, predominantly albumin||50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline||50% increase in urinary protein loss (at least 1 g/24 h), or 25% worsening of creatinine or creatinine clearance|
|Heart||Echo: mean wall thickness > 12 mm, no other cardiac cause||New:
NT-proBNP response c
(> 30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥ 650 ng/L)
Improvement by 2 NYHA classes without an increase in diuretic use or in wall thickness
≥ 2 mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or
Improvement of ejection fraction by ≥ 20%
NT-proBNP progression c
(> 30% and > 300 ng/L increase) a OR
cTn progression (≥ 33% increase)
Increase in NYHA class by 1 grade with a decreasing ejection fraction of ≥ 10%.
Increase in cardiac wall thickness by ≥ 2 mm (2-D ECHO)
|Liver||Total liver span > 15 cm in the absence of heart failure or alkaline phosphatase > 1.5 times institutional upper limit of normal||≥ 50% decrease in an initially elevated alkaline phosphatase level, or
Decrease in liver size by at least 2 cm (radiographic determination).
|≥ 50% increase of alkaline phosphatase above lowest level|
|Nerve, peripheral||Clinical symmetric lower extremity sensorimotor peripheral neuropathy||Improvement in electromyogram nerve conduction velocity (rare)||Not defined|
|Nerve, autonomic||Gastric-emptying disorder, pseudo-obstruction, voiding dysfunction not related to direct organ infiltration||Not defined||Not defined|
|Gastrointestinal tract||Direct biopsy verification with symptoms||Not defined||Not defined|
|Lung||Direct biopsy verification with symptoms
Interstitial radiographic pattern
|Not defined||Not defined|
|Soft tissue||Tongue enlargement, clinical
Claudication, presumed vascular amyloid
Myopathy by biopsy or pseudohypertrophy
Lymph node (may be localized)
|Not defined||Not defined|
a The final version of the latest International Consensus Response criteria have not been finalized.
b Biopsy of affected organ or biopsy at an alternate site with clinical involvement.
c Patients with progressively worsening renal function cannot be scored for NT-proBNP progression.
NYHA, New York Heart Association.
6.1. Hematologic response
Hematologic response is important not only for “real time” assessment of the efficacy of therapy, but it is one of the most important prognostic determinants for both organ response and for overall survival.93 and 94 When bone marrow biopsy, electrophoresis and immunofixation electrophoresis of the serum and urine were the only tools available for measurement of hematologic response, fewer than 50% of patients had “measurable” disease as defined by the multiple myeloma response criteria (i.e. serum M-protein greater than or equal to 1 g/dL or urine M-protein greater than 200 mg/24 h). Moreover, urine M-protein measurement is not reliable in a patient with nephrotic syndrome due to contamination with background non-specific proteinuria. Many patients were destined to have their hematologic “measurement” limited to a binary determination of positive or negative immunofixation studies. However, with introduction of the serum FLC measurement, nearly 75% of patients have measurable disease.71, 88, and 89
The International Response Consensus Criteria are in flux. 197 To date, four modifications have been made: First, a new criterion called very good partial response has been introduced, and it is defined as an involved serum immunoglobulin free light chain of less than 40 mg/L ( Fig. 7 A, Table 4 ). 95 A 90% reduction, consistent with the VGPR definition used in myeloma, was a serious contender for the definition,96 and 97 but based on better performance characteristics of the 40 mg/L, the absolute value was chosen. Second, the definition of “measurable disease” was changed from an involved immunoglobulin free light chain of 100 mg/L to the difference of involved and uninvolved free light chains of 50 mg/L. 95 The third change in the criteria was the promotion of the serum immunoglobulin free light chain to primary importance 96 and demotion of serum protein electrophoresis derived M-protein to secondary status. 95 The final modification was the removal of the bone marrow requirement in the definition of amyloid complete response.
6.2. Organ response
Improvement of organ function is clearly the most important end point for patients both in terms of quality of life and for overall survival. The internationally accepted organ response criteria for patients with AL amyloidosis are shown in Table 5 along with upcoming—but not finalized—revisions.87, 95, and 197 The major change relates to cardiac response criteria. The echocardiogram will no longer be required, and cardiac response and progression will be based on levels of NT-proBNP.58 and 95 Patients will be assessable for cardiac response if their NT-proBNP is greater than or equal to 650 ng/L. A reduction of greater than 30% that is at least 300 ng/L qualifies as a response as does an improvement by 2 New York Heart Association classes without increase in diuretic use or in wall thickness. 98 The NT-proBNP response definition has been validated in a multi-institutional setting ( Fig. 7 B).92 and 95 A potential concern with the NT-proBNP response is that lenalidomide treatment appears to be associated with NT-proBNP rises.99, 100, 101, and 102 In the recent international collaborative report that validated NT-proBNP response, fewer than 5% of patients had lenalidomide based therapy. 95 The rationale for using the cardiac biomarkers in lieu of the echocardiogram for measuring response is that cardiac function in AL appears to rapidly improve when there is a reduction of the circulating amyloidogenic precursor, despite the amount of cardiac amyloid deposits remaining apparently unaltered, as measured by echocardiography. 58 There has also been interest in using troponin levels as markers of response.95 and 99
Median time to organ response is 6–12 months, depending on the treatment.78 and 93 The organ response criteria focus on renal, cardiac, and liver responses. Hematologic response precedes organ response ( Figs. 1 B and 8 ). Of those patients who achieve a complete hematologic response—be it through high dose chemotherapy with autologous peripheral blood stem cell transplantation (ASCT) or a simpler oral regimen like melphalan and dexamethasone—approximately 66 to 87% will achieve an organ response.93 and 94 Of those who achieve a partial hematologic response, 30–56% will achieve an organ response. It is rare to have an organ response in the absence of a hematologic response, and in most series the most important time dependent prognostic factor is the ability to achieve response. Even when melphalan and prednisone chemotherapy was the only therapy available, those patients achieving organ response had a median survival of 89 months. 78 Now that serum immunoglobulin free light chain response is an available measure, most trials are geared toward hematologic response for the following reasons: 1) free light chain responses are more rapid; 2) free light chain responses correlate highly with organ response; 3) free light chain responses are less subjective and more reproducible; and 4) free light chain responses have repeatedly been demonstrated to predict for overall survival.71, 88, 89, 93, 95, 96, 97, and 103
6.3. How deep a response is necessary
The question of how much of a response is necessary is uncertain, there is no simple data driven answer given the narrow therapeutic window of therapy in patients with AL. Patients with deeper hematologic responses are more likely to have organ response and live longer; however, response in patients with organ impairment can become a significant cost. Patients not infrequently decompensate with the addition of immune modulator drugs (IMiDs). 99 Prolonged alkylator increases the risk for myelodysplastic syndrome. 104 Corticosteroids are fraught with their own toxicities and can also worsen existing congestive heart failure or edema. The most recent consensus is to aim for very good partial response or at least a 90% reduction in the involved free light chain if it can be achieved without putting the patient into too much jeopardy. Organ responses can occur with a hematologic partial response in as many as 30–56% of patients, and survival is markedly improved in patients achieving partial response as compared to no hematologic response even when corrected using landmark analysis.
Whether long term outcomes will differ depending on the means of arriving at a partial or complete hematologic is unknown. 105 This is most notable in the context of high dose chemotherapy with autologous stem cell transplant versus standard dose melphalan and dexamethasone. For patients achieving hematologic CR, the 5 year overall survival is about 70% regardless of the treatment modality used to arrive at hematologic CR.103, 106, and 107 For patients undergoing ASCT and achieving CR, 10 year survival rates approach 60%. 106
The biggest body of literature on adjuvant/consolidative chemotherapy in AL comes from Memorial Sloan Kettering. Two phase 2 studies have been done in which patients not achieving CR receive adjuvant thalidomide ± dexamethasone 108 or bortezomib ± dexamethasone. 109 In the former study, thirty-one patients began adjuvant therapy, with 52% completing 9 months of treatment, and 42% achieving a deeper hematological response. By intention-to-treat, overall hematological response rate was 71% (36% complete response) with 44% having organ responses. 108 In the latter study, 17 of 23 patients undergoing transplantation received adjuvant bortezomib and dexamethasone; 74% achieved a CR, and 58% had organ responses. 109
At present, all treatments are directed at destroying the underlying plasma cell clone, which in turn reduces or eliminates the amyloidogenic clonal immunoglobulin light chain. It had been assumed that the amyloid fibrils detected in tissue biopsies were the source of tissue injury and dysfunction and that chemotherapy produced improvement in organ function by shifting the equilibrium from fibril formation to fibril dissolution. That hypothesis has been challenged with the hypothesis that the clonal amyloidogenic light chains form toxic intermediates responsible for the tissue damage. 110 In every day clinical practice, this debate is less important since there are currently no approved drugs that directly attack and/or dissolve the amyloid. The approach of using molecules and/or antibodies directed against serum amyloid protein or antibodies directed at the tertiary structure of the amyloid may be treatments of the future.111, 112, and 113 Other characteristics of these plasma cells that may eventually be targeted include CD20, which is expressed in approximately 40% of cases, 114 CD32, which is the low-affinity IgG Fc receptor, 115 and calretictulin, 116 which is a pleiotropic calcium-binding protein. Other potential therapies could include small interfering RNA molecules to inhibit pathologic immunoglobulin free light chain production. 117
Nearly all cases of systemic AL will require therapy. Determining the extent of organ involvement helps estimate the risk associated with different treatment options. Which parameters will be followed to modulate on-going treatment decisions should also be defined. This last recommendation cannot be overemphasized; patients with AL are complex, often very ill, and have multiple disease parameters to follow, making it difficult to track a patient's progress in a busy clinical practice. Treatment assessment focuses on 3 parameters ( Fig. 1 ): 1) toxicity monitoring/management; 2) hematologic response; and 3) organ response. The goal in these patients is to achieve a reduction or disappearance of the precursor protein (clonal immunoglobulin free light chain), which can potentially halt the progression of organ damage and to allow for significant improvement of organ function ( Table 5 ). 103
Fig. 9 illustrates the current treatment strategy employed for patients with systemic AL seen at the Mayo Clinic. Given the paucity of randomized trials and the heterogeneity of the disease, providing evidence based recommendations is a challenge. Simply stated, the two standards best studied to date are melphalan plus dexamethasone and high-dose melphalan with autologous stem cell transplantation. As will be discussed the experience with immune modulator drugs and proteasome inhibitors is relatively scanty.
7.1. Standard chemotherapy
The successful use of cytotoxic chemotherapy to produce regression of AL was reported nearly 40 years ago,118, 119, and 120 and its value was verified in a double blinded prospective randomized study of melphalan and prednisone versus placebo in 1978. 121 Melphalan and prednisone doubled the overall survival as compared to colchicine in two subsequent randomized trials, making it the standard therapy for most patients with AL until the mid-2000s.91 and 122 The median time to response was 1 year. Although only 18% of patients responded to melphalan and prednisone, responders enjoyed a median survival of 89 months, whereas nonresponders had a median survival of 15 months. Nephrotic only patients with a normal serum creatinine enjoyed an organ response rate of 39%; whereas, patients with cardiomyopathy had organ response rates of only 15%. 78 Other treatments including single agent dexamethasone and VAD (vincristine, adriamycin, and dexamethasone) may produce responses in patients ( Table 6 ).88, 123, 124, 125, 126, 127, 128, 129, and 130
|N||Hematologic response, %||Organ response, %||Median survival, m|
|MP91, 120, 121, and 122||~ 200||28||20–30||18–29|
|Melphalan IV (25 mg/m2 every 4–6 weeks) 88||20||50||…||~ 50|
|Dex123 and 124||77||…||15–35||12–21|
|VAD88, 126, 127, 128, 129, and 130||~ 100||42–50||…||…|
|Melphalan-Dex a 93 and 105||96||52–67||39–48||57–60|
Multi-agent alkylator based therapy did not improve overall survival, 131 but replacing the prednisone with dexamethasone resulted in higher response rates and better overall survival. 93 In 2004, Palladini et al. reported their experience treating 41 patients who were not transplant candidates with melphalan and dexamethasone. Hematologic response rates of 67%, including 33% complete responses, and organ response rates of 48% were reported. 93 In a five-year update, these patients had an overall median survival of 5.1 years and progression-free survival of 3.8 years. 107 A total of 21 patients—13 nonresponders and 8 responders—died after a median of 1.6 years (range, 0.1–5.7 years). Death was not amyloid-related in 4 patients who responded to melphalan and dexamethasone, whereas it was due to progressive cardiac amyloidosis in the remaining cases. Two other phase 2 studies examining melphalan and dexamethasone had markedly inferior results with 3-month mortality rates of 23 and 28% and median overall survivals of 10.5 to 17.5 months.59 and 132 These 2 series included patients with severely impaired cardiac function as assessed by soluble cardiac biomarkers demonstrating the relationship between patient selection and outcome. 133
The value of melphalan and dexamethasone was further validated in a prospective randomized study of 100 patients randomized to autologous stem cell transplant with high dose melphalan compared to oral melphalan and dexamethasone. 105 In this highly selected population, there was no difference between the two arms for hematologic responses, and the landmark analysis performed to correct for early mortality associated with transplant also showed no difference in overall survival. On an intention to treat basis, the median survival for melphalan and dexamethasone was 57 months versus 22 months for the stem cell transplant arm. This important study is limited by its small size for a disease that is as heterogeneous as AL. Among the 50 patients randomized to receive HSCT, only 37 actually received the planned transplant and 9 of those died within 100 days, a 24% treatment-related mortality, leaving only 28 patients for the landmark analysis. In contrast, of the 50 patients randomized to melphalan and dexamethasone, 43 patients received 3 or more cycles of therapy.
The historical concern for myelodysplastic syndrome among AL patients receiving oral alkylator has been attenuated by more recent data demonstrating rates of myelodysplasia of 2.4%93 and 107 rather than the historical rate of 7% of the total patient population, with a 42 month actuarial risk of myelodysplasia or acute leukemia of 21%. 134 This lower rate is attributed to the modest total dose of melphalan administered (median, 288 mg; range, 48–912 mg), even considering the additional cycles delivered in relapsing patients.93 and 107
7.2. High-dose chemotherapy with stem cell transplant
In routine practice, the first question asked is whether a patient is a candidate for high-dose chemotherapy with autologous peripheral blood stem cell support (ASCT) not because it is the best therapy, but because it is the therapy that is most restrictive and that requires the most planning. Risk factors for ASCT related mortality include physiologic age, performance status, cardiac function as determined by serum troponin T and functional class, uric acid, and number of organs involved.53, 54, 77, 80, and 135 In our practice, we use a troponin T of greater than 0.06 ng/mL as an exclusion factor given a 28% 100 day all cause mortality among such patients in contrast to a 7% all cause mortality among those with a value below that threshold. 77 Capitalizing on the improved overall survival observed in patients with myeloma undergoing ASCT, ASCT has been widely applied to patients with AL, and over 1000 patients have been reported in the literature. The most commonly used conditioning regimen is melphalan 200 mg/m2. Hematologic responses have been reported anywhere from 32% to 68% and complete hematologic responses from 16% to 50%.80, 90, 94, 105, 136, 137, and 138 Organ response is time dependent, and a median time to response can take up to one year. Organ response rates range anywhere from 31% to 64%. Patients with the deepest hematologic responses are more likely to have long term survival.103 and 138 The treatment-related mortality is quoted from 6% to 27% at day 100 with the majority of deaths due to cardiac causes, but patients also succumb to multi-organ failure, hepatic insufficiency, hemorrhage and sepsis %.80, 90, 94, 105, 136, and 137 At Mayo Clinic, the day-100 mortality is 7%, 139 and the median survival of patients with three-organ involvement is 30 months, two-organ involvement 68 months, and 98 months for patients with one-organ involvement. 80 Overall survival of 337 patients is a projected median of 82 months. More recently, the Boston University group updated their transplantation results. Among 421 patients treated with HDM/SCT, the CR rate was 34%, the median event-free survival was 2.6 years, and the overall survival was 6.3 years. The seeming low event free survival was largely due to the poor outcomes of patients requiring attenuated doses of conditioning melphalan. This high risk group had a median EFS of 21 months in contrast to 43 months for those patients well enough to receive full dose melphalan. In a landmark analysis of patients surviving 1 year who achieved or did not achieve CR, respective overall survival rates were 13.2 years and 5.9 years with EFS of 8.3 and 2 years. 138
An alternative conditioning regimen incorporating bortezomib days − 6, − 3, + 1, and + 4 has been explored in a pilot of 10 patients. 140 In this very fit population, the combination was well tolerated without any deaths during the 23 month follow-up. Response rates were encouraging with hematologic complete responses in 67% of patients.
Often the question arises whether patients should receive induction therapy before moving to ASCT. Only one small randomized trial addressed this question. Patients were randomized to receive two cycles of oral melphalan and prednisone prior to transplant versus a direct transplant approach. There was no difference in overall survival between the two groups, and fewer patients in the pre-treatment group received a transplant. 141
Allogeneic hematopoietic stem cell transplantation is not a standard therapy for patients with AL. The European Group for Blood and Marrow Transplantation registry reported 19 patients with AL who underwent allogeneic (n = 15) or syngeneic (n = 4) hematopoietic stem cell transplantation between 1991 and 2003. 142 With a median follow-up time of 19 months, overall and progression-free survival rates were 60% and 53% at 1 year, respectively. Forty percent of patients died of transplant-related mortality.
7.3. Is high-dose chemotherapy with autologous stem cell transplantation the best therapy?
Many will ask whether ASCT is the best therapy for patients with AL. Our opinion is that among those young patients with good risk disease, ASCT is an excellent option with potential for long event free survivals. There is, however, no randomized trial data support that it is superior therapy. 105 If done at institutions with low treatment related mortality, long term event free survival appears to be unsurpassed.80, 138, and 143 These excellent outcomes are somewhat confounded by selection bias, but there was a case controlled study performed that suggested that it was the better option, making ASCT an option worthy of discussion. 143 In contrast, for those patients who have significant comorbidity related to their AL meriting consideration of reduction of conditioning melphalan dose intensity, based on data from the randomized control trial and single arm outcomes from both Mayo Clinic and Boston University, transplant is likely not a preferred option.103, 105, and 138
7.4. Novel therapies for AL
New therapies for amyloidosis involving incorporation of novel agents have also been described. Thalidomide, as a single agent, has a heightened toxicity in patients with amyloidosis and no hematologic or organ responses have been reported ( Table 7 ).144 and 145 In contrast, in combination with dexamethasone, 48% of 31 patients achieved hematologic response, with 8 (26%) organ responses. Median time to response was 3.6 months (range, 2.5–8.0 months). Treatment-related toxicity was frequent (65%), and symptomatic bradycardia was a common (26%) adverse reaction. 146 Wechalekar and colleagues treated 75 patients with a cyclophosphamide, thalidomide, dexamethasone combination. 147 A hematological response occurred in 74% of 65 evaluable patients including complete hematological responses in 21%. With a median follow-up of 22 months, median estimated overall survival from commencement of treatment was 41 months. Toxicity was not adequately assessed because this was not a clinical trial and further study of this combination has shown it to be less well tolerated than previously thought. 148 Palladini et al. treated 22 patients with cardiac involvement with the combination of melphalan, thalidomide and dexamethasone. 149 Despite a hematologic response rate of 36%, only 20% of patients were alive at 1 year.
|Regimen||N||No prior Rx, %||≥ 2 organs, %||Cardiac, %||Heme response (CR), %||Organ response, %||Grades 3–4 AE, %||Median f/u, mo||OS|
|Thal 200–800 mg 144||16||6||31||25||25||0||50||NR||NR|
|Thal 200–800 mg 196||12||58||67||42||0||11||58||2 a||NR|
|Thal 50–200 mg 145||18||28||50||67||0||11||75||6 a||NR|
|CTX/Thal/Dex 147||65||41||≥ 50||16||74 (21)||33||32||18||2 years 77%%|
|Mel–Dex–thal 149||22||86||NR||100||36 (5)||18||27||28||1 year 20%|
|Len ± Dex 151||22||43||57||65||43 (5)||26||83||17||2 years 50%|
|Len ± Dex 152||34||9||≥ 32||38||47 (21)||21||> 35||NR||NR|
|Len ± Dex 100||24||0||NR||75||38 (0)||4||50||23||1 year 50%|
|Mel–Len–Dex 154||26||100||62||58||58 (23)||50||81||19||2 years 81%|
|Cyclo–Len–Dex 155||20||0||NR||60||40 (5)||15||60||NR||1 year < 80%|
|Cyclo–Len–Dex 156||35||69||28||63||60 (6)||24||69||9||1 year < 66%|
|Pom–Dex 157||29||0||NR||83||38 (0)||10||72||8||1 year 77%|
|Bortez ± Dex 92||94||19||NR||73||72 (25)||30||29||12||1 year 76%|
|Bortez158 and 159||52 b||0||> 44||56||67 (29)||24 c||NR||18, 10, 38||1 year 90%|
|Mel–Bz–Dex 160||17||94 (56)||11||NR|
a Median time on treatment.
b The18 patients receiving dose escalation doses are excluded.
c The denominator (n = 62) for this calculation includes some of the 18 dose escalation patients since that group contained 5 of the 15 organ responses.
Rx, treatment; AE, adverse events; Cardiac, cardiac involvement; Dex, dexamethasone; f/u, follow-up; mo, months; IFN, interferon; Thal, thalidomide; Len, lenalidomide.
As lenalidomide has been used to treat AL, serious cardiac and renal toxicity have been reported, making it imperative to consider drug toxicity rather than ‘disease progression’ if patients on lenalidomide deteriorate.99, 100, 101, 102, and 150 In a trial of 23 patients, one patient had a hematologic and organ response with lenalidomide alone. 151 Eleven additional patients received dexamethasone, and overall response rates of 12 patients who completed more than three cycles of therapy were 10/12 with 9/12 hematologic and 5/12 organ responses. Ten patients did not complete three cycles of therapy, and analysis demonstrated that the cardiac troponin T level was highly predictive of patients being able to complete protocol therapy. In a similar study, with more restrictive entry criteria, of 24 evaluable patients, the overall hematologic response rate was 67%, including a 29% hematologic complete response. 152 These data have been updated, including 69 patients. Sixteen percent of patients achieved a CR, and time to progression among patients achieving CR was 50 months. 153 Of the 11 patients achieving CR, there was 1 death and an additional 4 patients progressed off therapy. Two remained on treatment, and 4 had continued CR off therapy with a median time off therapy of 24 months. Both of these trials, and other subsequent studies have demonstrated that the starting dose of lenalidomide should be no higher than 15 mg per day administered days 1–21 every 28 days.151 and 152 Most recently, Palladini et al. have reported their experience using lenalidomide and dexamethasone in patients who had failed both melphalan and bortezomib. 100 In this heavily pretreated group, there was a 38% response rate with complete responses. Risk factors for poorer outcomes included a high troponin I and diagnosis duration of less than 18 months. Only 50% of patients were alive at one year.
The combination of lenalidomide with alkylator has been reported in 3 clinical trials. The most promising was that of melphalan, lenalidomide, and dexamethasone which was employed in 26 newly diagnosed patients with AL. 154 The population was highly selected since enrollment required an ECOG performance status of 0 or 1. Fifty-eight percent of patients achieved a PR including 23% who achieved a CR. Results with cyclophosphamide, lenalidomide, and dexamethasone do not appear as favorable, but selection criteria for these studies were less restrictive.155 and 156 In these studies, hematologic response rates ranged from 40–60% with CR rates of only 5–6%. One year survivorship was less than 66–89%. The newest immune modulator drug, pomalidomide has been combined with dexamethasone, and produced a hematologic response rate of 41%, including a 43% hematologic response rate in IMiD refractory patients. 157 The one year overall and progression free survival were 77% and 59% respectively.
Bortezomib appears to be a highly active treatment in patients with AL, but to date there is very limited safety data available. Initial reports of hematologic response rates using bortezomib alone or with dexamethasone as part of clinical practice were approximately 70% including 25% complete response and 30% organ responses. 92 These reports have been succeeded by a large phase I/II trial of single agent bortezomib that included patients with previously treated AL.158 and 159 The CAN2007 trial by Reece et al. evaluated two schedules of therapy, that is the standard twice weekly (days 1, 4, 8, 11, every 21 days) and a once weekly (days 1, 8, 15, and 22 every 35 days) schedule. The maximum tolerated dose was not reached after treating 31 patients, so the phase 2 portion of the study commenced using 1.3 mg/m2 twice weekly and 1.6 mg/m2 weekly in an additional 39 patients. Patients were highly selected in that they were required to have a Karnofsky performance status of 70% or higher, a NYHA classification of I or II, a systolic blood pressure of 90 mm Hg or higher, no symptomatic orthostatic hypotension, no atrial fibrillation, as well as no grade 2 or 3 atrioventricular block or sustained or recurrent nonsustained ventricular tachycardia along with the other usual eligibility criteria. Hematologic response rates were comparable at 67% and 68%, respectively, and the CR rate appeared to favor the once weekly schedule with rates of 24% (twice weekly) and 37%(once weekly). Time to both first response and best response was slightly more rapid using the twice weekly schedule (0.7 and 1.2 months, respectively) than the once weekly schedule (2.1/3.2 months), but with both schedules hematologic resposnes were rapid. Organ responses occurred in 15 patients overall. Rates of grade 3 or greater toxicity were observed in 79% of the twice weekly group as compared to 50% in the once weekly group. One year PFS was 75% and 72%, respectively, and the one year overall survival was 84% and 94%, respectively. The most common AEs were gastrointestinal. Comparing toxicity with the twice weekly schedule to that of the once weekly schedule, orthostasis was more than 3-times as common, cardiac disorders nearly 5-times as common and thrombocytopenia was 4-times more frequent.
Early reports of combinations of alkylator and bortezomib also appear promising, but safety data are sparse. The combination of melphalan, dexamethasone and bortezomib has produced response rates of 94%, but follow-up is short and toxicity data are lacking. 160 Case series of cyclophosphamide, dexamethasone and bortezomib have also been published with response rates of 93%. 161 These regimens cannot be considered standard until more comprehensive safety data are published.
7.5. Adjunctive and supportive therapy for AL
Supportive care for these patients can be challenging, but careful attention to these issues is imperative. The three systems that require the most care are cardiac, renal, and nervous system.
There are special considerations among patients with cardiac amyloidosis. These patients typically have diastolic dysfunction, and management approaches for systolic dysfunction often worsen patients' clinical status. Beta-blockade may cause clinical decompensation and should be used with caution. Afterload reduction with angiotensin converting enzyme inhibitors and angiotensin receptor blockers also tends to adversely impact patients unless they are used for the specific indication of hypertension. Diuretics are the mainstay of care with the best results achieved with a combination of loop diuretics and spironolactone. Metolazone may be of use as may periodic thoracentesis. 162 Patients with cardiac amyloid are at risk for intracardiac thrombi163 and 164; in one study 35% of patients with AL who had transesophageal echocardiograms had atrial thrombus, the majority of which were located in the right atrial appendage or left atrial appendage. 164 Anticoagulation should be considered recognizing that gastrointestinal bleeding is a potential risk.
For those patients with atrial fibrillation, rate control can be a challenge since beta-blockade and calcium channel blockers are often poorly tolerated. Digoxin is considered contraindicated in cardiac amyloidosis due to concerns regarding digoxin binding and an increased risk of toxicity, but digoxin is often preferable over calcium channel blockers and beta-blockers for rate control in atrial fibrillation. 165 Non-dihydropyridine calcium channel blockers should be avoided due to its associated bradycardia and negative inotropic effects. 166 In our experience amiodarone is best tolerated, and electrophysiological maneuvers including atrioventricular ablation with permanent pacing may also be an option.
Patients with cardiac amyloidosis are susceptible to malignant rhythms including ventricular tachycardia, ventricular fibrillation, and pulseless electrical activity.51 and 167 The role of implantable cardioverter-defibrillators is controversial in these patients, since both successes and failures have been documented.167, 168, 169, and 170 No formal recommendation about their use can be rendered.
Among patients with renal involvement, which is nephrotic syndrome in the majority, the major problem is third spacing due to hypoalbuminemia. This may be further exacerbated by coexisting cardiomyopathy. Diuretics are the mainstay of therapy. It is not unusual for nephrologists to institute an angiotensin converting enzyme inhibitor based on their management of diabetic nephropathy. There are no data to support this intervention in AL, but as long as patients have high blood pressure and adequate cardiac function, this intervention is not unreasonable as long as patients tolerate the medication. Adequate suppression of the underlying clone is the most important maneuver to improve renal function. 97 In one series from Italy, 67% of patients who presented with renal involvement had developed ESRD by 5 years, with early deaths censored. 171 The most important prognostic determinant for overall survival among these patients was the presence or absence of cardiac involvement with respective 5-year OS rates of 47% and 60%. In a recent report from the National Amyloidosis Center in the United Kingdom, among 752 patients with AL involving the kidney with an eGFR greater than or equal to 15 mL/min at baseline, 13% experienced progression to ESRD at a median of 27 months. On multivariable analysis, risk factors for renal progression included low serum albumin, especially lower than 20 g/L, and the absence of a 90% reduction in involved serum immunoglobulin free light chain at 6 months. Median survival from dialysis dependence was 39 months. 97 Patients with on dialysis may struggle with hypotension which can be successfully managed with pre-dialysis midodrine. In an earlier study performed at the Mayo Clinic that involved 211 patients seen before 1990, 18% received dialysis at approximately 14 months and approximately one-third of the renal patients went on to dialysis; however, none of the patients presenting with a creatinine less than 2 g/dL and a 24 hour urinary protein less than 2 g progressed to dialysis. The median survival of those instituting dialysis was 8.3 months, with the majority (21/31) dying of extrarenal causes of amyloidosis. 172
Amyloidosis patients with neuropathy typically have small fiber involvement which can be treated symptomatically with amitriptyline, nortriptyline, gabapentin, pregabalin, or duloxetine. Topical preparations that include various combinations of lidocaine, ketamine, and/or amitriptyline may also provide relief. For patients with neuropathy due to carpal tunnel syndrome, carpal tunnel release or carpal tunnel braces are of benefit. The autonomic insufficiency can be very difficult to manage, especially among patients with severe nephrotic syndrome or severe cardiomyopathy. Fludrocortisone and salt tablets are only useful in a minority of these patients since it may aggravate congestive heart failure or peripheral edema. The alpha-1 receptor agonist midodrine or the anticholinergic pyridostigmine can improve neurogenic orthostatic hypotension 173 and metoclopramide, used in diabetic gastroparesis, can help with gastric emptying.
7.6. Organ transplantation
Solid organ transplantation (Tx) is a controversial intervention among patients with AL. Because the disease is systemic and presumably incurable, there is concern that the amyloid will either reoccur in the transplanted organ or progress in another organ resulting in a poor outcome. As illustrated in Table 8 and below, the best outcomes have occurred in the setting of careful patient selection, excluding patients with clinically evident multi-organ involvement, and among those who received adjuvant chemotherapy to eradicate the clone either before or after the solid organ Tx.
|Registry of ISHT1990, 1991177 and 178||10†||Heart||1 year 88%
4 year 38%
|UK 2004 174||17||Heart||1 year 59%
5 year ~ 37%
|UK 2010 179||14||Heart||1 year 86%
5 year 45%
|Mayo 2008 175||11||Heart||1 year 82%
5 year 65%
|French registry 2008 182||8||Heart||1 year 89%|
|Heidelberg 2009 183||12||Heart||1 year 83%
3 year 83%
|Spanish registry2009 184||13||Heart||1 year 43%
5 year 16%
|Boston 2010 176||9||Heart||1 year 78%
5 year 56%
|Boston 2003 187||3||Kidney‡||Alive at 5.3, 5.4, and 6 years|
|UK 201097 and 179||22||Kidney‡||1 year 95%
5 year 67%
No renal graft failure at 4.8 years
|Mayo 2011 186||19||Kidney‡||1 year 84%
5 year 76%
ISHT, International Society for Heart Transplant.
Unclear how much overlap between these two groups. Interval for Dubrey series was 1982–2002 and for Sattianayagam series, interval was 1984–2004, but there was no reference of which patients had been previously reported.
†At least 8 were AL; unclear what other 2 were.
‡Six other renal series have been excluded since they were a mix of patient with AL and other types of amyloidosis.
7.6.1. Cardiac transplantation
Even when patients are placed on a cardiac Tx list, only a minority actually survive to surgery.174, 175, and 176 In all series, long term survival for AL patients is inferior to that of patients undergoing cardiac Tx for other causes. The initial reports from an international registry for heart Tx were quite favorable 177 ; however, with additional follow-up, enthusiasm waned with a 4 year survival rate of approximately 38%. 178 A potential explanation for the extremely poor outcomes was that all but one patient had multisystem involvement prior to the cardiac Tx.
The reported experience from the UK included 31 cases from two publications,174 and 179 however, it is unclear which cases are overlapping. In the earlier publication including 17 cases of AL, 15 died from 0 to 116 months after the heart Tx with a 1 year survival of 59%. The survival of those patients receiving adjuvant chemotherapy was superior to those who did not with respective 2-year overall survival rates of 71% and 50%. 174 The updated UK series, included 14 cases of cardiac Tx for AL, appeared to be improved with a 1 year OS of 85% and a 5 year OS of 45%. Eight of these patients received an ASCT after their cardiac Tx. 179 With a median follow-up of 95 months in 5 of these patients, only 2 had died related to clonal relapse with progressive organ dysfunction. 180
In a report of 69 cardiac transplants from the UNOS database for the indication of amyloidosis, the 1- and 5-year survival estimates were 75% and 54%. 181 The difficulty with this study is that there is no separation between AL amyloidosis and other types of amyloidosis, and outcomes differ between orthotopic heart recipients with AL versus other types of amyloidosis. 174
Reports from the US predominantly include a strategy of cardiac Tx followed by ASCT.175 and 176 Of 20 cases, the 1- and 5-year OS rates ranged from 78 to 82% and 56–65, respectively. In these two series, there was a total of 3 ASCT treatment-related deaths, and delayed deaths were mostly due to recurrent multi-organ amyloidosis. ASCT is most commonly performed 6–8 months after cardiac Tx. Doses of melphalan conditioning ranged from 140 to 200 mg/m2.
A French study included 8 patients, all of whom had extracardiac amyloid involvement. Five of the patients received chemotherapy prior to heart Tx, and 4 received chemotherapy after cardiac transplantation. Six received melphalan and dexamethasone and 3 received ASCT. Median follow-up was only 27 months, and there were 2 deaths, one at 1.5 months and another at 50 months. 182
In the Heidelberg series, 19 patients were considered for cardiac Tx, but only 12 survived long enough to receive a heart. 183 The transplanted group had superior baseline cardiac parameters both lower troponin and NT-proBNP. Another interesting aspect of this series is that four of the patients received their heart more than a year into their diagnosis, with one getting a cardiac transplant approximately 5 years into his diagnosis. Four patients had their heart transplantation after achieving a hematologic complete response and 5 patients had an ASCT after their cardiac transplantation with only 1 achieving a complete hematologic response. The authors identified “DANGER,” which included diarrhea, autonomic nervous system abnormalities, nutritional status, gastrointestinal bleeding history, elimination (renal function), and respiratory tract abnormalities as risk factors for poor outcome.
In contrast the Spanish experience with cardiac Tx for AL appeared less promising. 184 Thirteen patients had cardiac transplant between 1984 and 2008, and all but 4 had died. Three deaths occurred in the first month. Four patients died of progressive systemic amyloidosis. One patient died of graft rejection during SCT. In six patients ASCT was planned, but performed in only 3 due to either peri-operative complications (n = 2) or inability to collect stem cells (n = 1). Of the 4 survivors, 2 had ASCT, 1 did not, and SCT was planned in another. 184
There is one case of orthotopic cardiac transplant followed by allogeneic stem cell transplant. 185 At 18 months, this patient was alive with excellent performance status, but was not in hematologic complete response and with recurrence of amyloid in the myocardium.
7.6.2. Renal transplantation
Most of the reports of renal Tx for amyloidosis combine AL with AA amyloidosis making outcomes for the former condition difficult to discern. The largest series are from the UK and the Mayo Clinic.97, 179, and 186 Among the 22 patients receiving a renal transplant over 25 years in the UK, there were no renal graft failures at 4.8 years and the 1- and 5-year overall survival rates were 95% and 67% respectively. Seventeen patients received chemotherapy without ASCT either before or after renal transplantation; 4 patients had ASCT prior to kidney transplantation. In the Mayo series, which included 19 patients with AL receiving renal transplantation over the course of 10 years, all but one had a living related donor. 183 Eight patients had an ASCT prior to kidney transplant, 6 had ASCT after kidney transplantation, and 5 patients received another form of chemotherapy to kill the plasma cell clone. With a median follow-up of 41 months, the 1- and 5-year overall survival rates were 84% and 76%. There were no graft failures. Causes of death included pulmonary embolism, post-transplant lymphoproliferative disorder, stroke, and a decision not to receive further care in the US. A small study from Boston University included 3 patients who had ASCT prior to kidney transplantation; patients are alive at 5.3, 5.4, and 6 years. 187
7.6.3. Liver transplantation
Unlike hereditary amyloidosis, liver transplantation is rarely performed for patients with AL amyloidosis.179 and 188 Outcomes are poor. In the UK series of 9 patients, the 1- and 5-year overall survival rates were 32% and 22%, respectively. Four had extrahepatic involvement at the time of transplantation. Six of the seven patients who died did so within 1 year of liver transplantation. Two of the 3 patients who received ASCT survived. In another case report, one year after liver transplantation, the recipient of OLT was alive and well, but with recurrent AL in the graft. 188
7.7. Treating localized amyloidosis
The location of the amyloid is an important clue in recognizing the amyloid as being localized. The most frequent sites of localized amyloid are respiratory tract, genitourinary tract, and skin. 33 Pulmonary amyloid can be subdivided into nodular, laryngeal/tracheobronchial, or diffuse interstitial. Only the third represents a manifestation of systemic AL.189 and 190 The nodular form of amyloid presents as solitary pulmonary nodules or multiple nodules. This does not represent the systemic form of AL. 191 These nodules are not calcified and often require resection to exclude a diagnosis of malignancy. The usual treatment for tracheobronchial AL is yttrium–aluminum–garnet (YAG) laser resection of the tissue and more recently external beam radiation therapy. 192 Obstructive ureterovesicular amyloidosis is always localized. Patients present with hematuria or obstruction. 193 Surgery 194 and dimethylsulfoxide instillation 195 are the standard approaches.
8. Practice points
- Consider the diagnosis with systemic symptoms and a monoclonal protein
- Confirm diagnosis is AL and not another form of amyloidosis by using mass spectrometry of the amyloid biopsy specimen
- Fully appreciate extent of disease, making sure that baseline cardiac biomarkers and serum immunoglobulin free light chains are completed
- Optimize supportive management
- Treat patients on clinical trials whenever possible
- Do not reflexively apply multiple myeloma regimens to AL patients since toxicity profile is always greater in AL patients
- Consider possibility that clinical deterioration is therapy related rather than disease related
- Follow for both hematologic and organ response
9. Research agenda
- Early detection of disease
- Improvement of outcomes for patients with severe cardiac involvement
- Maximizing risk stratified therapy approaches
- Unraveling the genomic and proteomic drivers of disease
- Development of fibril directed therapies
Conflict of interest statement
A.D. receives research funding from Celgene and Millenium and honoraria from Binding Site. M.A.G. receives honoraria from Celgene and Millennium, and is a member of an entity’s Board of Directors or advisory committees for Millennium. FB has no conflict.
Financial support: This work was supported in part by the The JABBS Foundation and The Predolin Foundation. AD is supported in part by grants CA125614, and CA107476 from the National Cancer Institute.
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