Rapid Review
Treatment of Primary Amyloidosis (AL)
William B. Ershler, MD
There are several forms of amyloidosis, each with distinct patterns of protein deposition and resulting clinical presentations. Primary amyloidosis (AL) is to be distinguished from secondary forms (AA), and is the result of deposition of monoclonal immunoglobulin light chains occurring in patients with some form of clonal plasma-cell dyscrasias. Approximately 10% of patients with AL have overt multiple myeloma. Light-chain deposition disease (LCDD) is similar to AL, but the light-chain fragments do not have the biochemical properties to form typical amyloid fibrils (antiparallel, beta pleated sheets). With both AL and LCDD, tissue deposition is highly variable, but most commonly involves kidney, heart, liver, and small intestine.
Patients with AL amyloidosis have clinical presentations that vary with sites of amyloid deposition. In some, only a single organ will be involved, whereas others will have multisystem involvement. Patients may present with nephrotic syndrome, neuropathy, restrictive cardiomyopathy, hepatomegaly, macroglossia, or purpura, and the typical patient will have more than one of these manifestations.1 The disease is progressive, with the worst outcomes seen in patients with circulating plasma cells, high beta-2 microglobulin (> 2.7 ug/mL), bone marrow plasma cells > 10%, or prominent cardiac involvement.2 Markers of cardiac involvement include N-terminal pro-brain natriuretic peptide (NT-pro BNP) and troponin, and elevated levels of either are associated with mortality risk.3,4 Also, detectable levels of circulating free light chains (FLC) have prognostic value, and measurement also can assist in determining treatment response.5-7
Untreated patients with AL have a median overall survival (OS) of approximately 6-12 months,8 and median OS is even shorter if there is prominent cardiac involvement.8,9 Oral melphalan and prednisone were used for two decades or more, but with only a modest improvement, perhaps six additional months.10 High-dose melphalan, followed by autologous stem cell transplant (SCT), resulted in substantial improvement, with an OS of 55 months reported by one group.11 However, SCT was not applicable for all patients, and for those not eligible, survival remained poor. Nonetheless, Palladini et al reported that for those ineligible for high-dose melphalan and SCT, oral melphalan and high-dose dexamethasone was quite effective, resulting in a median OS of 61 months.12,13 Subsequently, a group in France compared, in a randomized trial, oral melphalan-dexamethasone with high-dose melphalan/SCT, and found a median survival of 60 months for those in the melphalan/dexamethasone (no SCT) arm, with no advantage for those randomized to SCT.14 In fact, the median survival in the SCT group was only 22 months, reflecting a 28% treatment-related mortality.
To reconcile these differences, the details need to be reviewed. Survival using the same analogous protocols has been quite variable from institution to institution. In a very instructive review, Palladini et al15 compared results from two centers, one in Europe and one in the United States, that had reported quite different survival rates (30 months vs. 12 months, respectively). They found that the group reporting shorter survival had, on average, older patients and a higher percentage with cardiac involvement.
Just recently, Dietrich et al16 from Heidelberg, Germany, reported on 61 patients with advanced AL who were treated with intravenous melphalan and dexamethasone. Of these, 17 died within three months, 20 patients had a hematological response, and seven had a complete response. Importantly, pretreatment levels of circulating free light chains, as well as physical performance (Karnofsky Index) were predictive of mortality. Plasma levels of cardiac biomarkers (troponin and NT-proBNP) were strong negative predictors of overall survival. Similarly, in a trial of lenalidomide, with or without dexamethasone, there were several early deaths, adverse events, and drop-outs, and the pre-treatment presence of these cardiac biomarkers predicted which patients would be affected.17
Thus, AL patients who are free of cardiac involvement have low levels of circulating light chain and good performance status are likely to respond to melphalan/dexamethasone treatment. Treatment of patients with more advanced disease remains problematic, particularly if there is cardiac involvement. Such patients have not fared well with high-dose melphalan/SCT, and lower-dose regimens provide only modest improvement. At this point, it would be reasonable to stratify future clinical trials based upon the presence of cardiac involvement, and hopefully develop non-cardiotoxic regimens to be tested in carefully conducted clinical trials.
References
1. Kyle RA, Gertz MA. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45-59.
2. Pardanani A, et al. Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis. Blood. 2003;101:827-830.
3. Dispenzieri A, et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet. 2003;361:1787-1789.
4. Palladini G, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107:2440-2445.
5. Dispenzieri A, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2006;107:3378-3383.
6. Lachmann HJ, et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol. 2003;122:78-84.
7. Palladini G, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood. 2006;107:3854-3858.
8. Falk RH, et al. The systemic amyloidoses. N Engl J Med. 1997;337:898-909.
9. Kyle RA, Greipp PR. Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc. 1983;58:665-683.
10. Kyle RA, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997;336:1202-1207.
11. Skinner M, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: An 8-year study. Ann Intern Med. 2004;140:85-93.
12. Palladini G, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004;103:2936-2938.
13. Palladini G, et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007;110:787-788.
14. Jaccard A, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007;357:1083-1093.
15. Palladini G, et al. Multicentre versus single centre approach to rare diseases: the model of systemic light chain amyloidosis. Amyloid. 2005;12:120-126.
16. Dietrich S, et al. Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement. Blood. 2010;116:522-528.
17. Dispenzieri A, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007;109:465-470.
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