AL Amyloidosis

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Chapter

15

SECTION 3 - AL amyloidosis and light chain deposition disease

AL Amyloidosis

Contents

In patients with AL amyloidosis, serum free light chains:
  1. In combination with immunofixation of serum and urine provide an efficient diagnostic screen for AL amyloidosis.
  2. At baseline provide important prognostic information.
  3. Are usually the most effective marker for evaluating the early effects of chemotherapy.
  4. When used for monitoring, provide prognostic information on overall survival and organ responses.
  5. Increase during renal failure, independently of light chain synthesis.

15.1. Introduction

Diagram showing conformational change from monomeric monoclonal free light chains to a polymeric beta-pleated sheet structure in AL amyloidosis
Figure 15.1. A. AL amyloidosis showing formation of amyloid fibrils from FLC domains. B. Classic facial features with periorbital purpura. (Courtesy of PN Hawkins).
Part A is a photo of a section a heart from a patient with AL amyloidosis, part B is a photo of an enlarged tongue in a patient with AL amyloidosis
Figure 15.2. A. AL amyloidosis in the heart showing thickening of the left ventricular walls leading to heart failure. B. AL amyloidosis showing macroglossia that occurs in 20% of patients. (Courtesy of PN Hawkins).
Part A is scanning densitometry of a serum protein electrophoresis gel showing a nephrotic pattern: reduced albumin, raised alpha-2 and low gamma globulins and no obvious paraprotein (monoclonal protein). Part B is serum immunofixation electrophoresis showing faint band of lambda free light chains
Figure 15.3. A. Serum from a patient with AL amyloidosis showing a nephrotic pattern on SPE. B. Serum IFE (sIFE) reveals a small (nonquantifiable) monoclonal λ protein in the β/γ region. (Courtesy of RA Kyle and JA Katzmann).
Part A is scanning densitometry of urine protein electrophoresis gel showing a paraprotein, typed in part B by urine immunofixation electrophoresis as lambda free light chains
Figure 15.4. A. UPE and B. urine IFE (uIFE) from the same patient as in Figure 15.3, showing a monoclonal λ protein band. (Courtesy of RA Kyle and JA Katzmann).

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) [1]. 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) [1][2].

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 [1].

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) [1]. 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 [2]. 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 [3].

The median concentration of involved κ or λ FLCs are 314 mg/L and 194 mg/L, respectively [2], which is considerably lower than those concentrations seen in multiple myeloma (MM) [4]. 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 [2] (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 [5][6]. Overall survival (OS) is similar for κ and λ AL patients, with a 4-year median OS from diagnosis of 42% [5]. 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% [5].

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 [7], which is equivalent to approximately 600 new cases per year in the UK [8]. 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 [8]. 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 [8].

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

Bar chart showing that the diagnostic sensitivity of the serum free light chain assay alone was 88.3%. This increased to 97.1% with the inclusion of serum immunofixation electrophoresis. Further addition of urine immunofixation electrophoresis to the screening panel only increased the diagnostic sensitivity to 98.1%
Figure 15.5. Comparison of the diagnostic sensitivity of screening panels in 581 patients with confirmed AL amyloidosis.
Serum free light chain concentrations in AL amyloidosis tend to be slightly lower than in light chain multiple myeloma, with a predominance of monoclonal lambda free light chains over kappa free light chains
Figure 15.6. sFLCs in 262 patients with AL amyloidosis at diagnosis, 282 normal sera, 224 patients with LCMM and 28 patients with NSMM.

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 [9]. 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) [1]. DNA analysis can be used to distinguish AL amyloidosis from hereditary forms of amyloid, which may coexist with monoclonal gammopathy of undetermined significance [10].

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 [11]. 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% [12]. 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% [13][14][15][16][17]. 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%) [13] (Figure 15.6). This observation has been supported by some studies [14] but not by others [15][16][17]. 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) [18]. 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 [19].

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.

Serum protein electrophoresis scanning densitometry showing hypogammaglobulinaemia with no obvious monoclonal protein (paraprotein). Serum immunofixation electrophoresis identified a weak band of monoclonal lambda free light chains
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

Figure 15.8. Relationship between overall survival outcome and sFLC measurements at diagnosis. A. AL amyloidosis patients grouped according to sFLC ratio at baseline (normal versus abnormal). B AL amyloidosis patients grouped according to baseline dFLC (high: >196 mg/L versus low: <196 mg/L) [2]. (Citation Information: Blood, journal of the American Society of Hematology. HighWire Press Copyright 2010. Reproduced with permission of American Society of Hematology).

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 [20]. 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 [12]. 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 [2].

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:

1. Antigen excess. It is noteworthy that structurally aberrant FLC molecules occasionally produce antigen excess conditions even at low concentrations and may very rarely produce normal FLC results (see Section 4.2F).
2. Failure of the sFLC immunoassay to recognise a particular patient's FLC epitopes. This is highly unlikely, and there has only ever been one reported case in light chain MM in 2004 [21], a problem that has since been corrected [22].
3. Production of monoclonal proteins that comprise only the variable domains of the light chains. Such molecules may not be detected by FLC antibodies but are detected by antibodies directed against whole light chains, as used in IFE. However, there are no reported cases of this phenomenon to date in the literature.

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 [11]. Possible explainations include:

1. Some FLC molecules may have a high affinity for the amyloid deposits, resulting in any circulating FLCs being rapidly removed.
2. In a similar manner, patients with extensive amyloid deposits might have a huge capacity for FLC removal. Any newly synthesised molecules would be cleared rapidly by a combination of binding to the amyloid mass and glomerular filtration, thereby preventing the accumulation of FLCs in serum.
3. The amyloid may be due to the deposition of a different protein [10].

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 [18]. 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) [2]. 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) [2].

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) [2][16]. 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 [2].

High baseline FLC levels have also been shown to be associated with poor outcome in AL amyloidosis patients undergoing stem cell transplant [23].

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) [2]. 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 [2]. 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

Rapid reductions in serum free light chain concentrations observed in all responding patients within two cycles of bortezomib and dexamethasone
Figure 15.9. Monitoring response to bortezomib/dexamethasone with sFLCs [24]. Analysis of sFLCs was performed before each cycle of treatment. (Reproduced with permission of Haematologica).

“The introduction of the serum immunoglobulin free light chain assay has revolutionized our ability to assess hematological responses in patients with low tumor burden.......”

Dispenzieri A, Gertz MA, Kyle RA. Blood 2004 [25].

“The Freelite® serum free light chain assay represents a landmark advance in the management of AL amyloidosis.....”

Wechalekar AD, Hawkins PN, Gillmore JD. Br J Haem 2008 [26].

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 [8].

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 [27]. 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% [6]. In contrast, the majority of patients have measurable disease as assessed by sFLCs, and defined as dFLC ≥50 mg/L [6][28].

Due to their short serum half-life, sFLCs are usually the most effective marker for evaluating the early effects of chemotherapy in AL amyloidosis [8][29]. International guidelines now recommended sFLC analysis for the quantitative monitoring of patients with AL amyloidosis (Chapter 25) [18].

In a study evaluating the combination of bortezomib and dexamethasone in patients with AL amyloidosis, sFLCs were assessed before each cycle of therapy [24]. 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.

Monoclonal kappa free light chains were detectable at AL amyloidosis presenation, fell in response to treatment (peripheral blood stem cell transplantation) and increased during development of progressive disease
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

Reductions in AL amyloidosis deposits shown by radio-labelled serum amyloid P scans and serum free light chain measurments
Figure 15.11. I123 labelled serum amyloid P scans in a 52-year-old woman, viewed posteriorly. Reduction of AL deposits in the liver and spleen after one year of chemotherapy can be seen. Serum κ FLCs reduced from 551 mg/L to 52 mg/L over the same period. (Courtesy of PN Hawkins).
The mean percentage of remaining serum free light chains in AL amyloidosis patients 12 months after commencing chemotherapy were 23% in those with regression of AL amyloidosis deposits, 44% in those with stable disease and 125% in those with progressive disease, as judged by serum amyloid P scans
Figure 15.12. Comparison of disease status from serum amyloid P scans and serum FLCs in 127 patients with AL amyloidosis before and 12 months after commencing chemotherapy. The mean percentage of remaining FLCs in each group are indicated (Kruskal-Wallis test: p <0.0001). (Courtesy of PN Hawkins).

I123-labelled serum amyloid P (SAP) scintigraphy was developed at the National Amyloidosis Centre, UK for the diagnosis and quantitative monitoring of amyloid deposits [30]. 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 [13]. 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

Reductions in serum free light chains post stem cell transplant or melphalan and dexamethasone treatment predict survival
Figure 15.13. Prognostic value of reductions in sFLC. A and B. Kaplan Meier survival analysis of AL amyloidosis patients with a baseline dFLC ≥100 mg/L who survived at least 100 days post SCT. The median OS among those with a ≥90% reduction in dFLC (n=77) was not reached compared with 37.4 months for the remaining patients (n=48), p<0.001 (25). C and D. Kaplan Meier survival analysis of AL amyloidosis patients with a baseline dFLC >100mg/L who survived three cycles of therapy with melphalan and dexamethasone. The median OS among those with a ≥50 % decrease in dFLC was not reached compared with 12.2 months for the remaining patients. The median OS among those patients with a ≥90% decrease in dFLC was not reached compared with 15.3 months for the remaining patients [6]. (Reproduced with permission of John Wiley and Sons).

Kumar et al. studied the prognostic significance of dFLC reductions in 347 patients undergoing autologous SCT [6]. 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) [6]. 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 [13][31][32][33].

The relative contribution of changes in monoclonal intact immunoglobulin protein and dFLC in predicting overall survival has also been studied [6]. Reductions in dFLC were shown to be superior to changes in intact immunoglobulins in predicting OS.

15.8 AL amyloidosis haematological response criteria

Significant differences in survival between AL amyloidosis patients achieving different haematological responses: amyloid complete response, very good partial response, partial response or non response
Figure 15.14. Prognostic relevance of haematological response assessed 6-months after the initiation of treatment. International case series of 649 patients treated with melphalan and dexamethasone (MDex, 43.6%), stem cell transplant (SCT, 11.4%), immunomodulatory drug-based therapy (IMiD-based, 22%) or bortezomib and dexamethasone (3%) [9][34].(Citation Information: Hematology by American Society of Hematology. Education Program Copyright 2010. Reproduced with permission of American Society of Hematology).

Uniform criteria for the definition of organ involvement and response to treatment in AL amyloidosis, first published in 2005 [35], were updated at the 12th International Symposium on Amyloidosis in 2010 [28][36][34]. The definition of measurable absolute concentration of FLC was revised to a dFLC of >50 mg/L [28], and covers approximately 85% of newly diagnosed AL amyloidosis patients [37]. 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) [34] (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) [34]. The haematological response criteria were subsequently validated in a prospective study of 374 patients, supporting the use of these criteria in future clinical trials [34].

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 [38]. 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 [28][39], and should be monitored to assess response to therapy, in parallel with the assessment of haematological response [28][40].

The important link between cardiac dysfunction in AL amyloidosis and falling sFLC concentrations was first observed by Palladini and colleagues [41]. 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 [42].

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 [43]. 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 [43].

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).


Test Questions
  1. What is the frequency of an abnormal κ/λ sFLC ratio in AL amyloidosis?
  2. How frequently should sFLCs be assessed in patients undergoing treatment for AL amyloidosis?
  3. What are the major prognostic factors for AL amyloidosis outcome?


Chapter 14 Back to Contents Page Chapter 16

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