What is the initial treatment approach for cardiac amyloidosis?

Initial Treatment Approach for Cardiac Amyloidosis

The initial treatment for cardiac amyloidosis is fundamentally determined by amyloid type: for AL (light chain) cardiac amyloidosis, daratumumab plus CyBorD (cyclophosphamide, bortezomib, dexamethasone) is now the standard of care for newly diagnosed patients, while for ATTR (transthyretin) cardiac amyloidosis, tafamidis 80 mg daily (or tafamidis meglumine 61 mg daily) is the FDA-approved disease-modifying therapy. 1, 2

Step 1: Confirm Amyloid Type Before Treatment

• Definitive amyloid typing is mandatory before initiating therapy, as AL and ATTR amyloidosis require completely different treatment approaches 1, 3
• Mass spectrometry-based analysis (LC-MS/MS) of biopsy tissue is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 4
• For AL amyloidosis, confirm plasma cell disorder through serum free light chain assay, serum and urine immunofixation electrophoresis 1, 4
• For ATTR amyloidosis, perform DNA mutational analysis to differentiate hereditary from wild-type disease 3, 4

Step 2: AL Cardiac Amyloidosis Treatment Algorithm

First-Line Therapy for Most Patients

Daratumumab plus CyBorD has emerged as the standard of care for newly diagnosed AL amyloidosis based on the landmark ANDROMEDA trial, which demonstrated very good partial responses or better in 78.5% of patients versus 49.2% with CyBorD alone 1

• Daratumumab is the only FDA-approved agent specifically for AL amyloidosis treatment 1
• This regimen is appropriate for both transplant-eligible patients (as induction therapy) and the 75% of patients who are not transplant candidates 1

Modified Approach for Advanced Cardiac Involvement

For patients with severe cardiac involvement (NT-proBNP >8,500 pg/mL), use single-agent daratumumab with minimal dexamethasone to minimize potential cardiotoxicity 1

• This approach reduces the risk of hemodynamic decompensation in fragile patients with advanced disease 1

Autologous Stem Cell Transplantation (SCT) Consideration

• High-dose melphalan followed by autologous SCT should be considered for highly selected patients, offering median survival exceeding 15 years in complete responders 1
• Key eligibility criteria: EF ≥40%, ability to tolerate fluid shifts and infections, bone marrow plasma cells >10% 1
• Treatment-related mortality is approximately 3% in experienced centers 1
• Only about 25% of newly diagnosed AL amyloidosis patients are eligible for this intensive treatment 1
• Use 2-4 cycles of bortezomib-based regimen for induction before SCT in eligible patients 1

Alternative Regimens

For patients who cannot receive daratumumab or as alternative options:

• CyBorD (cyclophosphamide, bortezomib, dexamethasone) alone 1
• Bortezomib-melphalan-dexamethasone 1

Step 3: ATTR Cardiac Amyloidosis Treatment

Disease-Modifying Therapy

Tafamidis is the only FDA-approved treatment for ATTR cardiac amyloidosis (both wild-type and hereditary) 2, 5

• Dosing: Either tafamidis meglumine 80 mg (four 20-mg capsules) OR tafamidis 61 mg (one capsule) orally once daily 2
• These formulations are NOT substitutable on a per-mg basis 2
• Capsules must be swallowed whole, not crushed or cut 2
• Indicated to reduce cardiovascular mortality and cardiovascular-related hospitalization 2

Transplantation Considerations

• Combined heart-liver transplantation may be considered for hereditary ATTR amyloidosis, with 5-year survival of 50-80% 3
• Heart transplantation alone is an option for wild-type ATTR or after liver transplantation for hereditary ATTR 3

Step 4: Supportive Cardiac Management (All Types)

Heart Failure Management

Diuretics are the mainstay of supportive therapy for managing congestion and heart failure symptoms 3, 5

• Use cautiously to avoid hypotension, as patients are preload-dependent 3
• Standard heart failure medications (ACE inhibitors, ARBs, beta-blockers) are often poorly tolerated and less effective 3, 6

Anticoagulation

Anticoagulation with warfarin or direct thrombin inhibitors is strongly indicated for patients with atrial fibrillation or history of embolic stroke, regardless of CHA2DS2-VASc score 3

• Atrial thrombi can occur even in sinus rhythm due to atrial dysfunction from amyloid infiltration 3

Critical Medications to AVOID

Never use digoxin in cardiac amyloidosis patients - it binds to amyloid fibrils causing toxicity even at normal serum levels 3

Avoid calcium channel blockers - they bind to amyloid fibrils causing exaggerated hypotension and negative inotropy 3

Step 5: Monitoring Treatment Response

For AL Amyloidosis

Monitor both hematologic and organ responses 1, 3:

Hematologic Response Criteria:

• Complete response: Absence of amyloidogenic light chains on immunofixation AND normal FLC ratio 1
• Very good partial response: dFLC <40 mg/L 1
• Partial response: dFLC decrease ≥50% 1

Cardiac Response Criteria:

• Decrease in NT-proBNP by >30% AND <300 ng/L (if baseline NT-proBNP >650 ng/L) 1

Timing:

• Hematologic response typically observed within 3-6 months 1
• Organ response generally observed 6-12 months after hematologic response 1

Assessment Tools

• Serial NT-proBNP and troponin measurements 1, 3
• Echocardiography to assess cardiac function 1, 3
• Serum free light chains for AL amyloidosis 1

Critical Pitfalls to Avoid

Do not initiate treatment before confirming amyloid type - treating AL amyloidosis with ATTR therapies (or vice versa) provides no benefit and delays appropriate therapy 3, 4

Do not assume AL amyloidosis in patients with monoclonal gammopathy - over 10% of patients with monoclonal gammopathy can have ATTR deposits 4

Do not use standard heart failure medications reflexively - ACE inhibitors, ARBs, and beta-blockers are often poorly tolerated and may worsen hypotension 3, 6

Avoid aggressive diuresis - patients are preload-dependent and excessive diuresis can precipitate hemodynamic collapse 3

Recognize that only 25% of AL amyloidosis patients are SCT candidates - most patients require chemotherapy-based approaches 1