What are the primary types of amyloidosis and their treatments?

Primary Types of Amyloidosis and Their Treatments

The main types of amyloidosis are AL (light chain), ATTR (transthyretin), AA (reactive), isolated atrial, and dialysis-related amyloidosis, each requiring specific treatment approaches based on the underlying protein abnormality. 1

Major Types of Amyloidosis

AL Amyloidosis (Primary/Light Chain)

• Most common type, affecting approximately 10 people per million/year 1
• Caused by increased production of light chain portions of antibodies by plasma cells in bone marrow 1
• Often associated with multiple myeloma or Waldenström's macroglobulinemia 1
• Cardiac involvement occurs in up to 50% of cases 1
• Median survival is approximately 13 months, decreasing to 4 months with heart failure 1
• Extracardiac manifestations include kidney, liver, nervous system, and skin involvement 1

ATTR Amyloidosis (Transthyretin)

• Two subtypes: hereditary and acquired (wild-type) 1

• Hereditary ATTR amyloidosis:

  • Caused by mutation in TTR gene, resulting in abnormal "variant" TTR 1
  • Can manifest as familial amyloid polyneuropathy (primarily affecting nerves) or familial amyloid cardiomyopathy (primarily affecting heart) 1
  • Median survival approximately 70 months 1
  • Extracardiac manifestations include kidney, nervous system, and vision problems 1

• Wild-type ATTR amyloidosis (formerly senile amyloidosis):

  • Normal "wild-type" TTR protein misfolds due to aging 1
  • Common cardiac involvement 1
  • Median survival approximately 75 months 1
  • Affects multiple organ systems 1

AA Amyloidosis (Reactive/Secondary)

• Results from chronic inflammatory or infectious diseases (rheumatoid arthritis, Crohn's disease, ulcerative colitis) 1
• Caused by deposition of amyloid type A protein in organs 1
• Cardiac involvement in less than 10% of cases 1
• Median survival approximately 25 months 1
• Primarily affects kidney and liver 1

Other Types

• Isolated atrial amyloidosis: Limited to heart, caused by atrial natriuretic factor 1
• Dialysis-related amyloidosis: Caused by β2-microglobulin, affecting joints and causing carpal tunnel syndrome 1

Treatment Approaches

AL Amyloidosis Treatment

• Goal: Eradicate pathological plasma cells and remove affected light chains 2

• For transplant-eligible patients:

  • High-dose melphalan followed by autologous stem cell transplantation (ASCT) 2
  • Daratumumab-CyBorD (cyclophosphamide, bortezomib, dexamethasone) as first-line therapy 2
  • Median overall survival exceeds 10 years for patients achieving complete responses after stem cell transplant 3

• For transplant-ineligible patients:

  • Daratumumab-CyBorD as preferred first-line option 2
  • Alternative: CyBorD (cyclophosphamide, bortezomib, dexamethasone) 2

• Medication considerations:

  • Daratumumab (anti-CD38 antibody): FDA-approved for AL amyloidosis; monitor for cardiac toxicities including cardiac failure (12%), arrhythmias (8%), and atrial fibrillation (6%) 2
  • Proteasome inhibitors (bortezomib, carfilzomib, ixazomib): Monitor for heart failure, decreased LVEF, and pulmonary hypertension 2
  • Immunomodulatory agents (lenalidomide, pomalidomide, thalidomide): Require cardiac and renal monitoring 2

ATTR Amyloidosis Treatment

• FDA-approved therapy: Tafamidis for treatment of cardiomyopathy in wild-type or hereditary ATTR amyloidosis to reduce cardiovascular mortality and hospitalization 4
• Other options: RNA-interference agents patisiran and inotersen 3

AA Amyloidosis Treatment

• Focus on controlling the underlying inflammatory or infectious disease 5

Diagnostic Approach

• Accurate diagnosis requires:
  • Serum free light chain assay (sFLC)
  • Serum immunofixation electrophoresis (SIFE)
  • Urine immunofixation electrophoresis (UIFE) 2
• Tissue biopsy with Congo Red staining showing characteristic apple-green birefringence under polarized light 2, 6
• Typing of amyloid protein using mass spectrometry (gold standard), immunohistochemistry, or immunofluorescence 2

Important Clinical Considerations

• Cardiac involvement is the main driver of disease prognosis and mortality 2
• Collaboration between hematologists, cardiologists, and nephrologists is crucial 2
• Differentiation between AL and ATTR amyloidosis is essential as management differs significantly 2
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma 2
• Close monitoring for cardiac decompensation during therapy is essential 2

Common Pitfalls

• Delayed diagnosis is common and detrimental to outcomes 3, 7
• Misdiagnosis between different types of amyloidosis can lead to inappropriate treatment 6
• Standard protein electrophoresis (SPEP/UPEP) alone has insufficient sensitivity for AL amyloidosis diagnosis 2
• No absolute contraindications to plasma cell-directed therapies exist based solely on ejection fraction or cardiac status in AL cardiac amyloidosis 2
• Amyloidosis should be considered in patients with multisystem disorders involving heart, kidney, liver, or nervous system 7