joirrrid of’ lriterrid Medicine 1992: 232. 523-524
Primary systemic amyloidosis R. A. K Y L E Frorti the Depurtnient of Hematology and Internal Medicine. Mago Clinic. Rochester, MN. USA
Primary systemic amyloidosis (AL) is characterized by fibrils composed of the variable portion of a monoclonal light chain. The light-chain class is more frequently A than K (2 : 1).Interestingly, all patients with ILV, subgroup have A],. The incidence of AL is 8.9 per million per year. The median age is 62 years. Weakness, fatigue, and weight loss are the most frequent symptoms. Paresthesias, light-headedness, syncope, change in voice, macroglossia, dyspnoea, paedal oedema, and steatorrhoea may occur [1]. Approximately one-third of patients have a nephrotic syndrome at the time of diagnosis. Congestive heart failure is present initially in about one-quarter of patients, and one-sixth present with orthostatic hypotension or peripheral neuropathy. The presence of one of these syndromes and a monoclonal protein in the serum or urine raises a strong suspicion of amyloidosis. In the Mayo Clinic, 9 0 % of patients with AL have a monoclonal protein in the serum or urine. The diagnosis depends on the demonstration of amyloid deposits in tissue. Tmmunostaining characteristically reveals a reaction of the fibrils with K or i, antisera (see article by Dr Pepys, pp. 519-521). The initial diagnostic procedure should be an abdominal fat aspiration because this test is positive in almost 80% of patients. If it is negative, a bone marrow aspiration and biopsy may be helpful because marrow contains amyloid in about one-half of patients with AL. If the bone marrow and abdominal fat aspirations are negative, a rectal biopsy should be performed. This is reasonably free of complications and produces positive findings in about 80% of patients. If these sites are negative for amyloid, tissue should be obtained from a suspected involved organ such as the kidney, liver, or heart or from sural nerve. The heart is frequently involved. Echocardiography is a valuable technique for the evaluation of amyloid heart disease. Doppler studies are useful and show abnormal relaxation early in the course of the disease, whereas advanced involvement is characterized by restrictive haemodynamics.
Treatment of AL is unsatisfactory. The amyloid fibrils consist of the variable portion of monoclonal immunoglobulin light chains that are synthesized by plasma cells. Increased numbers of monoclonal plasma cells are commonly found in the bone marrow of patients with AL. It is therefore reasonable to attempt treatment with alkylating agents that are known to be effective against plasma cell proliferative processes such as multiple myeloma. Colchicine has also been used in the treatment of patients with AL. It inhibits casein induction of amyloidosis in mice and has been effective in the control of abdominal pain and in the prevention of amyloidosis in patients with familial Mediterranean fever. It may inhibit amyloid deposition by blocking the formation of amyloid-enhancing factor. It also inhibits the secretion of amyloid A protein from hepatocytes. It may also interfere with microtubule function. In one study, the median duration of survival was 6 months for 2 9 untreated patients seen between 1 9 6 1 and 1 9 7 3 and 1 7 months for 53 patients seen between 1976 and 1983 who were treated with colchicine [2]. However, for patients in the first group (1961 to 1973), the condition may have been diagnosed later in the course of their disease. Furthermore, supportive therapy may not have been as effective as in the more recent group. In a prospective randomized study of melphalan (0.15 mg/kg per day for 7 days) and prednisone (0.8 mg/kg per day for the same 7 days) every 6 weeks compared with daily colchicine therapy, 101 patients were stratified according to their dominant clinical manifestation. If the disease progressed, the other regimen was added. There was no difference in overall duration of survival when the two groups were compared (the duration was 25.2 months in the melphalan and prednisone group and 18 months in the colchicine group; P = 0.23). When the survival duration of patients who received only one regimen was analysed or when it was analysed from the time of entry into the study to the time of progression of disease or death, significant differences 523
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(P < 0.001 and P < 0.0001, respectively) favouring melphalan and prednisone therapy were evident [3]. Four patients died of acute non-lymphocytic leukaemia, and two others had a myelodysplastic process. This study suggests that melphalan and prednisone therapy may be superior to colchicine therapy. We are currently engaged in a prospective study in which patients with AL are stratified according to their dominant clinical manifestation : (i) nephrotic syndrome or renal failure, (ii) congestive heart failure. (iii) peripheral neuropathy, or (iv) other. Patients are randomized to regimen I (colchicine, 0.6 mg twice a day, and the dosage is increased gradually to the point of toxicity), regimen I1 (melphalan, 0.15 mg/kg daily, and prednisone, 0.8 mg/kg daily, both for 7 days every 6 weeks), or regimen I11 (melphalan, prednisone, and colchicine as in regimens I and 11). Crossover between the regimens is not permitted. At interim analysis, 163 patients had been entered: 53 were assigned to regimen I, 57 to regimen 11, and 53 to regimen 111. Nephrotic syndrome was the most common manifestation, followed by congestive heart failure and peripheral neuropathy. Forty-four of the 53 patients in regimen I have died, 4 0 of the 57 patients in
regimen I1 have died, and 34 of the 53 patients in regimen I11 have died. The median duration of survival was 9 months in patients receiving colchicine, 16 months in the melphalan and prednisone group, and 18 months in the melphalan, prednisone, and colchicine group [4]. The study is continuing and soon will be completed and analysed. Therapy of AL is suboptimal, and newer agents and approaches are necessary.
References Kyle RA. Gertz MA. Systemic amyloidosis. Crit Rev Oricol Hematol 1990: 10: 49-87. Cohen AS. Rubinow A, Anderson JJ et a/. Survival of patients with primary (AL) arnyloidosis : colchicine-treated cases from 7976 to 1983 compared with cases seen in previous years (1961 to 1973). Am ]Med 1 9 8 7 : 8 2 : 1182-90. Kyle RA. Greipp PR. Carton JP. Gertz MA. Primary systemic amyloidosis : comparison of melphalan/prednisone versus colchicine. Am 1 Med 7 985 : 79: 708-1 6. Kyle RA. Amyloidosis. In: Hoffman R. Benz EJ Jr, Shattil SJ. Furie B. Cohen HI. eds. Hematologg: Basic Principles and Practice. New York: Churchill Livingstone. 1991 : 1 0 3 8 4 7 . Received 10 June 1992, accepted 23 June 1 9 9 2 Correspondence: Robert A. Kyle. MI>, Mayo Clinic. 200 First Street SW. Rochester, Minnesota 55905. USA.
Primary systemic amyloidosis R. A. K Y L E Frorti the Depurtnient of Hematology and Internal Medicine. Mago Clinic. Rochester, MN. USA
Primary systemic amyloidosis (AL) is characterized by fibrils composed of the variable portion of a monoclonal light chain. The light-chain class is more frequently A than K (2 : 1).Interestingly, all patients with ILV, subgroup have A],. The incidence of AL is 8.9 per million per year. The median age is 62 years. Weakness, fatigue, and weight loss are the most frequent symptoms. Paresthesias, light-headedness, syncope, change in voice, macroglossia, dyspnoea, paedal oedema, and steatorrhoea may occur [1]. Approximately one-third of patients have a nephrotic syndrome at the time of diagnosis. Congestive heart failure is present initially in about one-quarter of patients, and one-sixth present with orthostatic hypotension or peripheral neuropathy. The presence of one of these syndromes and a monoclonal protein in the serum or urine raises a strong suspicion of amyloidosis. In the Mayo Clinic, 9 0 % of patients with AL have a monoclonal protein in the serum or urine. The diagnosis depends on the demonstration of amyloid deposits in tissue. Tmmunostaining characteristically reveals a reaction of the fibrils with K or i, antisera (see article by Dr Pepys, pp. 519-521). The initial diagnostic procedure should be an abdominal fat aspiration because this test is positive in almost 80% of patients. If it is negative, a bone marrow aspiration and biopsy may be helpful because marrow contains amyloid in about one-half of patients with AL. If the bone marrow and abdominal fat aspirations are negative, a rectal biopsy should be performed. This is reasonably free of complications and produces positive findings in about 80% of patients. If these sites are negative for amyloid, tissue should be obtained from a suspected involved organ such as the kidney, liver, or heart or from sural nerve. The heart is frequently involved. Echocardiography is a valuable technique for the evaluation of amyloid heart disease. Doppler studies are useful and show abnormal relaxation early in the course of the disease, whereas advanced involvement is characterized by restrictive haemodynamics.
Treatment of AL is unsatisfactory. The amyloid fibrils consist of the variable portion of monoclonal immunoglobulin light chains that are synthesized by plasma cells. Increased numbers of monoclonal plasma cells are commonly found in the bone marrow of patients with AL. It is therefore reasonable to attempt treatment with alkylating agents that are known to be effective against plasma cell proliferative processes such as multiple myeloma. Colchicine has also been used in the treatment of patients with AL. It inhibits casein induction of amyloidosis in mice and has been effective in the control of abdominal pain and in the prevention of amyloidosis in patients with familial Mediterranean fever. It may inhibit amyloid deposition by blocking the formation of amyloid-enhancing factor. It also inhibits the secretion of amyloid A protein from hepatocytes. It may also interfere with microtubule function. In one study, the median duration of survival was 6 months for 2 9 untreated patients seen between 1 9 6 1 and 1 9 7 3 and 1 7 months for 53 patients seen between 1976 and 1983 who were treated with colchicine [2]. However, for patients in the first group (1961 to 1973), the condition may have been diagnosed later in the course of their disease. Furthermore, supportive therapy may not have been as effective as in the more recent group. In a prospective randomized study of melphalan (0.15 mg/kg per day for 7 days) and prednisone (0.8 mg/kg per day for the same 7 days) every 6 weeks compared with daily colchicine therapy, 101 patients were stratified according to their dominant clinical manifestation. If the disease progressed, the other regimen was added. There was no difference in overall duration of survival when the two groups were compared (the duration was 25.2 months in the melphalan and prednisone group and 18 months in the colchicine group; P = 0.23). When the survival duration of patients who received only one regimen was analysed or when it was analysed from the time of entry into the study to the time of progression of disease or death, significant differences 523
524
R.A.KYLE
(P < 0.001 and P < 0.0001, respectively) favouring melphalan and prednisone therapy were evident [3]. Four patients died of acute non-lymphocytic leukaemia, and two others had a myelodysplastic process. This study suggests that melphalan and prednisone therapy may be superior to colchicine therapy. We are currently engaged in a prospective study in which patients with AL are stratified according to their dominant clinical manifestation : (i) nephrotic syndrome or renal failure, (ii) congestive heart failure. (iii) peripheral neuropathy, or (iv) other. Patients are randomized to regimen I (colchicine, 0.6 mg twice a day, and the dosage is increased gradually to the point of toxicity), regimen I1 (melphalan, 0.15 mg/kg daily, and prednisone, 0.8 mg/kg daily, both for 7 days every 6 weeks), or regimen I11 (melphalan, prednisone, and colchicine as in regimens I and 11). Crossover between the regimens is not permitted. At interim analysis, 163 patients had been entered: 53 were assigned to regimen I, 57 to regimen 11, and 53 to regimen 111. Nephrotic syndrome was the most common manifestation, followed by congestive heart failure and peripheral neuropathy. Forty-four of the 53 patients in regimen I have died, 4 0 of the 57 patients in
regimen I1 have died, and 34 of the 53 patients in regimen I11 have died. The median duration of survival was 9 months in patients receiving colchicine, 16 months in the melphalan and prednisone group, and 18 months in the melphalan, prednisone, and colchicine group [4]. The study is continuing and soon will be completed and analysed. Therapy of AL is suboptimal, and newer agents and approaches are necessary.
References Kyle RA. Gertz MA. Systemic amyloidosis. Crit Rev Oricol Hematol 1990: 10: 49-87. Cohen AS. Rubinow A, Anderson JJ et a/. Survival of patients with primary (AL) arnyloidosis : colchicine-treated cases from 7976 to 1983 compared with cases seen in previous years (1961 to 1973). Am ]Med 1 9 8 7 : 8 2 : 1182-90. Kyle RA. Greipp PR. Carton JP. Gertz MA. Primary systemic amyloidosis : comparison of melphalan/prednisone versus colchicine. Am 1 Med 7 985 : 79: 708-1 6. Kyle RA. Amyloidosis. In: Hoffman R. Benz EJ Jr, Shattil SJ. Furie B. Cohen HI. eds. Hematologg: Basic Principles and Practice. New York: Churchill Livingstone. 1991 : 1 0 3 8 4 7 . Received 10 June 1992, accepted 23 June 1 9 9 2 Correspondence: Robert A. Kyle. MI>, Mayo Clinic. 200 First Street SW. Rochester, Minnesota 55905. USA.
