What is the management and treatment of amyloidosis?

Management and Treatment of Amyloidosis

The management of amyloidosis requires early diagnosis before irreversible end-organ damage occurs, followed by targeted therapy based on the specific amyloid type, with AL amyloidosis treatment being primarily transplant-driven or bortezomib-based, while TTR amyloidosis requires different targeted therapies. 1

Types of Amyloidosis and Diagnostic Approach

• Amyloidosis is characterized by extracellular deposition of misfolded proteins in tissues, leading to organ dysfunction 2

• Major types include:

  • AL (light chain) amyloidosis - most common, associated with plasma cell disorders 1
  • ATTR (transthyretin) amyloidosis - either wild-type (age-related) or variant (hereditary) 1
  • AA (secondary) amyloidosis - associated with chronic inflammatory conditions 1

• Diagnosis requires:

  • Tissue biopsy (fat pad, bone marrow, salivary gland, or involved organ) with Congo Red staining showing characteristic apple-green birefringence under polarized light 1, 3
  • Typing of amyloid protein using mass spectrometry (gold standard), immunohistochemistry, or immunofluorescence 1, 4
  • Identification of underlying plasma cell clone through bone marrow examination and serum/urine immunofixation 1

Treatment of AL Amyloidosis

Risk Stratification

• Treatment decisions are based on risk stratification using cardiac biomarkers 1
• Mayo staging systems use troponin T and NT-proBNP levels to classify patients into stages I-III 1

ASCT-Eligible Patients (~20%)

• Autologous stem cell transplantation (ASCT) remains the standard of care for eligible patients 1
• Eligibility criteria typically include:
  • Adequate cardiac function
  • Good performance status
  • Limited organ involvement 1
• ASCT may be preceded by bortezomib-based induction therapy 1
• Complete hematologic response occurs in approximately 40% of patients and is associated with prolonged survival 1

ASCT-Ineligible Patients

• Bortezomib-based regimens are the backbone of treatment 1

• Options include:

  • Bortezomib, cyclophosphamide, and dexamethasone (VCD) 1
  • Daratumumab (anti-CD38 antibody) has been recently approved and is becoming part of the standard of care 1
  • Melphalan and dexamethasone - shown to produce hematologic response in 67% of patients 1
  • Lenalidomide and dexamethasone 1, 5

• Treatment goals:

  • Achieve deep hematologic responses (elimination of clonal plasma cells) 5
  • Minimize treatment-related toxicity 5
  • Prevent further organ damage 1

Treatment of ATTR Amyloidosis

• Differentiation from AL amyloidosis is crucial as management differs significantly 1
• TTR cardiac amyloidosis is treated with targeted therapies such as tafamidis 1
• For variant ATTR with polyneuropathy, specific FDA-approved therapies are available 1, 6

Management of Organ-Specific Complications

Cardiac Involvement

• Heart failure management may require careful fluid balance 1
• Neurohormonal antagonists (ACE inhibitors, ARBs, beta-blockers) may be poorly tolerated 1
• Heart transplantation may be considered in select patients without significant extracardiac involvement 1

Renal Involvement

• Manifests as proteinuria, nephrotic syndrome, and progression to end-stage kidney disease 4
• Supportive care includes blood pressure control and eventually dialysis if needed 1
• Renal transplantation may be considered in selected patients 1

Neurologic Involvement

• Peripheral and autonomic neuropathy may require symptomatic management 1
• Severe neurologic involvement may contraindicate heart transplantation 1

Gastrointestinal Involvement

• GI manifestations include early satiety, weight loss, abdominal pain, nausea, constipation, and diarrhea 1, 3
• Management focuses on symptom control and nutritional support 3

Monitoring and Follow-up

• Regular monitoring of:
  • Hematologic response (serum free light chains) 1, 5
  • Organ function (cardiac biomarkers, renal function, liver enzymes) 1
  • Serum amyloid A (SAA) protein and CRP as markers of inflammation 1
• Early detection of relapse/refractory disease is crucial 1

Prognosis

• Without treatment, prognosis is poor - 25% of AL amyloidosis patients die within 6 months of diagnosis 6
• Cardiac involvement is the main driver of disease prognosis and mortality 1
• Deep hematologic responses correlate with improved organ function and survival 5
• Organ response typically lags behind hematologic response 5

Key Pitfalls to Avoid

• Delayed diagnosis - consider amyloidosis in patients with multisystem disorders involving heart, kidney, liver, or nervous system 6
• Misdiagnosis of amyloid type - can lead to inappropriate treatment 2, 4
• Nephrotoxic drugs should be avoided in patients with renal amyloidosis 1
• NSAIDs should be avoided in patients with renal involvement 1