The Question
What is your approach to newly diagnosed patients with immunoglobulin light-chain amyloidosis (AL) cardiac involvement?
Our Response
AL is a protein deposition disease resulting from toxicity of misfolding light chains that are produced by a clonal plasma cell neoplasm. The disease is characterized by significant clinical heterogeneity, depending on the organ that is involved and the severity of organ dysfunction. The strongest predictor of inferior patient outcome is advanced cardiac involvement that is frequently a result of diagnostic delay. Median overall patient survival has been shown to range from more than seven years in patients without cardiac involvement, to as little as six months in patients presenting with significant cardiac disease burden.1,2 Earlier diagnosis, improved supportive care and light-chain–directed therapy, and the emergence of organ-directed therapies are expected to result in better outcomes.
Clinical Features and Diagnostic Work-up
At the time of initial hematology referral, the diagnosis of AL with cardiac involvement is often highly suspected on the basis of typical features such as the low-voltage echocardiogram, characteristic patterns seen on echocardiography including interventricular septal thickening or ventricular strain pattern, and evidence of increased serum-free light chains. Every suspected diagnosis requires confirmation by tissue biopsy (endomyocardial biopsy or biopsy of a surrogate site such as the abdominal fat pad) with Congo red staining and amyloid subtyping by immunohistochemistry or mass spectrometry. In addition to serum and urine monoclonal protein studies, a bone marrow biopsy is undertaken to identify the underlying clonal plasma cell disease (or rarely, other light-chain–producing B-cell neoplasm). A detailed history and physical examination focusing on cardiac and other possible AL organ involvement should be performed, including assessment of volume status, orthostatic hypotension, and neurologic examination. Baseline measurements of 24-hour urine protein, N-terminal of the prohormone brain natriuretic peptide (NT-ProBNP), cardiac troponin-T, alkaline phosphatase, and nerve conduction studies if there is concern for peripheral nerve involvement, should be considered standard of care.3 The revised Mayo cardiac staging system, which assigns points based on binary cutoffs of three variables at time of diagnosis (differential free light chains ≥ 18 mg/dL, NT-ProBNP ≥ 1,800 pg/mL, and troponin-T ≥ 0.025 ng/mL), is useful for risk stratification and prognostic counseling.
Management
A multidisciplinary team approach to supportive care, with the involvement of experienced cardiologists and a heart failure team focusing on cardiac AL, is essential for management of fluid status and arrhythmias, adherence to salt restriction and support stockings, pharmacologic management of autonomic neuropathies, and selection of patients who may benefit from advanced heart failure interventions including cardiac transplantation.
Light-chain–suppressive therapy directed at treating the underlying clonal plasma cells relies on approved drugs for multiple myeloma as there are currently no U.S. Food and Drug Administration–approved drugs for AL. While high-dose therapy (HDT) with melphalan and autologous stem cell transplantation is commonly used upfront for patients with multiple myeloma, patients with AL and cardiac involvement are frequently deemed ineligible for this approach based on cutoffs in troponin-T and NT-ProBNP that predict high transplant-related mortality. Furthermore, there is no prospective randomized clinical trial evidence showing that upfront HDT is superior to novel-agent–induction regimens with regard to hematologic or organ response rates or to overall survival.4 We therefore consider upfront HDT in selected qualifying patients and use an individualized approach, taking into account patient preferences and individual risk.
Table
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| Hematologic Response Criteria |
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| Cardiac Response Criteria |
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| Hematologic Response Criteria |
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The goal of any light-chain–directed therapy is a rapid and deep hematologic response defined by consensus guidelines.5 Cardiac response is also defined by consensus guidelines (Table) and is associated with improvement in survival. While it is clear that patients achieving hematologic response are more likely to achieve cardiac response, predicting which patients will achieve cardiac responses is difficult. Combination novel agent induction regimens, similar to those used in multiple myeloma are used in the treatment of AL. In cohorts of patients with advanced cardiac AL, bortezomib, cyclophosphamide, and dexamethasone (VCD) has been shown to produce hematologic very good partial response (VGPR), or better, rates of 42 percent, and cardiac response rates of 32 percent.6 Similarly, an upfront approach with lenalidomide in combination with cyclophosphamide and dexamethasone (RCD) produced VGPR or better hematologic response rates of 43 percent and cardiac response rates of 26 percent in a prospective phase II trial.7 For patients failing to achieve adequate responses or with relapsed disease, single-agent carfilzomib has been shown to produce hematologic responses in 78 percent of patients.8 There are also prospective data to support the use of pomalidomide and bendamustine with dexamethasone, respectively, in relapsed AL.9
Consideration for clinical trial enrollment is always a priority for newly diagnosed or relapsed/refractory patients with cardiac AL, but when initially treating patients not as part of a clinical trial on cardiac AL, we will typically use a combination regimen such as VCD or RCD, assessing markers of hematologic and organ response as well as tolerability on a cycle-to-cycle basis. In addition to this physician-directed care, we also suggest exploration of complementary services including guidance for nutrition and exercise as well as specialty local and national support groups for patients with amyloidosis to provide another level of psychosocial support and engagement (for example, www.arci.org and www.amyloidosis.org).
The Future
Novel approaches with anti-fibril activity are currently being evaluated in clinical trials of AL. Among the 14 patients with cardiac involvement included in the phase I/II study of the anti-fibril antibody NEOD001, median NT-ProBNP was 1,103 pg/mL, and eight (57%) of 14 subjects met criteria for achieving cardiac response.10 Ongoing studies of NEOD001 (VITAL and PRONTO), are evaluating this agent as part of upfront combination therapy and also in patients with persistent cardiac dysfunction despite achieving hematologic response with standard light-chain suppressive therapy. A clinical study evaluating sequential activity of the serum amyloid P component (SAP) –clearing molecule CPHPC and an SAP-antibody did not include patients with cardiac AL, but demonstrated rapid clearance of amyloid deposits from patients with hepatic AL.11 Other fibril-reactive antibodies, including 11-1F4, are also in development and have shown promising organ responses even in dose-escalation cohorts.12 The optimal strategy of incorporating anti-fibril-based treatments with light chain suppressive therapy (in combination or sequential) is uncertain. Their promise, however, underscores the importance for all AL patients to be evaluated at a tertiary referral center as early in their disease course as possible.
Table. Abbreviations: NT-proBNP N-terminal of the prohormone brain natriuretic peptide; NYHA, New York Heart Association; EF, ejection fraction; CR, complete response; IFE, immunofixation electrophoresis; FLC, free light chains; dFLC, difference between involved and uninvolved FLC; VGPR, very good partial response; PR, partial response.
References
Competing Interests
Dr. Kaufman and Dr. Liedtke indicated no relevant conflicts of interest.
