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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-09-2707.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Clinical Biochemistry and
Immunology, the Division of Hematology, and the Division of
Biostatistics, Mayo Cancer Center, Mayo Clinic, Rochester, MN.
Light chain-associated amyloidosis (AL) is a plasma cell
dyscrasia in which the secreted monoclonal immunoglobulin (Ig)
light chains form amyloid fibrils. There is considerable heterogeneity in clinical presentation, and prognosis of the disease relates to the
severity of organ dysfunction induced by amyloid deposits. The
mechanisms by which the amyloid fibrils are deposited as well as the
predilection for specific organ sites have not been clearly elucidated.
This study characterizes the repertoire of immunoglobulin light chain
variable genes used by the clonal B cell in AL amyloid patients, and
the association of light chain variable region (VL) genes with clinical
presentation and outcome is assessed in 58 (32
Light chain-associated amyloidosis (AL) is an uncommon plasma cell
disorder characterized by the transformation of immunoglobulin (Ig)
light chains into amyloid, which can be deposited as fibrils, throughout the body.1 The clinical manifestations of the
disease are caused by the presence of amyloid in the major organs of
the body.2 The average age at diagnosis is 65 years3 with a marginal male predominance.3
Once the disease becomes symptomatic, it can become rapidly progressive
and is usually fatal, with a median survival of 12 to 18 months and
less than 5% surviving 10 years or longer.4-6
Only 22% of AL patients have more than 20% plasma cells in their bone
marrow (BM), whereas most (~ 80%) have less than 20%
plasmacytosis.7 The degree of plasma cell clonality and
the number of plasma cells have been inversely correlated with
survival.8 There is also a preponderance of It has been recently shown that VL gene usage may dictate which organs
are preferentially affected by amyloid deposition,10 suggesting an organ tropism for the light chains. Also, there appears
to be a bias in germ-line donor use in AL patients10-12 compared with the healthy population. Because there is a predominance of Patients
Classification of clinical presentation
Cardiac AL was diagnosed if there was classic echocardiographic evidence of infiltrative cardiomyopathy.2,17 The presence of albuminuria higher than 1000 mg/24 h or a creatinine clearance of lower than 10 mL/min were considered indicative of renal disease. Neurologic disease was defined on the basis of orthostatic hypotension, GI motility abnormalities, or sensorimotor peripheral neuropathy. The sole presence of carpal tunnel syndrome was not considered indicative of a neurologic manifestation of AL. A diagnosis of hepatic involvement was made if a liver biopsy showed evidence of amyloid infiltration or the serum alkaline phosphatase level was 1 1/2 times greater than the normal and there was palpable hepatomegaly. The term "soft-tissue AL" has been used in this study to refer to patients who had evidence of macroglossia, skin involvement, or carpal tunnel syndrome without vital organ dysfunction due to amyloid deposits. Identification of VL gene usage BM aspirates were collected from patients with biopsy-proven AL who were seen in the Hematology Division at the Mayo Clinic. The marrow preparations were layered on Ficoll Paque (Amersham Biosciences, Uppsala, Sweden) to remove red blood cells, and the mononuclear cells were washed and frozen. Total RNA was extracted from approximately 107 BM cells using Trizol (Gibco-BRL, Gaithersburg, MD). The RNA obtained was used for the preparation of cDNA, using the Superscript reverse transcriptase (RT) kit (Life Technologies, Grand Island, NY).11,18 The cDNA was subjected to polymerase chain reaction (PCR) amplification using 5' primers specific for the FR1 region of 7 V (V I, V II/V, V III, V
IVa, V IVb, V VI) and 4 V (V I/III, V
II V IV) families, along with the 3' constant region primer C or a pan-C primer.19 Each patient sample
was subjected to multiple cycles of amplification and PCR products were
sequenced from 3 to 4 independent reactions. Each set of experiments
was run with a positive and control (kindly provided by Drs
R. L. Comenzo and Y. Zhang, Memorial Sloan Kettering Cancer
Center, New York, NY). The appropriate band was cut and cleaned using centrifugal filter units (Millipore, Billerica, Spain). The
PCR product was sequenced with forward and reverse primers at the Mayo
Molecular Biology Sequencing Core Facility. The clonal VL gene used was
determined if one gene was clearly overrepresented in each patient and
the CDR3 region was identical for 3 to 7 separate products. Additional
PCR amplification was done using the appropriate 5' leader region
primers (VL) along with the individual 3' CL primers,
because of the possibility of small errors in the sequence being
introduced by the FR1 primers. VL genes with the correctly sequenced
FR1 regions were evaluated for their homology to germ-line donor
sequences, which also provided information on somatic hypermutation (R.S.A. et al, manuscript in preparation).
Classification of VL genes The sequences obtained by the methods described in the previous paragraph were analyzed using the National Center for Biotechnology Information (NCBI) BLAST (Basic Local Alignment Search Tool) program and DNAPLOT (Hans-Helmar Althaus, Werner Muller, Koln, Germany), and assignation of germ-line donors was done using a database of rearranged immunoglobulin genes, V-BASE, based on comparison of sequences for maximum nucleotide homology. The homology analysis was undertaken for complete VL gene sequences with the exception of the codons that form the VJ junction and the last FR segment (FR4). All sequences obtained were submitted to GenBank (AF 490906-490969).Statistical analysis Patient selection.
Patients were selected based on a stratified sampling approach. The
intention of this strategy was to select approximately equal numbers of
both Correlation of light chain V gene use with clinical presentation.
The correlation between VL gene usage and clinical presentation in AL
patients was assessed by 2-sample t tests and Wilcoxon rank
sum tests for continuous variables and Survival analyses Overall survival was defined as the time from the date of diagnosis of amyloidosis to the date of death due to any cause and was estimated using the Kaplan-Meier method. Survival differences for various factors were assessed univariately using the 2-tailed log-rank test. The criteria for evaluating survival in this cohort of AL patients included light chain diagnosis, VL gene usage, dominant clinical presentation, and sex. The survival analysis was not statistically significant in all the categories assessed, which was likely due to the small sample size. Survival analysis was also done for the larger group of patients in the overall database. These analyses had sufficient power to detect meaningful differences, but only on the limited number of variables of interest collected in the database.All P values represented are 2-sided, and statistical significance was declared at a P value of .05 or less. Because these analyses were exploratory in nature, multiple comparison corrections were not used.
Selection of AL patients The 60 AL patients were selected from a larger group of 1962 patients representing the AL patients seen at the Mayo Clinic over a period of 19 years (1982-2001). To ensure the lack of a selection bias in choosing these patients the subset group was compared with the overall group for certain key clinical and biochemical criteria. The subset was not significantly different from the overall group except for light chain usage (P = .001), which was a reflection of the deliberate selection of patients with AL amyloid. In this
study, equal numbers of and patients were chosen, as there is
little information available on VL usage and clinical presentation in
AL patients in the body of published literature. The subset and
overall groups were compared for clinical presentation, frequency of
MM, and overall survival (Tables
1-3).
None of the standard biochemical markers were significantly different between the groups indicating that the subset group, which was randomly chosen, was comparable with the total database. The subset was also evaluated for the presence of serum and urine M-protein by immunofixation with 51 and 54 of 60 patients, respectively, being positive. The patients were also stratified on the basis of the monoclonal protein they expressed either in serum or urine. Most patients (47%; 28/60) had less than 10% plasma cells in their BM, whereas 32% (19/60) had between 10% to 20% plasma cells and 22% (13/60) had more than 20% plasmacytosis. Clinical features of the subset group More than half the patients (63%; 38/60) had 2 or more organs affected by severe amyloid deposition, whereas 35% (21/60) had 1 organ involved. Only one patient had no evidence of systemic disease with only BM staining positive for light chain amyloid. The dominant clinical manifestation at diagnosis was renal disease with 43% of the patients affected. The remainder of the patients presented with cardiac (30%) or soft-tissue, hepatic, neurologic, pulmonary, or GI amyloid. The breakdown of the 60 patients into clinical categories revealed that approximately half the patients had renal (50%) and/or cardiac involvement (52%). The findings were consistent with MM in 18% (11/60) of patients. BM plasmacytosis higher than 10% and anemia, hypercalcemia, or lytic bone disease (9/11) was present. Pulmonary disease was present in only 2 AL patients.Identification of the clonal VL gene in AL The dominant V or V gene family was identified as described
earlier by RT-PCR and DNA sequencing using V and V
family-specific primers. Of the 28 patients selected, we were
unable to identify a dominant clonal V family in 2 patients. This
may have been because there were too few plasma cells in the sample,
and consequently these patients were excluded from further analyses.
Most patients used the V I family (77%; 20/26), whereas the
remainder (19%; 5/26) used the V IV gene family. Only 1 patient of
the 26 used the V II family. In the group, the V I patients
primarily used 2 germ-line
genes,
O18/O8 (9 patients) and O12/O2 (4 patients) (Figure 1A; Table
4
). The V I donor, LVFK 431, which has been reported as
being commonly used in AL patients10 was used in only
one patient in our cohort. The remaining 6 V I patients used either
L12 or L1 germ-line genes. The single V II
patient used the L5 gene, whereas the V IV patients (5 patients) all used the B3 germ-line donor (Figure 1A; Table
4). In the patients, the J 2 gene was used by most patients followed by J
4 (data not shown).
In the Association between VL gene usage and symptomatic organ involvement A natural corollary to the observation of a bias in VL gene usage leading to AL was the correlation with the clinical presentation, in terms of organs affected by amyloid deposition. There was a sex bias with 18 of the 26 and 21 of the 32 patients being male. On
correlating organ involvement with VL gene usage, certain trends were
observed. There were 3 major clinical categories
identifiedcardiac, renal, and "other," comprising GI, pulmonary,
hepatic, neurologic (autonomic), and soft-tissue (macroglossia, skin
involvement, and carpal tunnel syndrome) AL.
Patients in each VL family subgroup were assessed for clinical
presentation. V
Among the The data shown in Table 5 outline the proportion of patients in each
specific light chain variable gene family (VL family or group) with
defined organ involvement. However, it was also useful to assess
clinical presentations in the
Correlation of urine or serum M-protein with clinical presentation Urine M-protein levels were significantly lower in patients with dominant cardiac presentation compared with those who did not present with cardiac disease (medians: 0.0915 and 0.4375 mg/dL, respectively; P = .0145). As expected however, urine M-protein levels were significantly higher in patients with dominant renal presentation than in those without primary kidney amyloid manifestation (medians: 0.5825 and 0.0605 mg/dL, respectively, P = .0004). In fact, patients who had any form of renal amyloid deposition, even if it was not the primary organ affected, had significantly higher urine M-protein levels than those who had no kidney disease (medians: 0.4700 and 0.0560 mg/dL, respectively; P = .0022). Interestingly, there was a significant difference between serum M protein levels in and patients (medians: 0.50 and 0.90 g/dL, respectively; P = .03) (data not shown). However, this difference may
merely be a reflection of reduced renal clearance because light
chains preferentially exist as dimers and, in some instances, can form even larger aggregates.20 The correlation between serum
and urine M-protein with VL germ-line genes was analyzed and did not reveal any statistically significant findings (data not shown).
Correlation of organ involvement with overall survival Survival analyses were done using log-rank statistics and Kaplan-Meier estimation methods to determine if sex, clinical presentation (organs affected by amyloid deposition), and V or V
gene usage affected survival of AL patients. Because of the small
numbers of patients in the various subcategories, the power to detect statistically significant differences was low, particularly with VL
germ-line gene use and survival; however distinct trends were observed
that may be of clinical relevance. In general, for the survival
analyses on the subset of patients, we had at least 80% power to
detect significant differences in survival if one group was at 3 times
greater risk of death than another, assuming that the breakdown of risk
groups was 20% to 80%. The power increased with more balanced numbers
in the subgroups. Depending on the proportionality of patients with a
marker of interest (eg, V VI), as many as 100 to 150 patients would
be required for at least 80% power to detect a 2-fold risk for one
group with the marker of interest versus those without it. If the
proportion of those with the marker is 35% to 50%, then it would be
anticipated that 100 patients would be sufficient; otherwise, if the
proportion is 20% to 35%, then at least 150 patients would be
required. The use of or light chains did not significantly
affect clinical outcome in the subset of AL patients (Figure
3A).
Despite the small numbers of patients using each germ-line VL gene, it
was observed that patients using the V IV gene family, which in our study was associated with cardiac AL, showed a reduction in overall survival (Figure 3B). The V II family also associated with cardiac AL showed a similar decrease in survival (Figure 3C). There was evidence to suggest that use of the V VI germ-line gene had a favorable prognosis as the majority of these patients had renal disease
(Figure 3C). The V I family of genes also correlated with stable
disease and enhanced survival. Sex influenced survival, with females
living longer than males (4.3 years vs 1.4 years, P = .02). Also, by univariate analysis, the presence of
cardiac (1.9 years vs 3.0 years, P = .87) and renal (4.3 years vs 1.1 years, P = .44) involvement affected survival
(Figure
4).
Patients who had coexisting AL amyloidosis with MM had a poorer
prognosis, with a median survival of 1.1 years (versus 2.92 years, P = .81) (Figure 4).
As the Mayo AL database had a larger number of patients with the
relevant clinical information, survival analyses were done on this
group of patients using 3 major clinical presentations as a read-out.
The presence of cardiac (0.9 years; P = < .0001), neurologic (1.4 years; P = .013), and renal (2.5 years;
P = < .0001) disease significantly affected clinical
outcome (data not shown). However, the use of either One of the most notable findings in our study was the strong
correlation of the V
The primary objective of this study was to analyze the
immunoglobulin light chain variable gene (VL) repertoire used by the clonal B cell in AL Clonal analysis of the most commonly used light chain V gene families
in the 58 patients studied revealed a predominance of V To test our hypothesis and accurately evaluate correlations between
light chain V gene use leading to AL and the organ specificity of
amyloid deposition, it was important to determine first whether individual germ-line genes were overrepresented in the AL population. The frequency of use in the germ-line repertoire has been characterized in the circulating peripheral B-cell pool in healthy
individuals24-27; however, this does not permit
comparisons with the BM B-cell population in AL patients. More
recently, however, the germ-line genes used by polyclonal B cells in
normal BM has been described.12 From the normal BM
analysis12 it appears that difference between the normal
and AL B-cell repertoire lies not so much in the V gene family but in
the specific germ-line donor used.12 There is considerable
evidence suggesting a predominance in the use of the V In the It is possible to speculate that there are a variety of factors that
may account for the skewing of the VL genes used in AL, including
events in the selection of the primary antibody repertoire. It has been
shown that the early B-cell transcription factors, E2A and
EBF, when expressed ectopically along with the recombination activating gene in nonlymphoid cells can induce rearrangement of both Ig heavy and light chain genes.35 The various gene
families are interspersed throughout the V The phenomenon of organ tropism has already been alluded to in a recent
study on light chain variable gene use in AL amyloidosis, with a
correlation suggested between V gene receptor specificity and the
presence of amyloid in various organs.10 The data obtained in the present study support our initial hypothesis by delineating important trends with regard to light chain gene use and organ involvement; however as the numbers of patients in the individual gene
groups were small, the data did not achieve statistical significance in
all instances. There was a strong association between the use of the
V One of the unusual features of AL and a key to understanding its pathophysiology is the diversity of amyloid deposition in various organs.9,37 The heterogeneity of amyloid in organs and, therefore, clinical presentation indicate that deposition may be primarily vascular or interstitial, or both. No apparent relationship has been established between the molecular mass of the protein deposit and the organ affected.38 It is important to bear in mind that despite a dominant organ involvement on presentation, usually other organs are affected by amyloid deposition over time. It is still uncertain whether this selective affinity for tissues is a feature of the primary structure of the light chain inducing a local interaction with the tissue microenvironment or is due to an "antigen recognition" dictated by receptor specificity39 (of these light chains) for certain tissue components. Yet another possibility that may account for the tissue specificity of AL amyloid is the interaction of the amyloidogenic light chains with glycosaminoglycans, in particular heparan sulfate.40 It is interesting to speculate that this specificity may probably come from an association of the amyloid fibrils with tissue-specific isoforms of heparan sulfate. However, it is still unclear whether structural features of the protein, tissue affinity, or plasma cell homing and local production of light chains individually or collectively contributes to the clinical diversity of AL amyloidosis. The effect of light chain use on survival was relevant only insofar as
it correlated with the presence of cardiac and renal amyloidosis. The
use of the V The data presented in this study showed strong concordance with the 2 previously published reports on light chain variable gene use in AL amyloidosis,10,12 suggesting that across different ethnic AL patient groups, there is a large uniformity in the representation of specific germ-line genes in the clonal light chain amyloid B-cell repertoire. The findings reported in this paper as well as the published studies clearly provide evidence of the importance of identifying the clonal light chain variable gene used in AL patients as a tool that could aid in the medical management of this disease. The strong association between VL germ-line genes and specific organ involvement could be used as an adjunct to the chemical analysis of amyloid deposits to determine the clinical course of disease and therefore the nature of therapeutic intervention. The organ specificity of the VL gene usage also suggests that some light chains may be more pathogenic than others and therefore may be appropriate targets for the development of new therapeutic strategies. We are in the process of characterizing the intrinsic ability of light chains to induce organ dysfunction in an organ-specific model system, as well as determining other cellular components of amyloid deposits that may be responsible for the pathogenic changes involved in light chain amyloidosis.
The authors wish to acknowledge Drs Raymond L. Comenzo and Yana Zhang, Memorial Sloan Kettering Cancer Center, New York, for their assistance in the project as well as providing reagents. We also wish to thank Dr Comenzo for critical reading of the manuscript.
Submitted September 4, 2002; accepted December 5, 2002.
Prepublished online as Blood First Edition Paper, December 19, 2002; DOI 10.1182/blood-2002-09-2707.
Supported by the CI-5 Damon-Runyon Clinical Investigator Award of the Damon-Runyon-Walter Winchell Foundation and a Leukemia and Lymphoma Society Translational Research Award (R.F.). This work was also supported in part by Public Health Service grant no. RO1 CA83724-01 (R.F.), the Hematologic Malignancies Fund, Mayo Clinic, and the National Cancer Institute, CA-62242.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Rafael Fonseca or Roshini S. Abraham, Division of Hematology, Stabile 6-28, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; e-mail: fonseca.rafael{at}mayo.edu, abraham.roshini{at}mayo.edu.
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 C. M. Doyle, J. Han, M. G. Weigert, and E. T. L. Prak Consequences of receptor editing at the {lambda} locus: Multireactivity and light chain secretion PNAS, July 25, 2006; 103(30): 11264 - 11269. [Abstract] [Full Text] [PDF]
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 A. M. S. Muller, A. Geibel, H. P. H. Neumann, A. Kuhnemund, A. Schmitt-Graff, J. Bohm, and M. Engelhardt Primary (AL) Amyloidosis in Plasma Cell Disorders Oncologist, July 1, 2006; 11(7): 824 - 830. [Abstract] [Full Text] [PDF]
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R. S. Abraham, K. V. Ballman, A. Dispenzieri, D. E. Grill, M. K. Manske, T. L. Price-Troska, N. G. Paz, M. A. Gertz, and R. Fonseca Functional gene expression analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis Blood, January 15, 2005; 105(2): 794 - 803. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
2 tests were
used to compare sex, treatment status (treatment prior to
being seen at Mayo Clinic), and light chain (
2-microglobulin, serum albumin, and
plasma cell labeling index, 2-sample t tests were used.
