In secondary AA amyloidosis, resorption may occur when the stimulus for amyloid formation is eliminated [1, 2]. It is generally agreed that no effective therapy exists for AL amyloidosis (formerly known as primary systemic amyloidosis), but a few patients have shown responses to alkylating agent-based chemotherapy [3]. The median survival after diagnosis is only 14 months. In patients with multiple myeloma, new therapeutic strategies involving higher doses of cytotoxic drugs sometimes combined with total body irradiation and autologous or allogeneic bone marrow transplantation have significantly increased the rate of complete remission [4, 5]. On the basis of these results we performed a syngeneic bone marrow transplantation in a 32-year-old patient with AL amyloidosis who had not benefited from treatment with melphalan and prednisone.

View larger version (76K): [in this window] [in a new window]   Figure 1. Investigation before and 2 years after bone marrow transplantation.Top. Abdominal anterior view 24 hours after injection of Iodine-123-labeled serum albumin precursor. The uptake in the spleen is high; uptake in the liver is slightly lower. There is scarcely any background activity. Bottom. Abdominal anterior view 24 hours after injection of Iodine-123-labeled serum amyloid precursor. A pronounced background (heart and blood vessels), shows the lower uptake in all tissues. Activity in spleen, liver, and kidneys (which are now visible because of the lower level of activity in the spleen and the liver) is about equal. Abbreviations: H = heart; K = kidney; L = liver; S = spleen.

Case Report

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Laboratory findings indicated a severe nephrotic syndrome (Table 1). Trace amounts of monoclonal free chains were present in the serum and urine. Similarly, immunofluorescence with monoclonal antibodies to human heavy (, µ, and ) and light [ and ] chains showed only -expressing plasma cells in cytocentrifuged mononuclear cells separated from a bone marrow aspirate from the posterior iliac crest. A renal biopsy specimen showed diffuse deposits of amyloid. Scintigraphy after intravenous administration of Iodine-123-labeled purified human serum amyloid P component showed amyloid deposits in the spleen and liver Figure 1, top) [6]. The clearance of Iodine-123-labeled serum amyloid precursor from the plasma was increased, with a low half-time of 9.8 hours. Cardiac involvement was suggested by electrocardiographic changes (lateral repolarization abnormalities and low voltage). Autonomic nerve involvement was shown by abnormal cardiovascular autonomic function, as measured by changes in blood pressure and heart frequency during standing deep breathing, Valsalva maneuver, and handgrip exercise (Table 1).

In June 1991, therapy was started with melphalan, 12 mg/d, and prednisone, 90 mg/d, for 4 days every 4 weeks. No clinical or subjective improvement occurred after four courses (Table 1). In December 1991, the patient underwent syngeneic bone marrow transplantation after conditioning with cyclophosphamide (60 mg/kg body weight on 2 consecutive days and total body irradiation [12 Gy, reduced to 8.5 Gy to the lungs]. Because the bone marrow graft was from an identical twin (as shown by DNA testing), prophylaxis for graft-versus-host disease—T-cell depletion of the donor marrow or immune suppression—was not done. The period after transplantation was uneventful, with complete hematopoietic reconstitution occurring within 6 weeks. The patient did not receive hematopoietic growth factors. Graft-versus-host disease did not develop. She improved gradually, performance status returning to normal during the next 6 to 12 months. Edema, proteinuria, hypoalbuminemia, hypercholesterolemia, and autonomic neuropathy resolved and electrocardiographic studies showed no abnormalities. Monoclonal light chains disappeared from both urine and serum 6 and 26 months after transplantation, respectively. Plasma cells expressing only chains were present 6 months after bone marrow transplantation but not at 12 and 24 months.

Evaluation of amyloid deposits with Iodine-123-labeled serum amyloid precursor scintigraphy showed a strong decrease in serum amyloid precursor accumulation in the spleen and a minor decrease in the liver. The change is shown in Figure 1. Before transplantation (top), there is scarcely any background activity. After transplantation (bottom), the decrease is clearly visible from the high, persistent, blood-background activity. (Both images were obtained 24 hours after injection.) The rate of Iodine-123-labeled serum amyloid precursor clearance from the plasma was still prolonged (half-time, 11.6 hours compared with 30 to 31 hours for normal persons), but the decrease in the amyloid mass was shown best by the prolonged 6-hour plasma retention (Table 2).

Discussion

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The pathogenetic mechanism of AL amyloidosis is the production of free light chains—usually chains—by a relatively small population of monoclonal plasma cells in the bone marrow. For the development of AL amyloidosis, minimal chain production is sufficient. Patients with the disease meet the criteria for benign monoclonal gammopathy. Chemotherapy including intermittent melphalan and prednisone does not completely eradicate the monoclonal plasma cells and therefore does not usually halt the progression of AL amyloidosis. We have shown a possible new approach to the treatment of AL amyloidosis. Our patient did not respond to therapy with melphalan and prednisone, but all clinical symptoms resolved after syngeneic bone marrow transplantation. This improvement was probably related to a marked decrease in the production of monoclonal chains, which were not detected 1 year after bone marrow transplantation. Dose intensification was probably responsible for the eventual elimination of the monoclonal plasma cell population.

All clinical symptoms disappeared completely; however, amyloid deposits, as shown by scintigraphy, had not disappeared Figure 1, but they had decreased markedly, especially in the spleen. Clearly, the rate of clearance of Iodine-123-labeled serum amyloid precursor from the plasma is more sensitive than quantitation of Iodine-123-labeled serum amyloid precursor accumulation alone for assessing the metabolism of amyloid [7, 8]. Patients with extensive systemic amyloidosis show rapid clearance of serum amyloid precursor from the circulatory system because of deposits of the isotope in the affected organs. In normal persons, the mean half-time for clearance of serum amyloid precursor from plasma is 31 hours, whereas the half-time in our patient was 9 to 10 hours.

Although the relative quantity of amyloid in the affected organs 2 years after bone marrow transplantation was diminished, clearance of serum amyloid precursor from the plasma remained at an increased level. Because amyloid degrades very slowly, more time would be needed to show a significant decrease in amyloid accumulation. Nevertheless, it is remarkable that clinical symptoms disappeared earlier than did the amyloid deposits. We cannot explain this phenomenon. Our patient's outcome indicates that intensive treatment may improve the prognosis in patients with AL amyloidosis. Further studies involving more patients and extensive follow-up are needed to further define the role of this new therapy.