Recent Advances in Treatment of Amyloidosis

https://meditropics.com/recent-advances-in-treatment-of-amyloidosis/

Prabhakar Yadav*

*PG Resident, Department of Medicine, Lady Hardinge Medical College 

 

Introduction

Amyloidosis is a rare disease that occurs when amyloid proteins are deposited in tissues and organs. Amyloid proteins are abnormal proteins that body cannot break down and recycle as it does with normal proteins. When amyloid proteins clump together, they form amyloid deposits. The buildup of these deposits damages organs and tissues.

Amyloidosis can affect different organs and tissues in different people, and it can affect more than one organ at the same time1. Amyloidosis can be either acquired or inherited, amyloid deposition is remarkably diverse in that it can be localized or systemic, rapidly lethal or merely an incidental finding. Amyloid deposits cause disease when they accumulate in the extracellular space sufficiently to disrupt the structure, integrity and function of affected tissues and organs all share a common core structure of anti-parallel β-strands lying perpendicular to the long axis of the fibril.

A strong cellular machinery happens to chaperon proteins during the process of synthesis and secretion, so that they achieve correct tertiary conformation and function, and to remove proteins that mis-folds. However, genetic mutation, incorrect processing may favour misfolding, with accumulation of abnormal protein function and intracellular or extracellular aggregation.2 This abnormal, highly ordered conformation causes the distinctive physicochemical properties of amyloid fibrils, including their ability to bind molecules of the dye Congo red, resulting in pathognomonic apple-green birefringence when viewed under cross polarized light.

AL or “primary” amyloidosis, in which fibrils are made up of a monoclonal immunoglobulin (Ig) light chain (LC), is most common and most severe form of amyloidosis. AL amyloidosis is generally a systemic disease and can have multiple organ and tissue involvement. Less frequently, it presents as a local disorder, limited to a single organ

Management

Management of amyloidosis includes early diagnosis and treatment. Ideally treatment should be started before irreversible organ damage has occurred. After making diagnosis of AL amyloidosis treatment should be decided based on efficacy of regime, clinical profile of patients, aim of treatment in AL amyloidosis is to reduce the supply of misfolded amyloid-forming monoclonal free light chains by suppressing the plasma cell dyscrasia while using supportive measures to preserve target organ function.

Treatment of AL amyloidosis  can be high dose melphalan or autologous stem cell transplant(ASCT), Daratumumab, alkylating agent(melphalan, cyclophosphamide), oral melphalan in combination with dexamethasone, bendamustine, proteosomes inhibitor(bortezomib, ixazomib), anti-serum amyloid p component, Immunomodulatory drugs( thalidomide, lenalomide).3

Options for treatment of AL amyloidosis include traditional chemotherapy as well as high-dose melphalan, followed by autologous stem cell transplantation (ASCT) but only about 20% of patients are candidates for ASCT on initial presentation. For those with good performance status and ≤10% plasma cell burden at presentation, proceeding directly to ASCT without any induction is an option, but induction chemotherapy prior to transplant has been shown to improve progression. For transplant-ineligible patients, melphalan and dexamethasone has been standard, however, bortezomib-based induction regimens, which are generally well tolerated and efficacious, has shown to be more effective. A randomized phase 3 trial comparing melphalan and dexamethasone with or without bortezomib demonstrated improved hematologic responses in 81% of subjects with triple drug therapy in contrast to 57% when bortezomib was omitted. The three-drug regimen of cyclophosphamide rather than melphalan in combination with bortezomib and dexamethasone(CyBorD) is more commonly used in the USA. The ANDROMEDA study, a large phase 3 randomized trial, was designed to improve upon the standard of care by comparing CyBorD with or without the addition of the anti-CD38 monoclonal antibody daratumumab4

Usually, we start treatment either on high dose melphalan, or ASCT. If plasma cells are more than 10 % than induction therapy should be added in form of 3 drugs bortezomib, lenalidomide, and low dose dexamethasone.5  These drugs do not reverse the buildup of amyloid proteins in tissues or organs, they may help the organs affected by amyloidosis work better. Without treatment survival is 1-2 years and with cardiac involvement even less4. The hematological response should be checked by serial measurements of serum free LC regularly.           

References

  1. https://www.niddk.nih.gov/health-information/kidney-disease/amyloidosis#:~:text=Kidney replacement therapy.,feel better and live longer.
  2. Lachmann HJ, Hawkins PN. Systemic amyloidosis. Current opinion in pharmacology. 2006 Apr 1;6(2):214-20.
  3. John L. Berk, Amyloidosis. In: Joseph Loscalzo, Dennis L. Kasper, Dan L. Longo, Anthony S. Fauci, Stephen L. hauser, J.Larry Jameson, editor. Harrison’s principles of internal medicine. 21st New York: Mc Graw Hill; 2022. P. 878
  4. Sanchorawala V. High-dose melphalan and autologous peripheral blood stem cell transplantation in AL amyloidosis. Acta Haematologica. 2020;143(4):381-7.
  5. Bianchi G, Zhang Y, Comenzo RL. AL amyloidosis: current chemotherapy and immune therapy treatment strategies: JACC: CardioOncology state-of-the-art review. JACC: CardioOncology. 2021 Oct 1;3(4):467-87.