Cardiac amyloidosis: An update on diagnosis and treatment

AL treatment

Risk stratification and prognostication for AL. The most important determinant of clinical outcome in AL is the extent of cardiac involvement, as congestive heart failure and sudden cardiac death are the most common causes of death. The level of NT-proBNP and the level of either troponin T or troponin I have strong prognostic value and form the basis for the staging system in AL. Various iterations have evolved over the years, but the most widely adopted is the 4-stage system developed and validated by Mayo Clinic. This system uses a cutoff value at diagnosis for NT-proBNP greater than 1,800 ng/mL, troponin T greater than 0.025 μg/L, and the difference between kappa and lambda free light chain levels greater than 180 mg/L. Stage level increases by the number of cutoff values exceeded, with stage IV carrying a median survival of 6 months.⁴⁷ Additionally, the troponin T level can help risk-stratify patients being considered for autologous stem cell transplant. In a retrospective study, troponin T greater than 0.06 μg/L was associated with increased mortality following stem cell transplant.⁶⁶ Ultimately, prognosis in AL-CA is related to the hematologic response to chemotherapy.

Current treatment strategies for AL. The survival of patients with AL has improved over the years with the advent of more effective chemotherapeutic regimens that kill the underlying plasma cell clone producing the unstable light chains. The goal of treatment is to achieve a complete hematologic response with normalization of the affected light chain and sFLC ratio as well as elimination of the M protein on immunofixation.

The development of the proteasome inhibitor bortezomib has improved efficacy and survival in AL causing a faster and more complete hematologic response than prior regimens.^43,67,68

The most commonly used first-line treatment consists of a 3-drug combination with the alkylating agent cyclophosphamide, the proteasome inhibitor bortezomib, and the steroid dexamethasone, which is given weekly.⁴³ A retrospective study by Sperry et al⁸ showed that patients receiving an alkylating agent, bortezomib, and a steroid had the best outcomes compared with other regimens.

For patients with refractory or relapsed disease, the CD38 monoclonal antibody daratumumab can be used if patients meet myeloma criteria and has been found to be effective thus far.^68,69 Newer proteasome inhibitors such as ixazomib, which is taken orally, are being studied in alternative combination regimens.⁷⁰ High-dose chemotherapy with autologous stem cell transplant can be considered in patients with an acceptable cardiac risk profile and may offer more complete and durable remission than chemotherapy, although this is controversial.^43,71

The cardiologist’s role in AL-CA. The hematologist directs the chemotherapy for AL but works closely with the cardiologist when there is cardiac involvement. The main role of the cardiologist is to manage volume status with diuretics, monitor for arrhythmia, and evaluate the cardiac response to treatment.^43,71 Cardiac response was traditionally measured by echocardiographic changes of wall thickness, diastolic function, and ejection fraction, as well as changes in New York Heart Association (NYHA) functional class.⁶⁷ However, it is uncommon to see reduction in LV wall thickness or significant improvement in ejection fraction and if it does occur, it is a slow process that usually takes more than 1 year. With the advent of longitudinal myocardial strain imaging, improvements in strain can be seen despite the lack of structural changes on echocardiogram.⁷² In 2012, consensus criteria defined a cardiac response as a greater than 30% reduction in NT-proBNP.⁷³ Misfolded light chains are toxic to cardiomyocytes by causing increased oxidative stress and impairing contractility. Thus, reduction in light chain levels can lead to clinical improvement and significant reductions in NT-proBNP without changing amyloid fibril burden in the heart.

Heart transplant for patients with AL-CA. For patients who have a good hematologic response to initial chemotherapy but have limited predicted survival due to severe heart failure, heart transplant followed by autologous stem cell transplant, is a treatment strategy that can be considered. The patient must have clinically isolated severe cardiac disease, minimal amyloid burden in other organs, and a plasma cell clone that is responsive to therapy. Initial reports of heart transplant showed poor survival rates due to recurrent amyloid in the transplanted heart and progressive amyloid deposition in other organs. However, due to improved anti-plasma-cell-directed therapy and refinement in patient selection, outcomes have improved. Contemporary series of patients undergoing heart transplant followed by stem cell transplant showed that outcomes are almost comparable to heart transplant for other indications, with a 5-year survival rate of approximately 65%.⁷⁴

Future therapies for AL. There is an AL amyloid-directed monoclonal antibody designed to remove amyloid fibrils from affected organs and is currently undergoing clinical trials. NEOD001, a humanized murine monoclonal antibody that targets an epitope exposed during light chain misfolding, binds to the light chain amyloid fibril and signals an immune response to clear the deposits. This agent has completed phase 1 and 2 clinical trials of 27 patients previously treated with at least 1 plasma cell-directed therapy. It showed good tolerability and achieved both renal and cardiac responses in most patients.⁷⁵

A phase 2b clinical trial (NCT02632786) of patients with AL with a previous hematologic response to treatment and persistent heart dysfunction is underway and expected to be completed in January 2018. A phase 3 clinical trial (NCT02312206) of NEOD001 as an adjunct to chemotherapy is also ongoing and results are expected in February 2019.