HAEM4Backup:Primary Amyloidosis

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Primary Author(s)*

Heather E. Williams, PhD, MS, PgD, ErCLG

Cancer Category/Type

Mature B-cell neoplasms

Cancer Sub-Classification / Subtype

Monoclonal immunoglobulin deposition disease

Definition / Description of Disease

  • A member of the group of “monoclonal immunoglobulin deposition diseases” that are characterized by visceral and soft tissue deposition of aberrant immunoglobulin (Ig), which subsequently results in organ dysfunction[1][2][3][4][5][6][7][8][9]
  • These monoclonal Ig deposition diseases overlap as clinically similar conditions—but likely represent chemically distinctive manifestations of similar pathological processes, which can be placed into two major categories: 1) primary amyloidosis (detailed herein); 2) light chain and heavy chain deposition diseases[9][10]
  • An acquired systemic amyloidosis, primary amyloidosis or the preferred term “AL amyloidosis,” results from a plasma cell (pc) or in rare instances, a lymphoplasmacytic neoplasm
  • AL amyloidosis is a rare clonal plasma cell dyscrasia, with a particularly devastating clinical phenotype that results from the extracellular amyloid fibril deposition in vital organs[11][12][13]
  • The AL amyloid fibrils derive from N-terminal region of monoclonal immunoglobulin light chains that consist of the whole or part of the variable (VI) domain[14]
    • The structure and unique nature of all monoclonal light chains influences their inherent propensity (for some) to form amyloid fibrils[14]
    • The amyloid formed from monoclonal light chains can exist in a partly unfolded state, which involves loss of tertiary or higher order structures[14]. Amyloids will readily aggregate in the ß-sheet structure to create protofilaments and fibril; this process is progressive as a ‘seeding” event serves as a template that facilities further amyloid deposition, which allows expansion of deposition by capturing further precursor molecules[14]

Synonyms / Terminology

  • Immunoglobulin light chain amyloidosis (AL)
  • AL amyloidosis (preferred in recent literature over Primary Amyloidosis, the WHO term)
  • AL amyloidosis (ALA)

Epidemiology / Prevalence

  • AL amyloidosis is an uncommon disorder and its exact incidence is unknown[15]
  • Within the US, the incidence is estimated at 9-14 cases per million person years, but the true prevalence may be higher due to under diagnosis[10][16][17]
  • Considered a disease of the elderly, the incidence of AL amyloidosis increases with age[10][16]
    • A small proportion of patients (~1.3%) are diagnosed under the age of 34, with the median age at diagnosis of 63 years of age[18]
  • There is a male predominance, with men reported in recent studies to account for 55-70% of patients[5][18][19]
  • There is limited data regarding AL amyloidosis incidence across ethnic populations, however, the disease is known to occur in all races and geographical regions[9]

Clinical Features

  • The signs and symptoms that raise the clinical suspicion for a possible diagnosis of amyloidosis are generally nonspecific; therefore, the establishment of an AL amyloidosis is difficult and is highly reliant upon a clinical suspicion[17]
  • Clinical presentations vary, ranging from more rapidly progressive symptoms to slowly evolving or a paucity of symptoms among others[16]
  • Nearly 25% of patients are diagnosed late, and many present with advanced, irreversible cardiac damage, and often succumb to within 12 months of the diagnosis[12]
  • Clinical presentations generally relate and are of a consequence of amyloid in organs and tissues, and it is often the presentation of symptoms within a particular organ that predominate, which initiates the diagnosis[12][17]
  • Signs of the disease in the early stages include peripheral neuropathy (~15-20%), carpal tunnel syndrome (~21%), and bone pain (~5%)[9]. Other major symptoms, in addition to the extremely common presenting symptoms of fatigue and weight loss, relate to congestive heart failure (~15-20%), nephrotic syndrome (~28%), or malabsorption (~5%) are common[5][9]
  • Physical observations include hepatomegaly (~25-30%), macroglossia (~10%), and purpura, commonly of periorbital or facial presentation (~15%)[5]
  • Individuals with congestive heart failure or nephrotic syndrome often present with edema[5]
  • Few patients present with splenomegaly, lymphadenopathy, skin and soft tissue thickening, a hoarse voice (due to vocal cord infiltration), hypoadrenalism or hypothyroidism (due to deposits within the adrenal or thyroid glands, respectively)[20]
  • Overlooking the diagnosis of AL amyloidosis leads to therapy delay, and is a relatively common event, and it represents an error of diagnostic consideration which has resulted in an unsatisfactory survival for patients[15]

Sites of Involvement

  • The accumulation of amyloid light chain progressively disrupts numerous tissues and organs, e.g. subcutaneous fat, kidneys, heart, liver, gastrointestinal tracts, peripheral nervous system, and bone marrow, ultimately leading to organ failure[9]
  • The deposition of amyloid does not evoke (or of little) reaction locally within the tissues, and there is poor correlation between the level of amyloid depositions and the degree of impairment to organ function[14]
  • The morbidity and mortality in AL amyloidosis results from the effects of the toxic monoclonal protein, and impact to cardiac function is a critical determinate of survival[21][22]
  • AL amyloidosis is a progressive and fatal disease, with significant mortality within one year of diagnosis[12][23]

Morphologic Features

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Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Multiple Myeloma (MM). However, notably, the frequency of the [t(11;14)(q13;q32), IGH-CCND1] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and MM. The [t(11;14)(q13;q32), IGH-CCND1] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and MM (15-20%)[9][24]. The [t(11;14)(q13;q32), IGH-CCND1] fusion results from the juxtaposition of the CCND1 proto-oncogene at 11q13 with the immunoglobulin heavy chain (IGH) locus at 14q32[25][26][27].

Characteristic Chromosomal Aberrations / Patterns

Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations[24]. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence in situ Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases[28][29]. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with MM specific probe sets or panels. These panels vary, but may include enumeration of CKS1B (1q21), CDKN2C (1p32), D9Z1/D15Z4 (CEN9, CEN15), RB1 (13q14), TP53 (17p13), and break-apart probes for MYC (8q24.1) or IGH (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common IGH partners: [t(4;14)(p16.3;q32); IGH-FGFR3], [t(6;14)(p21;q32); IGH-CCND3], [t(11;14)(q13;q32); IGH-CCND1], [t(14;16)(q32;q23); IGH-MAF], [t(14;20)(q32;q12); IGH-MAFB]. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), CCND1-IGH aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes[30][31][32][33]. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis[30][31][34]. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(v;14) IGH-v translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and MM often carry gain of CKS1B (1q21), and deletions of 8p21 (PNOC), RB1 (13q14), and TP53 (17p13)[24]. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia[24]. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported[12][35].

Genomic Gain/Loss/LOH

Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see Characteristic chromosomal aberrations /Patterns)[34]. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in MM; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q[36]. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)[34]. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort[34]. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(v;14) IGH-unknown partner[34][37]. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis[36]. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see Gene mutations (SNV/INVDEL)[38].

Gene Mutations (SNV/INDEL)

Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients[34][39][36][40]. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (CDH1) and RCAN family member 3 (RCAN), and the pro-apoptotic genes GLI pathogenesis related 1 (GLIPR1) and Fas cell surface death receptor (FAS) were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (IFITM1) gene known to be associated with the development of aggressive solid tumors was observed[36][41]

Huang et al. (2019) identified four recurrent mutations in an AL amyloidosis cohort using a combination of WES and targeted gene sequencing panels[38]. The recurrent mutations include: ankyrin repeat and SOCS box containing 15 [ASB15 (c.844C>T)], activating signal cointegrator 1 complex subunit 3 [ASCC3 (c.1595A>G)], H1.4 linker histone, cluster member [HIST1H1E (c.311C>T)] and KRAS proto-oncogene, GTPase [KRAS (c.35G >A)][38]. In addition, the presence of these mutations in the ASB15, ASCC3 and HIST1H1E genes were found to be associated with inferior overall survival[38].

Overall, although AL amyloidosis and MM share similarity in recurrent genetic aberrations, the genetic profile of plasma cells in AL amyloidosis  involves substantially fewer genetic alterations (that are largely unique from genes altered in MM) when compared to MM—where the deregulation of ~400 genes has been documented[36][42][43]. Of note, individuals with t(11;14) had a lower total overall aberration burden when compared with other AL amyloidosis groups[34].

Other Mutations

Genetic analysis may be used to distinguish AL amyloidosis from hereditary amyloidosis. Testing for mutations in the transthyretin, fibrinogen Aα‐chain, lysozyme or apolipoprotein A-I genes are associated with hereditary disease. Genetic testing is often necessary as clinical features between diseases may be indistinguishable and family history evaluations may not be reflective given reduced penetrance[44][45].

Epigenomics (Methylation)

Not applicable

Genes and Main Pathways Involved

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Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine[14]. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years[5][12][23]. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease[19][46][47].

To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits[20][48]. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia[14]. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies[14][49]. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens[11][12][50].

Familial Forms

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Other Information

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Links

Monoclonal Immunoglobulin Deposition Diseases

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References

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