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Figure 2

Electrocardiogram changes in AL amyloidosis. (A) Baseline electrocardiogram of an AL patient with no signs of cardiac involvement. (B) Follow-up study only months later demonstrates changes resulting from cardiac amyloidosis, including pseudo-infarct pattern, and Q waves and loss of voltage in the limb leads. Reprinted from Wright et al60 with permission.

Misdiagnosis of AL is an infrequent but real occurrence. In a series of 375 patients diagnosed with AL in the United Kingdom, 10% were misdiagnosed, many because of misinterpretation of urine immunofixation findings associated with renal damage resulting from the fibrinogen A α hereditary variant.7^,51 Renal injury resulting from amyloidosis is associated with spillage of proteins, including Ig-related proteins, in the urine. Urine immunofixation may then show bands difficult to interpret for clonality.52 We have not encountered misdiagnosis of AL for fibrinogen A α in the United States, perhaps because of the frequency of renal biopsies and standard staining for fibrinogen. We have, however, identified black and peripheral neuropathy patients with amyloidosis who have 2 potential precursor proteins, a variantTTR gene and a monoclonal gammopathy. In those instances, the risk of misdiagnosis exists and tissue typing is required.8 Similarly, in elderly men with isolated cardiac involvement and monoclonal gammopathies, tissue typing will distinguish AL from SSA. Within the next decade, as proteomic techniques become more widely available, the risk of misdiagnosis will lessen, provided that the tissue samples tested contain adequate amounts of amyloid.50 Figure 3 contains an algorithm of our current approach to amyloidosis.

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Figure 3

Algorithm for clinical management of amyloidosis.

Treatment of AL has followed that of multiple myeloma. Oral melphalan and dexamethasone (MDex) and high-dose melphalan with SCT are considered standard therapies.22^,27 The hematologic response and survival rates achieved in the initial MDex trial were similar to SCT (Figure 4A).27 The French Myélome Autogreffe Groupe led a multicenter phase 3 trial randomizing AL patients to MDex versus high-dose melphalan with SCT (#NCT00344526).53 The median survival of patients in the MDex group was significantly better (Figure 4B); however, 13 of the 50 patients assigned to SCT never received melphalan because of death or early progression, and 9 died peri-SCT. This high early mortality was the result of inclusion of patients who would not have been considered SCT-eligible in the United States and to the limited experience many centers in the trial had with SCT for AL. Nonetheless, a landmark analysis examining patients surviving 6 months or more showed no advantage for SCT. The results with MDex, a 68% response rate and 57-month median survival, confirmed it as a standard therapy for AL, noting the risks of myelodysplasia and secondary leukemia from oral melphalan.54 Current criteria for SCT eligibility include 1 or 2 major organs involved, left ventricular ejection fraction greater than or equal to 45%, pulmonary diffusion capacity greater than or equal to 50%, and systolic blood pressure greater than or equal to 90 mm Hg. By these criteria, only one-third of newly diagnosed patients are SCT-eligible. The hematologic and organ responses with SCT in historical series are in Table 2.