SECTION 3 - AL amyloidosis and light chain deposition disease
|In patients with AL amyloidosis, serum free light chains:|
Primary systemic, or light-chain amyloidosis (AL) is a protein conformation disorder characterised by the accumulation of monoclonal free light chains (FLCs) or their fragments, as extracellular insoluble amyloid fibrils that cause functional and structural organ damage (Figure 15.1A) . A slowly growing clone of plasma cells secrete the monoclonal FLCs, which are more often of the λ subtype (κ to λ frequency: 1:3) .
Amyloid fibrils are formed from the N-terminal fragment of a monoclonal FLC, and comprise the variable region and part of the constant region. The ability to form amyloid fibrils appears to be related to the structural characteristics of a particular variable region, with an over-representation of VκI and VκIV, and Vλ6a and Vλ3r gene segments, in κ and λ AL amyloidosis respectively .
AL amyloidosis affects multiple organs, most frequently the kidney (74%), heart (60%), liver (27%), peripheral nervous system (22%) and autonomic nervous system (18%), although other organs may also be involved (Figures 15.1B, 15.2A and 15.2B) . The monoclonal FLC type impacts the spectrum of organ involvement: κ-type AL typically affects the gastrointestinal tract and liver, whereas nephrotic-range proteinuria is observed in a higher proportion of λ-type AL patients . The tissue distribution may be related to structural characteristics of individual FLCs. It is of interest that λ FLCs derived from the Vλ6a gene segment are preferentially associated with kidney involvement .
The median concentration of involved κ or λ FLCs are 314 mg/L and 194 mg/L, respectively , which is considerably lower than those concentrations seen in multiple myeloma (MM) . The higher concentration in κ AL amyloidosis patients is likely to reflect a combination of a higher tumour burden and higher prevalence of renal insufficiency  (see Chapter 20).
The survival of patients with AL amyloidosis is quite variable: median survival ranges from 12 to 18 months in different series, and is largely dependent on the number of organs involved and the degree to which their function is compromised . Overall survival (OS) is similar for κ and λ AL patients, with a 4-year median OS from diagnosis of 42% . Whilst survival in AL amyloidosis has improved over the past decade with the introduction of several new therapeutic options, the 1-year mortality remains high at 43% .
AL amyloidosis is 5 times less common than MM. The age-adjusted incidence of AL amyloidosis in the United States is estimated to be between 5.1 and 12.8 per million per year , which is equivalent to approximately 600 new cases per year in the UK . In an audit of 800 UK patients with AL amyloidosis, 66% were aged between 50 and 70 years of age at diagnosis, and 4% were aged less than 40 years . The male:female ratio was equal. AL amyloidosis coexists with MM in approximately 10 to 15% of patients, and more rarely with Waldenstrӧms macroglobulinaemia and other lymphoid malignancies .
The presence of a monoclonal protein in the serum and urine of patients is a common finding and an important diagnostic feature. However, the underlying monoclonal gammopathy can be subtle and monoclonal proteins are undetectable in between 5 and 20% of patients, depending upon the sensitivity of the electrophoretic method used. Figure 15.3 shows a typical serum protein electrophoresis (SPE) result from a patient with AL amyloidosis; it demonstrates a nephrotic pattern (low albumin, elevated α2 and low γ fraction) with no obvious monoclonal protein. Serum immunofixation electrophoresis (sIFE), however, reveals some polyclonal immunoglobulin in the γ region and a monoclonal λ FLC band in the β/γ region. This band is too small to be quantified by scanning densitometry of the SPE gel since it is undetectable against the background proteins. Figure 15.4 shows the urine protein electrophoresis (UPE) from the same patient. It contains a considerable amount of protein, particularly albumin, and there is a small monoclonal spike. Urine immunofixation electrophoresis (uIFE) indicates a monoclonal λ protein against a background of polyclonal κ and λ FLCs. The monoclonal band is difficult to quantify by UPE and is of modest utility for the purpose of disease monitoring.
15.2. Diagnosis of AL amyloidosis
Early diagnosis AL amyloidosis is critical, to facilitate early access to effective chemotherapy, and therefore suppress the production of amyloidogenic FLCs before irreversible organ damage occurs.
The diagnosis of amyloidosis should be based initially on tissue biopsy, followed by confirmation of the amyloid type and extent of organ involvement . Amyloid deposits in tissue biopsies stain with Congo red and produce pathognomonic red-green birefringence under polarised light. Immunohistochemical staining of tissue biopsies for immunoglobulin light chains is frequently not diagnostic in AL amyloidosis, but is useful in confirming or excluding other amyloid types, such as the AA type (characterised by deposition of serum amyloid A protein) . DNA analysis can be used to distinguish AL amyloidosis from hereditary forms of amyloid, which may coexist with monoclonal gammopathy of undetermined significance .
Whilst the detection of a monoclonal protein does not provide a definitive diagnosis of AL amyloidosis, it does provide supportive evidence of an underlying plasma cell dyscrasia. There are now numerous published studies comparing the diagnostic performance of sFLC and electrophoretic assays in screening for AL amyloidosis. A recent study compared diagnostic screening panels for identifying monoclonal gammopathy in patients suspected of having MM, AL amyloidosis and related monoclonal gammopathies . In 581 patients with a confirmed diagnosis of AL amyloidosis, the diagnostic sensitivity of the sFLC assays was 88.3%, which increased to 97.1% with the inclusion of sIFE (Figure 15.5). Importantly, addition of uIFE to the serum panel increased the sensitivity to 98.1% (representing an additional 6/581 patients), confirming that in only a minority of AL amyloidosis patients, monoclonal FLCs may be detected by urine studies alone (discussed in Section 15.3 below).
In a separate prospective study of 121 patients with biopsy-proven AL amyloidosis, the diagnostic sensitivity of the κ/λ sFLC ratio was 76% . In comparison, the diagnostic sensitivity of sIFE and uIFE was 96%. When AL amyloidosis patients were grouped according to monoclonal FLC type, the diagnostic sensitivity of the κ/λ sFLC ratio was significantly higher for κ clones than λ clones (97 vs 69% respectively), whereas the diagnostic sensitivity of sIFE was lower for κ clones than λ clones (60 vs 87%). The authors commented that this difference may be due to the formation of monoclonal κ FLC aggregates of variable size and electrophoretic mobility, resulting in the absence of a detectable monoclonal protein band by serum electrophoresis. They concluded that the diagnosis of AL amyloidosis should not rely on a single test, and that a screening algorithm comprising serum and urine IFE in combination with the κ/λ sFLC ratio had 100% diagnostic sensitivity for AL amyloidosis.
Previous studies on the diagnostic performance of the κ/λ sFLC ratio in AL amyloidosis reported a diagnostic sensitivity ranging from 75% to 98% . In the first published study of 262 AL amyloidosis patients at the National Amyloidosis Centre, London, the κ/λ sFLC ratio was associated with a greater diagnostic sensitivity than the combination of serum or urine IFE (98% vs 79%)  (Figure 15.6). This observation has been supported by some studies  but not by others . However, in all published studies to date, sFLC analysis has proven to be an important complementary technique to IFE for screening for monoclonal gammopathy in patients with suspected AL amyloidosis. This is now reflected in guidelines from the International Myeloma Working Group (IMWG), which recommend a combination of sFLC analysis and immunofixation of serum and urine to screen for AL amyloidosis (Section 25.2) . International guidelines also recommend that serial sFLC measurement should be routinely performed in patients with AL amyloidosis (see Sections 25.2 and 15.6).
Clinical case history No 5
|Clinical case history No 5. AL amyloidosis identified by FLC analysis when electrophoretic tests were doubtful .|
A 40-year-old woman, with spontaneous bruises, asthenia, abdominal pains and a possible cardiomyopathy, was investigated for suspicion of AL amyloidosis. Abdominal fat biopsy showed Congo Red positivity. SPE showed hypogammaglobulinaemia but no monoclonal proteins.
IFE showed a weak λ band without a corresponding intact immunoglobulin (Figure 15.7). A weak λ arc was also visible by serum immunoelectrophoresis. Quantitative immunoglobulin measurements were: IgG 4.9 g/L; IgA 1.02 g/L and IgM 0.32 g/L indicating hypogammaglobulinaemia. sFLC analysis showed: κ 7.8 mg/L; λ 210 mg/L and κ/λ ratio 0.04.
Nephelometric FLC quantification was therefore clearly abnormal and provided a measurable parameter for subsequent disease monitoring. In contrast, FLCs were barely detectable by conventional electrophoretic assays.
Figure 15.7. Clinical Case history No 5. SPE scan and IFE of the patient’s serum. A weak λ band is visible. (Courtesy of Dr Lucile Musset).
15.3. Discordant results in AL amyloidosis
For a proportion of patients with AL amyloidosis, sFLCs may be undetectable by sFLC analysis at diagnosis. Three possible scenarios are discussed below.
A. Monoclonal FLCs detectable in the urine by IFE but undetectable by sFLC immunoassay
sFLC analysis is generally more sensitive than urine electrophoresis for indicating the presence of monoclonal FLCs. This advantage is dependent upon efficient renal reabsorption of FLCs (see Section 3.4). Nevertheless, small amounts of monoclonal FLCs have been identified in the urine of some patients with normal sFLC ratios. This is discussed further in the section below and in Section 24.10. When comparing serum and urine results, it is essential to ensure that the samples were taken at the same time point. If there is a significant time delay between the collection of serum and urine samples, any observed difference may simply reflect response to treatment or disease progression.
The phenomenon of discordant sFLC and urine IFE results was studied in a cohort of 219 AL amyloidosis patients attending clinics at the National Amyloidosis Centre, London . Of these patients, 56 had abnormal sFLC ratios and monoclonal FLC detected in the urine; 52 had abnormal sFLC ratios but urine negative by IFE, and 16 had small monoclonal bands detected by uIFE but sFLC ratios within the normal range. Of this latter group, 12/16 had nephrotic-range proteinuria (>3g/day), so saturation of protein reabsorption by albumin and other proteins could explain the increased passage of FLCs into their urine. For the other 4/16 patients, other mechanisms must have been responsible. All 4 of these patients had sFLC ratios biased towards the tumour light chain (0.30, 0.34 and 0.49 for λ patients and 1.61 for the κ patient).
In a separate study by Palladini et al, 5 of 115 (4%) AL amyloidosis patients had monoclonal bands detectable by uIFE but sFLC ratios were within the normal range . Interestingly these 5 patients were all λ-type AL patients. This may reflect the fact that the proportion of patients with nephrotic-range proteinuria is higher for λ AL amyloidosis .
B. Monoclonal FLCs detectable by sIFE but undetectable by sFLC immunoassay
On very rare occasions, sFLCs may be undetectable by immunoassay but detectable in the serum by IFE. In such cases, further investigation is always warranted. Possible explanations include:
C. No monoclonal proteins detectable by any routine laboratory method
For a small proportion of AL amyloidosis patients, no monoclonal FLCs are detected by any standard laboratory techniques. For example, in a large screening study by Katzmann et al, 11 of 581 (2%) AL patients were normal by sFLC analysis, sIFE and uIFE . Possible explainations include:
15.4. Prognostic value of sFLCs at diagnosis
Evaluation of sFLCs at baseline provides important prognostic information in AL amyloidosis, and is recommended in IMWG guidelines . In a study of 730 patients, median OS was shorter among those with an abnormal sFLC ratio at baseline (16.2 months, n=644) than in those with a normal ratio (63.6 months, n = 86) (Figure 15.8A) . When the analysis was repeated grouping patients according to sFLC burden [defined as the difference between involved and uninvolved FLC (dFLC)] above or below the median value (196 mg/L), the OS for patients with high dFLC was 10.9 months compared with 37.1 months for those with low dFLC (p<0.001) (Figure 15.8B) .
AL amyloidosis patients with high FLC burden (dFLC >196 mg/L), had more frequent and severe cardiac involvement, with higher levels of cardiac biomarkers troponin T and B-type natriuetic peptide (NT-ProBNP) . However, in a multivariate analysis that included cardiac biomarkers, numbers of organs involved, ventricular septal thickness, ejection fraction, circulating plasma cells, and serum uric acid level, baseline dFLC remained an independent predictor of survival .
High baseline FLC levels have also been shown to be associated with poor outcome in AL amyloidosis patients undergoing stem cell transplant .
It is of interest that AL amyloidosis patients without detectable monoclonal immunoglobulin heavy chain had an inferior survival compared to those patients with a heavy chain identified (12.6 months vs 29.3 months, p=0.02) . The patients without monoclonal heavy chain had a higher dFLC (255 vs 153 mg/L, p<0.001) but on multivariate analysis both dFLC and the presence/absence heavy chain were independently prognostic for survival . This may suggest a potential future role for immunoglobulin heavy chain/light chain assays (Hevylite) in predicting AL amyloidosis outcome (see Section 32.5).
15.5. Monitoring patients with AL amyloidosis
“The introduction of the serum immunoglobulin free light chain assay has revolutionized our ability to assess hematological responses in patients with low tumor burden.......”
“The Freelite® serum free light chain assay represents a landmark advance in the management of AL amyloidosis.....”
The aim of therapy in AL amyloidosis is to suppress the monoclonal plasma cell clone that produces the amyloidogenic FLC, and to support and preserve organ function. Treatment regimens for AL amyloidosis have essentially been modified from those developed in MM. Patients must be monitored closely since the toxicity of chemotherapy may be substantially greater than in MM, due to reduced organ function and poor performance status.
Amyloid deposits exist in a state of dynamic turnover. When the supply of amyloid-forming protein is reduced by effective chemotherapy, the balance between amyloid deposition and clearance may be favourably altered. Although complete suppression of clonal plasma cells is desirable, reduction in the amyloidogenic sFLC concentrations is often sufficient to lead to stabilisation or gradual regression of amyloid deposits .
Traditionally, haematological response assessment in AL amyloidosis followed the same guidelines as MM, ie, using serial measurement of monoclonal protein, with measurable disease defined as >10 g/L . However, this approach has limited utility in AL amyloidosis as the proportion of patients with measurable monoclonal immunoglobulin is very low, typically between 15 and 20% . In contrast, the majority of patients have measurable disease as assessed by sFLCs, and defined as dFLC ≥50 mg/L .
Due to their short serum half-life, sFLCs are usually the most effective marker for evaluating the early effects of chemotherapy in AL amyloidosis . International guidelines now recommended sFLC analysis for the quantitative monitoring of patients with AL amyloidosis (Chapter 25) .
In a study evaluating the combination of bortezomib and dexamethasone in patients with AL amyloidosis, sFLCs were assessed before each cycle of therapy . Rapid haematological responses were observed, with a 50% reduction in involved FLC in all responding patients within two courses of treatment (Figure 15.9). The authors concluded that therapy may be discontinued after two cycles if there is no sFLC response, and that an alternative treatment could be considered.
Clinical case history No 6
|Clinical case history No 6. Use of sFLCs to monitor a patient with AL amyloidosis.|
A 49-year-old man presented with congestive cardiac failure. After establishing a diagnosis of AL amyloidosis, he was given a heart transplant. He was subsequently treated with melphalan and prednisolone for a year, but then gradually developed increasing autonomic neuropathy with gastrointestinal symptoms, weight loss, hypotension and proteinuria. A cardiac biopsy showed evidence of amyloid in the graft. Two years after his initial presentation, he was given high dose melphalan and a PBSCT. This was successful as judged by diminishing proteinuria from 5.5 to 2.3 g per day over the following months and more stable blood pressure. The patient regained some weight, returned to jogging and was relatively well for the following few years.
During his 6th year of illness, he gradually became short of breath, lost weight and renal function worsened. Deterioration continued with an episode of aspiration pneumonia followed by syncopal episodes. End-stage renal failure finally developed and he died seven and a half years after the initial presentation. Throughout his illness, he had a low level of monoclonal IgGκ protein in his serum, detectable only by IFE. Changes in its concentration had not been sufficient to act as a useful clinical marker (Figure 15.10).
Retrospective analysis of serum samples showed that a monoclonal κ FLC had been present at different stages of his disease. It was present in greatly elevated concentrations at presentation but fell following the PBSCT and was undetectable for several years. It then recurred, as minor symptoms developed. Investigations at that time were normal and it was considered that the amyloidosis remained under control. In retrospect, rising FLC concentrations indicated otherwise.
Subsequently, symptoms progressed in parallel with rising κ sFLC levels but the monoclonal IgGκ, detectable by IFE, remained unchanged. Development of progressive renal and cardiac failure indicated the terminal phase of the illness and he became too ill to be treated with chemotherapy. Perhaps, if FLC results had been available before the final illness, earlier treatment with chemotherapy could have produced a favourable outcome.
Figure 15.10. Changes in SAP scans and serum monoclonal proteins during the disease course of a patiewnt with AL amyloidosis. M&P: melphalan and prednisolone; ESRF: end stage renal failure. (Courtesy of PN Hawkins).
15.6 SAP scintigraphy and sFLCs
I123-labelled serum amyloid P (SAP) scintigraphy was developed at the National Amyloidosis Centre, UK for the diagnosis and quantitative monitoring of amyloid deposits . I123-labelled SAP localises rapidly and specifically to amyloid deposits in proportion to the quantity of amyloid present. Whole body SAP scintigraphy (SAP scans) allow the identification and quantification of amyloid deposits in affected organs, which varies greatly between patients. Furthermore, serial measurements demonstrate that amyloid deposits exist in a state of dynamic turnover, with variations in SAP uptake mirroring clinical status. This is seen in patients during treatment with chemotherapy and is compared with the concentrations of sFLCs in Figure 15.11.
Investigations by Lachmann et al. in 137 patients with AL amyloidosis confirmed the important relationship between amyloid deposits, as seen on SAP scans, and sFLC concentrations . Patients were divided into 3 groups dependent upon whether the SAP scans of the amyloid deposits showed regression, no change, or progression following chemotherapy. A good correlation with changes in sFLC concentrations was observed during the same period, indicating that sFLC measurments provide a simple measure of changes in disease status in patients with AL amyloidosis (Figure 15.12).
15.7 Prognostic value of sFLC response in predicting AL amyloidosis outcome
Kumar et al. studied the prognostic significance of dFLC reductions in 347 patients undergoing autologous SCT . A 50% decrease in dFLC provided little discriminatory value in predicting survival as the majority of patients in the study achieved this cut-off value (Figure 15.13A). In contrast, a 90% reduction in dFLC was observed in 38% of patients, and predicted a superior outcome. Furthermore, the median OS post-SCT among those patients who achieved a 90% reduction in dFLC was not reached, compared with the 37.4 months achieved in the remaining patients (p <0.001) (Figure 15.13B). The prognostic value of achieving a 90% reduction in dFLC was confirmed in a separate cohort of 96 patients treated with melphalan and dexamethasone (Figure 15.13C,D) . The authors concluded that assessment of the dFLC response allows clinicians to modify therapy in those patients failing to achieve a 90% reduction in dFLC. These results are supported by the findings of several other earlier studies .
The relative contribution of changes in monoclonal intact immunoglobulin protein and dFLC in predicting overall survival has also been studied . Reductions in dFLC were shown to be superior to changes in intact immunoglobulins in predicting OS.
15.8 AL amyloidosis haematological response criteria
Uniform criteria for the definition of organ involvement and response to treatment in AL amyloidosis, first published in 2005 , were updated at the 12th International Symposium on Amyloidosis in 2010 . The definition of measurable absolute concentration of FLC was revised to a dFLC of >50 mg/L , and covers approximately 85% of newly diagnosed AL amyloidosis patients . Follow-up data from an international cohort of 816 patients from seven referral centres were included, and haematological responses were assessed 3- and/or 6-months after initiation of first-line therapy. Four haematological response categories were defined: amyloid complete response (aCR; negative serum and urine IFE and normal sFLC ratio), very good partial response (VGPR; dFLC < 40 mg/L), partial response (PR; dFLC decrease >50%) and no response (NR)  (see Section 25.11). There was a strong correlation between the haematological response category at 3- or 6-months and overall survival (data not shown and Figure 15.14) . The haematological response criteria were subsequently validated in a prospective study of 374 patients, supporting the use of these criteria in future clinical trials .
15.9 sFLC response in predicting cardiac response
Organ responses are usually slow to appear in patients with AL amyloidosis, and are often dependent on an adequate haematological response. The presence of cardiac amyloidosis is the major prognostic determinant in AL amyloidosis. Although cardiac involvement is seen in only approximately half of patients at diagnosis, virtually all AL amyloidosis patients will die due to cardiac-related sequelae . Measurement of cardiac biomarkers, namely troponin and the amino-terminal fragment of natriuretic peptide type B (NT-proBNP) have been shown to be useful in defining prognosis at diagnosis , and should be monitored to assess response to therapy, in parallel with the assessment of haematological response .
The important link between cardiac dysfunction in AL amyloidosis and falling sFLC concentrations was first observed by Palladini and colleagues . Fifty-one AL amyloidosis patients with symptomatic myocardial involvement were given chemotherapy and monitored for sFLCs and NT-proBNP. During treatment, 22 patients had a reduction of sFLCs by more than 50%, including 9 patients who had disappearance of monoclonal immunoglobulins as assessed by IFE; a corresponding reduction of NT-proBNP levels was also observed (p <0.001). Survival was superior in responders than in non responders (p <0.001), a finding supported by subsequent studies, which have confirmed by multivariate analysis, that NT-proBNP and haematological responses are independently associated with survival .
These data demonstrate that a reduction in circulating monoclonal FLCs translates into a rapid improvement in cardiac function, and confirms the importance of targeting therapy to rapidly reduce the concentration of toxic sFLCs in patients with heart failure.
15.10 sFLC response and renal outcome
The value of the sFLC response in predicting long-term renal outcome has been studied in a large cohort of 923 patients with renal AL amyloidosis . Patients who achieved a greater sFLC response after chemotherapy demonstrated prolonged survival and superior renal outcomes. Patients who achieved more than a 90% FLC response at 6 months had an almost four-fold increase in the chance of renal response (P<0.001) and a 68% reduction in the chance of renal progression (P<0.001) compared with those achieving a FLC response of 0 to 50%.
Among 752 patients with a baseline estimated glomerular filtration rate (eGFR) of ≥15 mL/min, those who achieved a 50 to 90% reduction or more than a 90% reduction in dFLC were less likely to experience renal progression requiring dialysis than patients achieving a <50% reduction in dFLC .
It should be noted that in cases of renal insufficiency, use of a modified renal reference interval for the κ/λ sFLC ratio may be appropriate. Application of this reference interval has been demonstrated to improve the diagnostic specificity of the sFLC ratio without affecting diagnostic sensitivity in patients with renal impairment (see Section 5.4).
|Chapter 14||Back to Contents Page||Chapter 16|
- ↑ 1.0 1.1 1.2 1.3 1.4 Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006;108:2520-30 PMID: 16794250
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 Kumar S, Dispenzieri A, Katzmann JA, Larson DR, Colby CL, Lacy MQ et al. Serum immunoglobulin free light chain measurement in AL amyloidosis: prognostic value and correlations with clinical features. Blood 2010;116:5126-9 PMID: 20798235
- ↑ Comenzo RL, Wally J, Kica G, Murray J, Ericsson T, Skinner M, Zhang Y. Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation. Br J Haematol 1999;106:744-51 PMID: 10468868
- ↑ Snozek CL, Katzmann JA, Kyle RA, Dispenzieri A, Larson DR, Therneau TM et al. Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system. Leukemia 2008;22:1933-7 PMID: 18596742
- ↑ 5.0 5.1 5.2 Kumar SK, Gertz MA, Lacy MQ, Dingli D, Hayman SR, Buadi FK et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc 2011;86:12-8 PMID: 21193650
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Kumar SK, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR et al. Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis. Am J Hematol 2011;86:251-5 PMID: 21328431
- ↑ Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O'Fallon WM, Kurland LT. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood 1992;79:1817-22 PMID: 1558973
- ↑ 8.0 8.1 8.2 8.3 8.4 Bird JM, Cavenagh J, Samson D, Mehta A, Hawkins P, Lachmann H. Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol 2004;125:681-700 PMID: 15180858
- ↑ 9.0 9.1 Cohen AD, Comenzo RL. Systemic light-chain amyloidosis: advances in diagnosis, prognosis, and therapy. Hematology Am Soc Hematol Educ Program 2010;2010:287-94 PMID: 21239808
- ↑ 10.0 10.1 Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346:1786-91 PMID: 12050338
- ↑ 11.0 11.1 Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA et al. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009;55:1517-22 PMID: 19520758
- ↑ 12.0 12.1 Palladini G, Russo P, Bosoni T, Verga L, Sarais G, Lavatelli F et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem 2009;55:499-504 PMID: 19131635
- ↑ 13.0 13.1 13.2 13.3 Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, Hawkins PN. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol 2003;122:78-84 PMID: 12823348
- ↑ 14.0 14.1 Abraham RS, Katzmann JA, Clark RJ, Bradwell AR, Kyle RA, Gertz MA. Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis. Am J Clin Pathol 2003;119:274-8 PMID: 12579999
- ↑ 15.0 15.1 Katzmann JA, Abraham RS, Dispenzieri A, Lust JA, Kyle RA. Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 2005;51:878-81 PMID: 15774572
- ↑ 16.0 16.1 16.2 Bochtler T, Hegenbart U, Heiss C, Benner A, Cremer F, Volkmann M et al. Evaluation of the serum-free light chain test in untreated patients with AL amyloidosis. Haematologica 2008;93:459-62 PMID: 18287137
- ↑ 17.0 17.1 Akar H, Seldin DC, Magnani B, O'Hara C, Berk JL, Schoonmaker C et al. Quantitative serum free light chain assay in the diagnostic evaluation of AL amyloidosis. Amyloid 2005;12:210-5 PMID: 16399645
- ↑ 18.0 18.1 18.2 Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009;23:215-24 PMID: 19020545
- ↑ Guis L, Diemert MC, Ghillani P, Choquet S, Leblond V, Vernant JP, Musset L. The quantitation of serum free light chains: Three case reports. Clin Chem 2004;50:F38a
- ↑ Mead GP, Stubbs PD, Goodman HJB, Hawkins PN. Serum and urine light chains in AL amyloidosis. Clin Lymphoma Myeloma 2009;9:B153a
- ↑ Tate JR, Mollee P, Dimeski G, Carter AC, Gill D. Analytical performance of serum free light-chain assay during monitoring of patients with monoclonal light-chain diseases. Clin Chim Acta 2007;376:30-6 PMID: 16945362
- ↑ Robson E, Mead G, Carr-Smith H, Bradwell A. In reply to Tate et al Clin Chim Acta 2007;376:30-6. Clin Chim Acta 2007;380:247 PMID: 17368602
- ↑ Dispenzieri A, Lacy MQ, Katzmann JA, Rajkumar SV, Abraham RS, Hayman SR et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2006;107:3378-83 PMID: 16397135
- ↑ 24.0 24.1 Kastritis E, Anagnostopoulos A, Roussou M, Toumanidis S, Pamboukas C, Migkou M et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 2007;92:1351-8 PMID:18024372
- ↑ Dispenzieri A, Gertz MA, Kyle RA. To the editor: Determining appropriate treatment options for patients with primary systemic amyloidosis. Blood 2004;104:2992-3
- ↑ Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment of AL amyloidosis. Br J Haematol 2008;140:365–77 PMID: 18162121
- ↑ Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73 PMID:16855634
- ↑ 28.0 28.1 28.2 28.3 28.4 Gertz MA, Merlini G. Definition of organ involvement and response to treatment in AL amyloidosis: an updated consensus opinion. Amyloid 2010;17:CP-Ba
- ↑ Hawkins P. FLCs in the amyloidosis clinic. Hematology Reports 2010;2:p7
- ↑ Hawkins PN. Serum amyloid P component scintigraphy for diagnosis and monitoring amyloidosis. Curr Opin Nephrol Hypertens 2002;11:649-55 PMID: 12394612
- ↑ Goodman HJB, Wechalekar AD, Lachmann HJ, Bradwell AR, Hawkins PN. Clonal disease response and clinical outcome in 229 patients with AL amyloidosis treated with VAD-like chemotherapy. Haematologica 2005;90:PO1408a
- ↑ Tan TS, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR et al. Melphalan and dexamethasone is an effective therapy for primary systemic amyloidosis. Blood 2007;110:3608a
- ↑ Wechalekar AD, Goodman HJB, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood 2007;109:457-64 PMID:16990593
- ↑ 34.0 34.1 34.2 34.3 34.4 Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541-9 PMID: 23091105
- ↑ Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol 2005;79:319-28 PMID: 16044444
- ↑ Palladini G, Dispenzieri A, Gertz MA, Wechalekar A, Hawkins P, Schonland SO et al. Validation of the criteria of response to treatment in AL amyloidosis. Blood 2010;116:1364a
- ↑ Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain (AL) amyloidosis. Leukemia 2012;26:2317-25 PMID: 22475872
- ↑ Dubrey SW, Cha K, Anderson J, Chamarthi B, Reisinger J, Skinner M, Falk RH. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998;91:141-57 PMID:9578896
- ↑ Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22:3751-7 PMID:15365071
- ↑ Gertz MA. How to manage primary amyloidosis. Leukemia 2012;26:191-8 PMID:21869840
- ↑ Palladini G, Lavatelli F, Russo P, Perlini S, Perfetti V, Bosoni T et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 2006;107:3854-8 PMID: 16434487
- ↑ Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 2010;28:1031-7 PMID:20085941
- ↑ 43.0 43.1 Pinney JH, Lachmann HJ, Bansi L, Wechalekar AD, Gilbertson JA, Rowczenio D et al. Outcome in Renal AL Amyloidosis After Chemotherapy. J Clin Oncol 2011;29:674-81 PMID:21220614