From the Guidelines
Distinguishing subtypes of cardiac amyloidosis is crucial for appropriate treatment, with AL amyloidosis treated with chemotherapy regimens targeting abnormal plasma cells, and ATTR amyloidosis treated with tafamidis, a transthyretin stabilizer, which reduces cardiovascular mortality by 30% 1.
Diagnosis and Treatment
The two main subtypes of cardiac amyloidosis are AL amyloidosis (from light chain proteins) and ATTR amyloidosis (from transthyretin protein). Diagnosis typically involves tissue biopsy, but non-invasive methods include:
- Bone scintigraphy (showing strong uptake in ATTR but not AL)
- Serum free light chain assay (elevated in AL)
- Genetic testing for hereditary ATTR For AL amyloidosis, chemotherapy regimens target the abnormal plasma cells producing light chains, with options including:
- Bortezomib-based combinations (CyBorD: cyclophosphamide, bortezomib, dexamethasone)
- Daratumumab-based regimens
- Melphalan with dexamethasone For ATTR amyloidosis, tafamidis (20mg or 80mg daily) is the primary treatment, stabilizing transthyretin and reducing cardiovascular mortality by 30% 1.
Supportive Care
Supportive heart failure management is essential for all types, including diuretics, though standard neurohormonal blockers are often poorly tolerated. Early diagnosis is critical as treatment effectiveness diminishes with advanced cardiac damage, and multidisciplinary care involving cardiology, hematology, and neurology provides optimal management for this complex disease.
Chemotherapy Options
For AL amyloidosis, high-dose chemotherapy followed by autologous hematopoietic cell transplantation has been used, but patients with cardiac involvement have increased morbidity and mortality 1. Other chemotherapy options for AL amyloidosis include melphalan and dexamethasone or cyclophosphamide, thalidomide and dexamethasone.
Tafamidis and Other ATTR Treatments
Tafamidis is currently the only therapy to improve cardiovascular outcomes in ATTR-CM 1. Other ATTR treatments include patisiran and inotersen (RNA silencers) for hereditary forms. Diflunisal and tafamidis are TTR stabilizers which also slow the progression of ATTRv polyneuropathy, but tafamidis does not have FDA approval for treatment of ATTRv polyneuropathy 1.
From the FDA Drug Label
INDICATIONS AND USAGE VYNDAQEL and VYNDAMAX are transthyretin stabilizers indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. 12.1 Mechanism of Action Tafamidis is a selective stabilizer of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.
The FDA drug label does not provide information on how to distinguish subtypes of amyloidosis affecting the heart. Tafamidis is a chemotherapy option for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis.
- The drug works by stabilizing the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.
- Key points about tafamidis include:
- It is a selective stabilizer of transthyretin (TTR)
- It binds to TTR at the thyroxine binding sites
- It slows dissociation into monomers, the rate-limiting step in the amyloidogenic process
- It is indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization 2
From the Research
Distinguishing Subtypes of Amyloidosis Affecting the Heart
- Cardiac amyloidosis can be distinguished into several subtypes, including transthyretin type (ATTR), monoclonal immunoglobulin light chain type (AL), and rare forms such as secondary amyloidosis AA type, Apo A1, and Isolated Atrial Amyloidosis (AANF) 3.
- The two main types of cardiac amyloidosis are AL and ATTR, which can be quickly distinguished and treated effectively using advances in radioisotope scintigraphy, monoclonal protein testing, and mass spectrometry for typing 4.
- Diagnosis of cardiac amyloidosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis 5.
- Tissue biopsy is frequently needed to confirm the diagnosis of cardiac amyloidosis, as seen in a case where the presumptive diagnosis was ATTR amyloidosis but the endomyocardial biopsy confirmed the diagnosis of AL amyloidosis 6.
Chemotherapy Options for Amyloidosis
- Novel agents such as proteasome inhibitors, immunomodulators, and monoclonal antibodies against plasma cells have improved the prognosis for AL amyloidosis, with median overall survival exceeding a decade for patients achieving complete responses after stem cell transplant and consolidation 4.
- For ATTR amyloidosis, the stabilizer tafamidis and the RNA-interference agents patisiran and inotersen have improved the prognosis, with tafamidis slowing progression of ATTR amyloidosis and improving survival and preventing hospitalization compared to placebo 4, 5.
- Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure 5.
- Bortezomib, cyclophosphamide, and dexamethasone therapy can be used to treat AL amyloidosis, as seen in a case where the patient was started on this therapy after confirmation of the diagnosis 6.
Tafamidis (Transthryretin Stabilizer)
- Tafamidis is a protein stabilizer that inhibits misfolding of the TTR protein and has been shown to reduce mortality, hospitalizations, and slow progression of ATTR amyloidosis compared to placebo 5.
- Tafamidis is the only currently approved therapy for ATTR amyloidosis and is most effective when administered early in the disease course 5.