What is the treatment for amyloidosis (Amyloid Light-chain (AL) amyloidosis or Transthyretin (ATTR) amyloidosis) in the liver?

Treatment of Amyloidosis in the Liver

The treatment for amyloidosis in the liver depends on the type of amyloidosis, with AL amyloidosis primarily treated with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD), while ATTR amyloidosis is treated with tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg daily). 1

Diagnosis and Classification

Before initiating treatment, proper classification of amyloidosis is essential:

• AL amyloidosis diagnosis requires:

  • Tissue biopsy showing amyloid deposits (Congo red staining with apple-green birefringence)
  • Evidence of plasma cell dyscrasia (serum free light chains, serum and urine immunofixation) 1
  • Abdominal CT scan or ultrasound if alkaline phosphatase is elevated to evaluate liver involvement 2

• ATTR amyloidosis diagnosis requires:

  • Bone scintigraphy for cardiac involvement
  • TTR gene sequencing to differentiate hereditary from wild-type ATTR 1
  • Exclusion of AL amyloidosis first

Treatment Algorithm for Liver Amyloidosis

For AL Amyloidosis

1. First-line therapy: Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) 1

   • Only FDA-approved regimen specifically for AL amyloidosis
   • Offers improved outcomes compared to other regimens

2. For eligible patients (approximately 25% of newly diagnosed cases):

   • High-dose melphalan followed by autologous stem cell transplantation (HDM/SCT)
   • Offers possibility of long-lasting remission with 70% achieving very good partial response or better
   • Median survival >15 years in complete responders 1
   • Treatment-related mortality ~3% in experienced centers

3. Alternative regimens when daratumumab cannot be used:

   • CyBorD alone
   • Bortezomib-melphalan-dexamethasone (BMD) 1

4. For IgM-associated AL amyloidosis:

   • Requires specialized approach due to distinctive clinical characteristics
   • Consider bortezomib-based therapy 1

5. In cases of liver failure:

   • Liver transplantation may be considered as a rescue treatment in rapidly progressing hepatic amyloidosis with cholestatic jaundice 3
   • Sequential liver transplantation followed by autologous stem cell transplantation has shown promise in isolated acute liver failure caused by AL amyloidosis 4

For ATTR Amyloidosis

1. First-line therapy: Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg daily) 1, 5

   • FDA-approved for treatment of cardiomyopathy of wild-type or hereditary ATTR
   • Reduces cardiovascular mortality and cardiovascular-related hospitalization 5

2. Alternative therapy: Acoramidis (Attruby)

   • Novel TTR stabilizer that reduced all-cause mortality by up to 42% 1

3. For hereditary ATTR:

   • Combined heart and liver transplantation may be considered
   • Liver transplantation can cure the amyloidosis disease process in hereditary ATTR, as the TTR protein is synthesized in the liver 2

Monitoring and Follow-up

• Monthly monitoring during initial treatment:

  • Complete blood count
  • Basic biochemistry
  • NT-proBNP and troponin
  • Serum-free light chain quantification for AL amyloidosis 1

• Timing of response assessment:

  • Hematologic response usually observed within 3-6 months of treatment initiation
  • Organ response generally observed 6-12 months after hematologic response 1
  • Treatment should be continued despite initial worsening of cardiac biomarkers, which can occur transiently

Special Considerations for Cardiac Involvement

Cardiac involvement significantly impacts treatment options and survival:

• Avoid medications that can cause toxicity:

  • Digoxin (binds to amyloid fibrils and can cause toxicity even with normal serum levels)
  • Calcium channel blockers (bind to amyloid fibrils causing hypotensive and negative inotropic responses) 2

• Recommended medications:

  • Anticoagulation with warfarin (target INR 2-3) or direct oral anticoagulants for atrial fibrillation 2
  • Diuretics (use cautiously to prevent overdiuresis and volume contraction) 2

Prognosis

• Delayed diagnosis is common, with 25% of AL amyloidosis patients dying within 6 months of diagnosis 1
• Cardiac involvement significantly impacts treatment options and survival 1
• Hepatic amyloidosis often has poor outcomes, particularly when presenting with acute liver failure 6, 7
• Post-transplant survival for ATTR amyloidosis is better than AL amyloidosis, with 5-year survival rates of 50-80% for combined heart-liver transplantation in hereditary ATTR 2

Pitfalls and Caveats

• Avoid delaying treatment while waiting for organ response, as hematologic response precedes organ response by several months 1
• Be cautious with diuretics to prevent hypotension from volume contraction 2
• AL amyloidosis with liver involvement can rapidly progress to liver failure, requiring prompt intervention 3, 4
• Recurrence of amyloid deposits in transplanted organs can occur, as the underlying disease process may continue 3
• Poor outcomes are common in hepatic amyloidosis, highlighting the need for early diagnosis and aggressive treatment 6