Amyloidosis medical therapy

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• Primary amyloidosis

• Secondary amyloidosis

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• Wild-type (senile) amyloidosis

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• Beta-2 microglobulin related amyloidosis

• Gelsolin related amyloidosis

• Lysozyme amyloid related amyloidosis

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• 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[edit | edit source]

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[edit | edit source]

### Primary Amyloidosis (AL):[edit | edit source]

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.[1]

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[2]

* RNA interference therapy
* Inhibits hepatic synthesis of transthyretin

* 0.3mg/kg weekly

Dyspepsia, dyspnea, erythema, bronchitis, blurry vision

Daratumumab[3]

* 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):[edit | edit source]

* 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:[4]

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):[edit | edit source]

* 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.[5]
* 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):[edit | edit source]

* 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.[6]
* 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.[7]
* Genetic counseling is recommended for individuals with hereditary amyloidosis and their family members.

### Dialysis-related amyloidosis (β2-microglobulin)[edit | edit source]

* 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.

## References[edit | edit source]

1. ↑ Milani P, Merlini G, Palladini G (2018). "Novel Therapies in Light Chain Amyloidosis". Kidney Int Rep. 3 (3): 530–541. doi:10.1016/j.ekir.2017.11.017. PMC 5976806. PMID 29854961.CS1 maint: Multiple names: authors list (link)
2. ↑ Adams D, Suhr OB, Dyck PJ, Litchy WJ, Leahy RG, Chen J; et al. (2017). "Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy". BMC Neurol. 17 (1): 181. doi:10.1186/s12883-017-0948-5. PMC 5594468. PMID 28893208.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
3. ↑ van de Donk NW, Janmaat ML, Mutis T, Lammerts van Bueren JJ, Ahmadi T, Sasser AK; et al. (2016). "Monoclonal antibodies targeting CD38 in hematological malignancies and beyond". Immunol Rev. 270 (1): 95–112. doi:10.1111/imr.12389. PMC 4755228. PMID 26864107.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
4. ↑ Papa R, Lachmann HJ (2018). "Secondary, AA, Amyloidosis". Rheum Dis Clin North Am. 44 (4): 585–603. doi:10.1016/j.rdc.2018.06.004. PMID 30274625.
5. ↑ Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M; et al. (2018). "Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy". N Engl J Med. 379 (11): 1007–1016. doi:10.1056/NEJMoa1805689. PMID 30145929.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
6. ↑ Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M; et al. (2018). "Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy". N Engl J Med. 379 (11): 1007–1016. doi:10.1056/NEJMoa1805689. PMID 30145929.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK; et al. (2018). "Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis". N Engl J Med. 379 (1): 22–31. doi:10.1056/NEJMoa1716793. PMID 29972757.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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