Amyloidosis medical therapy

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Classification • Primary amyloidosis • Secondary amyloidosis • Familial amyloidosis • Wild-type (senile) amyloidosis • Cardiac amyloidosis • Beta-2 microglobulin related amyloidosis • Gelsolin related amyloidosis • Lysozyme amyloid related amyloidosis • Leucocyte cell-derived chemotaxin 2 related amyloidosis • Fibrinogen A alpha-chain associated amyloidosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

Overview

There are few available treatments for primary amyloidosis. Since the disease is typically discovered at an advanced stage, the initial treatment is aimed at preventing further organ damage and correcting the effects of organ failure.

Medical Therapy

Primary Amyloidosis (AL):

Some patients with primary amyloidosis respond to chemotherapy focused on the abnormal plasma cells. A stem cell transplant may be done, as in multiple myeloma.

• The initial step in the treatment of this disorder is to correct the organ failure, since the disease is discovered at an advanced stage when multiple organ systems may be affected.
  • Nephrotic syndrome is treated using supportive therapy and diuretics.
  • Renal failure is treated with dialysis.
  • Heart failure is treated using diuretics.
  • Gastrointestinal and nerve involvement are treated symptomatically.

The most commonly used regimen for AL amyloidosis is CyBorD, which consists of cyclophosphamide, bortezomib, and dexamethasone.

Therapy	Mechanism of Action	Dosing	Adverse Effects
Bortezomib	Reversibly inhibits the 26S proteasome, preventing recycling of proteins and inducing cell cycle arrest and apoptosis	Cycles 1-4: 1.3mg/m2 IV/SC on days 1, 4, 8, 11, 22, 25, 29, 32 Cycles 5-9: 1.3mg/m2 IV/SC on days 1, 8, 22, 29	Peripheral neuropathy, VZV reactivation, hepatic impairment, asthenia, diarrhea, nausea, constipation, arthralgia, edema, dizziness
Dexamethasone	Suppresses polymorphonuclear leukocytes Inhibits prostaglandins and proinflammatory cytokines Suppresses lymphocyte proliferation	40mg PO weekly	Infections, immunosuppression, bone loss, cataract formation, glaucoma, muscular atrophy
Melphalan	Inhibits DNA and RNA synthesis Crosslinks DNA and causes DNA replication failure	6mg PO daily for 2-3 weeks, OR 10mg PO daily for 7-10 days, OR 0.15mg/kg daily PO for 7 days, THEN 1-3mg or 0.05mg/kg PO daily after counts recover	Myelosuppression, nausea, vomiting, pulmonary fibrosis, stomatitis
Cyclophosphamide	Alkylating agent Crosslinks DNA and causes DNA replication failure	40-50mg/kg weekly	Myelosuppression, nausea, vomiting, hemorrhagic cystitis, secondary malignancies
Patisiran	RNA interference therapy Inhibits hepatic synthesis of transthyretin	0.3mg/kg weekly	Dyspepsia, dyspnea, erythema, bronchitis, blurry vision
Daratumumab	Anti-CD38 monoclonal antibody Depletes B lymphocytes and plasma cells	16mg/kg weekly for weeks 1-8, then every 2 weeks for weeks 9-24, then every 4 weeks thereafter	Anemia, neutropenia, false positive indirect Coomb's test, infusion reaction, lymphopenia

Treatment options with limited success include melphalan, prednisone, and colchicine.

Secondary Amyloidosis (AA):

• Medical or surgical treatment of the underlying chronic infection or inflammatory disease is recommended among all patients who develop AA amyloidosis.
• Aggressively treating the disease that is causing the excess amyloid protein can improve symptoms and slow down or halt the progression of the disease.
• Complications such as heart failure, renal failure, and other problems can sometimes be treated, when needed.
• Although the choice of therapy depends on the underlying cause of chronic inflammation, the aim is always to suppress production of SAA to within the normal range.
• Examples of treatments for the commonest disorders underlying AA amyloidosis:

Underlying Condition	Treatment Options	Examples
Inflammatory arthritis	Conventional disease-modifying agents	Gold Hydroxychloroquine sulfasalazine Azathioprine Methotrexate
	Other immunosuppressant agents	Cyclosporine Cyclophosphamide Mycophenolate Leflunomide
	Biologic agents	Infliximab Etanercept Adalimumab Tocilizumab Rituximab
Periodic fevers	On-demand agents	Nonsteroidal anti-inflammatory drugs Prednisone
	Colchicine (for familial mediterranean fever)	Colchicine
	Biologic agents	Anakinra Canakinumab
Inflammatory bowel disease	Conventional disease-modifying agents	Sulfasalazine Mesalazine Azathioprine Methotrexate
	Biologic agents	Infliximab Adalimumab
	Antibiotics	Metronidazole Ciprofloxacin Azithromycin
	Biologic agents	Infliximab Adalimumab
	Surgery	ileo-cecal resection and primary reconstruction
Immunodeficiency	Immunoglobulins
	Antibiotics	Cotrimoxazole Miconazole
Chronic infections	Antibiotics and surgery
	Physiotherapy (in case of bronchiectasis)
Immunodeficiency	Immunoglobulins
	Antibiotics	Cotrimoxazole Miconazole
Neoplasia	Chemotherapy and surgery	Varies according to type of cancer
	Biologic agents (in Castleman disease)	Tocilizumab

• Long-term inflammatory control can be accompanied by gradual regression of amyloid deposits and improvement in renal function.
• Currently a second clinical trial is in progress in order to evaluate a targeted inhibitor molecule, Kiacta, in the management of secondary amyloidosis.
• Novel therapies aimed at promoting clearance of existing amyloid deposits soon may be an effective treatment approach.

Wild-Type or Senile Amyloidosis (ATTRwt):

• Treatment is generally aimed at the symptoms of wild-type ATTR amyloidosis, such as treating amyloid deposits in the heart.
  • Because the heart is the most commonly affected organ, your disease will be monitored and treated by a cardiologist.
• For some patients with severe wild-type (senile) ATTR amyloidosis, a heart transplant may be the best option. Stanford is one of the world's leading centers for heart transplantation for amyloidosis.
• In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo.
• In ATTRwt amyloidosis, therapy is supportive, but both for this disease and for ATTR, pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated.

Familial Amyloidosis (ATTR):

• The optimal therapy for familial amyloidosis is removal of the source of abnormal TTR production.
  • The liver is the dominant source of transthyretin; hence, in patients with less advanced disease, liver transplant may be performed.
  • Patients with severe heart involvement may benefit from a heart transplant.
• In addition, multiple clinical trials are now testing medications that may slow or halt progression of familial ATTR amyloidosis.
  • Tafamidis is a drug recently approved for familial amyloid polyneuropathy (FAP) in Europe.
    • This agent is being tested in ongoing trials for other forms of ATTR.
  • Patisiran and Inoteresen are TTR gene silencers. Recently FDA approved their use for ATTRm amyloidosis with peripheral neuropathy.
• Genetic counseling is recommended for individuals with hereditary amyloidosis and their family members.

Dialysis-related amyloidosis (β2-microglobulin)

• There is no specific medical treatment for DRA.
• However, removal of significant amounts of beta2-microglobulin (beta2-m) may prevent or slow progression of the disease.
• This can be accomplished best by kidney transplantation.
• Other treatment opitons include:
  • Hemodialysis with a biocompatible high-flux dialysis membrane, hemodiafiltration
  • The use of ultrapure dialysate
  • A beta2-m adsorbent column may also result in lowering the level of beta2-microglobulin.
• Kidney transplantation is considered the definitive treatment for DRA in patients with end-stage renal disease.