AL Amyloidosis: Advances in Diagnostics and Treatment

Abstract and Introduction

Abstract

AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and which still has unsatisfactory survival of patients. The monoclonal light chains kappa (κ) or lambda (λ) or their fragments form the fibrils that deposit and accumulate in different tissues. Renal involvement is very frequent in AL amyloidosis and can lead to the development of nephrotic syndrome followed by renal failure in some cases. AL amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment, the importance of an early diagnosis of amyloidosis and correct assessment of its type is high. Histologic confirmation is based on Congo red detection of amyloid deposits in tissues but AL amyloidosis must also be distinguished from other systemic forms of amyloidoses with renal involvement, such as AA amyloidosis, amyloidosis with heavy chain deposition, fibrinogen Aα or ALECT2 (leukocyte chemotactic factor 2) deposition. Immunofluorescence (IF) plays a key role here. IF on formalin-fixed paraffin-embedded tissue after protease digestion, immunohistochemistry or laser microdissection with mass spectrometry should complete the diagnosis in unclear cases. Standard treatment with melphalan and prednisolone or with cyclophosphamide and dexamethasone has been replaced with newer drugs used for the treatment of multiple myeloma—bortezomib, carfilzomib and ixazomib or thalidomide, lenalidomide and pomalidomide. High-dose melphalan supported by autologous stem cell transplantation remains the therapeutic option for patients with low-risk status. These new treatment options prolong survival from months to years and improve the prognosis in a majority of patients.

Introduction

Amyloidoses are disorders of diverse aetiology in which deposits of abnormally folded proteins with fibrillar ultrastructure infiltrate extracellular spaces of affected organs. Currently, >32 different proteins (and many more variants) are known to be involved in amyloidoses and additional protein types are continually being added to this list. The International Society of Amyloidosis initiated development of a modern nomenclature of amyloidoses, which is based on the type of protein involved. The latest version was published in 2014^[1] and the most frequent systemic amyloidoses are described in Table 1.

AL amyloidosis is a result of clonal plasma cell disorder with an incidence of ~10 persons per million per year.^[2] The disease is caused by a usually small and low proliferating bone marrow plasma cell clone (infrequently a B-cell clone) secreting an unstable, amyloidogenic immunoglobulin light chain (LC).^[3] The probability of AL amyloidosis occurrence significantly increases with age and people >65 years are at the highest risk. It is the most common and most severe form of systemic amyloidosis. Amyloid deposits containing LCs infiltrate the tissues and can cause their dysfunction and failure. The most frequently affected organs are kidneys (74%), heart (60%), gastrointestinal tract (10–20%), liver (27%) and autonomous nervous system (18%). At the time of diagnosis, 69% of patients have more than one affected organ.^[4] There is no doubt that cardiac involvement is the main prognostic determinant in AL amyloidosis and the leading cause of death, if diagnosed late and not responding to therapy, in a majority of patients.^[5] The optimal management of patients with AL amyloidosis requires an early diagnosis, correct assessment of the type of amyloid, effective treatment with supportive therapy and very careful follow-up.

Table 1. The most frequent forms of systemic amyloidoses (nomenclature, fibril proteins and precursors)
Amyloid protein	Precursor	Systemic (S) or localized (L) form	Syndrome or involved organs
AL	Monoclonal immunoglobulin LCs	S (L)	Primary amyloidosis (plasma cell dyscrasias associated)
AH	Monoclonal immunoglobulin heavy chains	S	Systemic amyloidosis (plasma cell dyscrasias associated)
AA	Serum amyloid A	S	Secondary (reactive) amyloidosis
ATTR	Transthyretin—wild type	S	Senile systemic amyloidosis with prominent cardiac involvement
ATTR	Genetic variants of transthyretin	S	Familial amyloid polyneuropathy or hereditary amyloid cardiomyopathy
Aβ₂M	β₂-microglobulin	S	Dialysis associated
ACys	Cystatin C	S	Cerebral amyloid angiopathy (Island type)
AApoAI	Apolipoprotein AI	S	Familial (visceral involvement)
		L	Aorta
AApoAII	Apolipoprotein AII	S	Familial (kidney, heart)
AApoAIV	Apolipoprotein AIV—wild type	S	Sporadic systemic amyloidosis associated with ageing
AGel	Gelsolin	S	Familial (Finnish type)
ALys	Lysozyme	S	Familial (kidney, liver, spleen)
AFib	Fibrinogen Aα-chain	S	Familial (predominant kidney involvement)

Table 2. Indications for mass spectrometry investigation in patients with AL amyloidosis
Absence of tissue available for IF microscopy
Negative IF staining for kappa and lambda LCs together with negative immunohistochemical staining for serum amyloid A protein
Equal IF staining for both kappa and lambda LCs
Strong IF staining for immunoglobulin heavy chains, with or without LC staining
Positive IF staining for kappa and/or lambda LCs together with positive immunohistochemical staining for serum amyloid A protein
Equivocal Congo red staining

Modified from Said et al. [9].

Table 3. Definition of haematologic and cardiac response and progression
Type of response	Definition
Haematologic response
CR	Negative serum and urine immunofixation and normal FLC κ/λ ratio
VGPR	dFLC <40 mg/L
Partial response	dFLC decrease >50% (assessable in patients with baseline dFLC ≥50 mg/L)
No response	Other
Cardiac response and progression
NT-proBNP response	>30% and >300 ng/L decrease if baseline NT-proBNP≥650 ng/L
NT-proBNP progression	>30% and >300 ng/L increase
cTn progression	≥33% increase
NYHA class response	≥two-class decrease if baseline NYHA Class 3 or 4
EF progression	≥10% decrease
Standard staging system [26]: The system is based on NT-proBNP (cut-off point 332 ng/L) and cTnT (cut-off point 0.035 ng/mL). Stage I, II and III patients have none, one or two markers above the cut-off points, respectively. Revised staging system [27]: The revised staging system is based on NT-proBNP (cut-off point 1800 ng/L), cTnT (cut-off point 0.025 ng/mL) and dFLC (cut-off point 180 mg/L). Stage I, II, III and IV patients have none, one, two or three markers above the cut-off points, respectively.

The data are a compilation of those given in [24–27].
dFLC, difference in concentration between involved (amyloidogenic) and uninvolved free light chain; NT-proBNP, N-terminal natriuretic peptide type-B; NYHA, New York Heart Association.