Update on treatment of light chain amyloidosis

Abstract

Light chain amyloidosis is the most common type of amyloidosis as a consequence of protein misfolding of aggregates composed of amyloid fibrils. The clinical features are dependent on the organs involved, typically cardiac, renal, hepatic, peripheral and autonomic neuropathy and soft tissue. A tissue biopsy or fat aspirate is needed to confirm the presence/type of amyloid and prognostic tools are important in a risk stratified approach to treatment. Autologous stem cell transplant eligibility should be assessed at baseline, weighing the reversible or non-reversible contraindications, toxicity of treatment and chemotherapy alternatives available. Chemotherapy options include melphalan, thalidomide, bortezomib, lenalidomide, bendamustine in combination with dexamethasone. Many studies have explored these treatment modalities, with ongoing debate about the optimal first line and sequential treatment thereafter. Attaining a very good partial response or better is the treatment goal coupled with early assessment central to optimizing treatment. One major challenge remains increasing the awareness of this disease, frequently diagnosed late as the presenting symptoms mimic many other medical conditions. This review focuses on the treatments for light chain amyloidosis, how these treatments have evolved over the years, improved patient risk stratification, toxicities encountered and future directions. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n S. Mahmood et al.210 haematologica | 2014; 99(2) rectum or abdominal fat aspirate (the latter being an easy bedside procedure available for all patients including those with hemostatic impairment). 7 Fibril typing is critical in deciding appropriate therapy and performed by immunohistochemistry (widely available but specific only in 75-80% of cases of AL), 8 immunoelectron microscopy (highly specific but limited availability), 9 or lately, mass spectrometry of amyloid deposits obtained by laser capture (rapidly becoming an invaluable adjunct) 10 ( Figure 2). Detecting the underlying clone requires serum and urine electrophoresis and immunofixation, serum free light chain analysis, bone marrow examination and imaging for presence of myeloma-related bone disease.Base-line assessment of organ function (Table 2) is ECG showing small QRS complexes and late gadolinium enhancement of cardiac MRI. The pre-fibrillar light chain aggregates (and possibly the misfolded light chains) can have direct tissue toxicity. Cardiac toxicity of light chains appears to be a significant contributor to myocardial dysfunction seen in AL amyloidosis. This may also be the reason for rapid improvement in NT-proBNP which parallels a hematologic response to therapy often without any evidence of structural cardiac improvement but correlating with clinical improvement in the patients' cardiac symptoms. © F e r r a t a S t o r t i F o u n d a t i o nimportant for prognosis and selection of therapy. Formal testing for autonomic and peripheral neuropathy may be needed in selected cases. 123I labeled s...

Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case–control study on 174 patients

“…particularly cardiac dysfunction, not only directly affecting patients' survival but also limiting the possibility of employing effective regimens. 9,45 In the present study, we analyzed two cohorts of patients with AL amyloidosis matched for all the most important disease-related prognostic factors. All the 87 patients diagnosed at our center and treated with BMDex frontline during the study period were included.…”

First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction

“…[3][4][5] Amyloid accumulation progressively affects organ structure and function, 2 but diagnosis is often delayed because subtle symptoms at onset mimic those of common conditions. 2 For patients with cardiac amyloidosis, the extent of cardiac involvement is a major outcome determinant; most deaths are attributed to cardiac involvement, and survival is poor with advanced involvement. 1,2,6 No therapies for AL amyloidosis have received regulatory approval, and optimal treatment regimens remain undefined.…”

“…2 For patients with cardiac amyloidosis, the extent of cardiac involvement is a major outcome determinant; most deaths are attributed to cardiac involvement, and survival is poor with advanced involvement. 1,2,6 No therapies for AL amyloidosis have received regulatory approval, and optimal treatment regimens remain undefined. 7,8 Options include high-dose chemotherapy with autologous stem cell transplant, alkylating agents, steroids, proteasome inhibitors, and immunomodulatory drugs.…”

“…1 In immunoglobulin light chain (AL) amyloidosis, the most common form of systemic amyloidosis, 1 the amyloidogenic protein is a misfolded light chain or light chain fragment produced by clonal plasma cells. 1,2 Amyloid aggregates can affect multiple organs, including the heart (approximately 70% of patients), kidneys (70%), liver (17%), soft tissue (17%), nervous system (15%), and gastrointestinal tract (10%). [3][4][5] Amyloid accumulation progressively affects organ structure and function, 2 but diagnosis is often delayed because subtle symptoms at onset mimic those of common conditions.…”

The Evaluation of Amyloidosis Cases with Renal Involvement: A Single-Center Experience

“…Fibriller monoklonal hafif zincir fragmanlarından oluşmaktadır. Beyin dışında bütün organları tutabilir ve genellikle kötü seyirlidir (7,8).…”