What is the management of heart failure due to AL (Amyloid Light-chain) amyloidosis?

Management of Heart Failure in AL Cardiac Amyloidosis

For AL cardiac amyloidosis with heart failure, initiate daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) immediately after urgent hematology-oncology consultation, as this is the preferred first-line regimen achieving very good partial response or better in 78.5% of patients, while managing volume status cautiously with diuretics and avoiding standard neurohormonal antagonists. 1

Immediate Actions Upon Diagnosis

• Urgent hematology-oncology consultation is mandatory as AL cardiac amyloidosis is rapidly fatal without treatment of the underlying plasma cell disorder 1
• Confirm diagnosis with serum and urine immunofixation electrophoresis plus serum free light chains to quantify disease burden 2
• Consider cardiac or other tissue biopsy if diagnosis confirmation is needed 1

Disease-Directed Chemotherapy Selection

First-Line Therapy (Preferred)

• Daratumumab-CyBorD (daratumumab + cyclophosphamide + bortezomib + dexamethasone) is the preferred first-line regimen based on the ANDROMEDA trial showing 78.5% very good partial response versus 49.2% with CyBorD alone 1
• This regimen is appropriate for both stem cell transplant candidates and ineligible patients 1

Alternative First-Line Options

• CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) achieves 81.4% overall hematologic response with 41.9% complete response, particularly effective when used upfront 3
• High-dose melphalan with autologous stem cell transplantation may be considered for highly selected patients: age <60 years, ≤2 organs involved, no severe cardiac involvement, adequate performance status 1, 4
• Only ~25% of newly diagnosed AL patients are eligible for stem cell transplantation due to advanced cardiac and organ involvement 1

Treatment for Relapsed/Refractory Disease

• Daratumumab monotherapy (if not used first-line) is generally preferred due to lower cardiac and renal toxicity 1
• Alternative immunomodulatory agents include lenalidomide and pomalidomide 1
• Thalidomide should be used with extreme caution given significant cardiac toxicity 1

Heart Failure Management Principles

Volume Management

• Judicious diuresis is the cornerstone of heart failure therapy in AL cardiac amyloidosis 1, 4
• Use diuretics cautiously as patients are preload-dependent due to restrictive physiology 1

Medications to AVOID

• ACE inhibitors and ARBs should be avoided due to poor tolerance and risk of hypotension in restrictive cardiomyopathy 1
• Beta-blockers are poorly tolerated and should be avoided due to hypotension risk, despite theoretical benefit for diastolic filling time 1
• Standard neurohormonal antagonists used in typical heart failure are contraindicated 1

Anticoagulation Strategy

• Anticoagulation is reasonable for atrial fibrillation regardless of CHA₂DS₂-VASc score to reduce stroke risk, as AL amyloidosis carries inherent thrombotic risk 2, 1

Monitoring Treatment Response

Hematologic Response Assessment

• Monitor serum free light chain difference (dFLC) to assess hematologic response 1
• Complete hematologic response is defined as: negative serum and urine immunofixation with normal FLC ratio 1
• Very good partial response (VGPR) is defined as >90% decrease in dFLC 3

Cardiac Response Assessment

• Cardiac response is defined as: NT-proBNP decrease >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L) 1
• Assess cardiac response 6-12 months after achieving hematologic response 1
• Deep clonal responses (CR or VGPR-dFLC) are associated with significantly better progression-free survival and may overcome poor prognosis in advanced-stage disease 3

Critical Chemotherapy Cardiotoxicity Considerations

Daratumumab Toxicity

• Cardiac failure occurs in 12% (grade 3-4 in 6%) of patients 1
• Atrial fibrillation occurs in 6% of patients 1
• Close cardiac monitoring is essential during therapy 1

Bortezomib Toxicity

• Grade 3 heart failure occurs in 6.4% of patients 1

• 10% LVEF decrease occurs in 23% of patients 1

Corticosteroid (Dexamethasone) Toxicity

• Can cause peripheral edema, pulmonary edema, and fluid overload 1
• Particularly problematic in patients with restrictive cardiomyopathy 1

Prognostic Considerations

• Median untreated survival is <6 months in AL cardiac amyloidosis with symptomatic heart failure 5
• Initial treatment with bortezomib-based three-drug regimen (BDex+AA) is associated with decreased mortality (hazard ratio 0.209) compared to other regimens in patients with symptomatic NYHA class ≥II heart failure 5
• Median survival improves from 223 days with other regimens to 821 days with BDex+AA therapy 5
• Patients with Mayo Cardiac Stage III (74% of treated patients in one series) can achieve 97.7% two-year overall survival with CVD therapy 3

Common Pitfalls to Avoid

• Do not delay chemotherapy initiation while optimizing heart failure management—the plasma cell clone must be treated urgently 1
• Do not use standard protein electrophoresis (SPEP/UPEP) alone for diagnosis as sensitivity is inadequate; always obtain serum free light chains with immunofixation 4
• Do not assume patients are ineligible for chemotherapy based on ejection fraction or cardiac status—there are no absolute contraindications to plasma cell-directed therapies in AL cardiac amyloidosis 4
• Do not confuse AL amyloidosis with ATTR amyloidosis—management differs completely, and tafamidis (used for ATTR) has no role in AL amyloidosis 2
• Avoid aggressive fluid removal despite congestion, as excessive diuresis can precipitate hypotension and cardiogenic shock in restrictive physiology 1