What is the treatment approach for pulmonary amyloidosis?

Etiology, Diagnosis, and Treatment of Pulmonary Amyloidosis

Daratumumab-based regimens are the preferred first-line therapy for pulmonary amyloidosis associated with AL (light-chain) amyloidosis, while localized pulmonary amyloidomas may benefit from surgical resection, external beam radiation therapy, or bronchoscopic interventions depending on their location and symptoms. 1, 2, 3

Etiology

Pulmonary amyloidosis results from the deposition of misfolded proteins in the extracellular matrix of lung tissue. The main types include:

1. AL (light-chain) amyloidosis: Most common form affecting the lungs, derived from immunoglobulin light chains produced by abnormal plasma cells 2, 3

2. ATTR amyloidosis:

   • ATTRv (variant): Hereditary form caused by TTR gene mutations
   • ATTRwt (wild-type): Age-related form, previously called senile amyloidosis 4

3. AA amyloidosis: Secondary to chronic inflammatory conditions, rarely affects the lungs 1

Clinical Presentations

Pulmonary amyloidosis manifests in several distinct patterns:

1. Diffuse alveolar-septal amyloidosis:

   • Most common form, usually associated with systemic AL amyloidosis
   • Affects gas exchange, causing progressive dyspnea
   • May lead to respiratory failure 2, 5

2. Nodular pulmonary amyloidosis:

   • Usually localized AL amyloidosis
   • Often asymptomatic, discovered incidentally
   • Single or multiple nodules on imaging 2, 5

3. Tracheobronchial amyloidosis:

   • Deposits in airways causing obstruction
   • Symptoms include dyspnea, wheezing, hemoptysis
   • May lead to airway stenosis 2, 5, 6

4. Cystic pulmonary amyloidosis:

   • Rare form with thin-walled cysts
   • May be associated with Sjögren's syndrome 2, 5

5. Pleural amyloidosis:

   • Rare manifestation with pleural effusions or thickening 5

Diagnosis

Diagnosis requires a systematic approach:

1. Imaging:

   • Chest CT: Initial suspicion often arises from CT findings
   • Nodular form: Single or multiple nodules, often calcified
   • Diffuse form: Interstitial or alveolar opacities, septal thickening
   • Tracheobronchial form: Airway narrowing, wall thickening 2, 3

2. Tissue diagnosis:

   • Essential for confirmation and typing
   • Congo red staining showing apple-green birefringence under polarized microscopy 4
   • Immunohistochemistry to identify amyloid type (AL, ATTR, AA) 4

3. Biopsy approaches:

   • Bronchoscopic biopsy for tracheobronchial disease
   • Transthoracic needle biopsy for peripheral nodules
   • Surgical lung biopsy for definitive diagnosis in challenging cases
   • Abdominal fat pad biopsy to rule out systemic amyloidosis (sensitivity: 84% for AL-CM) 4, 2

4. Systemic evaluation:

   • Serum and urine protein electrophoresis and immunofixation
   • Serum free light chain assay
   • Bone marrow biopsy to rule out plasma cell dyscrasia
   • Cardiac assessment (echocardiography, cardiac biomarkers)
   • Mass spectrometry for definitive typing 4, 3

Treatment

Treatment depends on the type of amyloidosis, distribution, and organ involvement:

1. Systemic AL Amyloidosis with Pulmonary Involvement

First-line therapy:

• Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred treatment based on the ANDROMEDA trial showing unprecedented high rates of deep hematologic responses 1, 3

Alternative options:

• CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) for patients who cannot tolerate daratumumab 1
• High-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) for eligible patients without significant cardiac involvement 1
  • Treatment-related mortality is approximately 3%
  • 70% achieve very good partial hematologic response or better
  • Median survival >15 years in those achieving complete response 1

Eligibility criteria for HDM/SCT:

• Absence of significant cardiac involvement (LVEF >40%)
• Ability to handle fluid shifts and potential infections
• Only about 25% of newly diagnosed patients are eligible 1

2. Localized Pulmonary Amyloidosis

Nodular amyloidosis:

• Often asymptomatic and may only require monitoring
• Surgical resection for symptomatic lesions or when malignancy cannot be excluded 2
• External beam radiation therapy (EBRT) has shown success in case reports 7

Tracheobronchial amyloidosis:

• Bronchoscopic interventions including debulking and stenting
• External beam radiation therapy
• Laser therapy or argon plasma coagulation 2, 5

Cystic amyloidosis:

• Usually requires only monitoring 2

3. Monitoring and Follow-up

• Monthly monitoring: CBC, biochemistry, NT-proBNP, troponin, and serum-free light chain quantification 4
• Echocardiography with strain measurements and Holter ECG every 6 months 4
• Assessment of hematologic response (goal: very good partial response or better) 4
• Monitoring for treatment-related toxicities 1

Special Considerations and Potential Complications

1. Cardiac toxicities of treatment agents:

   • Proteasome inhibitors (bortezomib): Heart failure in 6.4%, LVEF reduction in 23%
   • Immunomodulatory agents: Paradoxical increase in cardiac biomarkers
   • Daratumumab: Cardiac failure in 12%, arrhythmias in 8% 1

2. Anticoagulation in cardiac amyloidosis:

   • Indicated for atrial fibrillation, embolic stroke/TIA, or intracardiac thrombus
   • Weigh benefits against increased bleeding risk in amyloid angiopathy 1

3. Advanced therapies:

   • Heart transplantation for select patients with advanced heart failure
   • Combined heart-liver transplantation for hereditary ATTR amyloidosis (5-year survival: 50-80%) 1, 4

4. Medication management:

   • Judicious use of diuretics for symptom management
   • Caution with β-blockers, digoxin, calcium channel blockers, and ACE inhibitors/ARBs 4

Pulmonary amyloidosis management requires a multidisciplinary approach involving pulmonologists, hematologists, cardiologists, and radiation oncologists to optimize outcomes and quality of life.