Amyloidosis: Improved Outcome with High-Dose Melphalan and Autologous Stem Cell
Amyloidosis: Improved Outcome with High-Dose Melphalan and Autologous Stem Cell Support
ABSTRACT & COMMENTARY
Synopsis: The deposition of amyloid in tissues (particularly heart, liver, and kidney) associated with a plasma cell disorder leads to death in half the patients at 13 months from diagnosis. A group of 25 such patients were treated with high-dose melphalan and autologous stem cells. At two years, 68% of patients are alive and 65% of those surviving have had an improvement in amyloid involvement of organ systems previously involved.
Source: Comenzo RL, et al. Blood 1998;91:3662-3670.
Amyloidoses are classified according to the protein deposited and whether the deposition is systemic or local (organ-limited). The most common amyloidosis is primary amyloidosis or light chain amyloidosis (designated AL). Only about 20% of patients with amyloidosis have myeloma, but they all have clonal plasma cell disorders. The distinction between amyloidosis and myeloma is that in myeloma, intact immunoglobulin molecules are produced with light chains being produced in excess; in amyloidosis, only light chains are produced. About 15-20% of all myeloma patients have amyloidosis.
Primary amyloidosis is usually diagnosed by detecting monoclonal light chains in the urine or serum plus any one of the following symptoms: nephrotic syndrome, hepatomegaly, carpal tunnel syndrome, macroglossia, malabsorption, peripheral neuropathy, or cardiomyopathy. Median survival for patients with primary amyloidosis is about a year. Treatment with approaches that are used in myeloma have been only moderately successful and, in general, diagnosis is not made until organ damage is largely irreversible. Given the aggressive nature of the disease, Comenzo and colleagues at Boston University School of Medicine have been exploring the use of high-dose melphalan and autologous stem cell transplantation in a series of 25 patients with primary amyloidosis.
Patients were 18-61 years old and had biopsy-documented amyloidosis in association with a clonal plasma cell disorder. Eight had dominant cardiac involvement, seven had dominant renal involvement, six had dominant hepatic involvement, three had dominant neuropathic involvement, and one had lymphatic involvement. Two patients died before receiving chemotherapy: one with hepatic disease died of a massive gastrointestinal bleed after stem cell collection but before receiving chemotherapy, and the other had cardiac involvement and died of hypoxia and hypotension within 24 hours after stem cell collection. The other 23 patients received melphalan at 200 mg/m2 (100 on day -4 and 100 on day-3) followed by either unselected peripheral blood stem cells or CD34-selected peripheral blood stem cells on day zero.
With a median follow-up time of two years, 17 of 25 patients (68%) are alive; 13 of 15 patients (87%) with up to two organ systems involved are alive, and 4 of 10 patients (40%) with more than two involved organ systems are alive. Complete hematologic responses were documented in 62% of the evaluable patients, including all eight patients without a serum paraprotein and five of 13 with serum paraprotein elevation. Three of the complete responders have relapsed. Improvement in amyloid-involved organ function was noted in 11 of 17 (65%) of the surviving patients, and four others have stable disease. Patients with dominant cardiac involvement fared the poorest, but three of eight patients with symptomatic amyloid cardiomyopathy survived and their cardiac function improved.
COMMENTARY
Death in patients with primary amyloidosis is related to dysfunction of organs infiltrated with immunoglobulin light chains. This disease is different from most other neoplastic diseases. The tumor product contributes more to the disease's natural history than to the tumor mass. This series of patients demonstrates that treatment aimed at the underlying malignant cell is capable of prolonging survival and reversing amyloid-induced organ dysfunction. The therapy clearly influences the production of immunoglobulin light chain; however, in addition, the improved function of infiltrated organs implies that tissue amyloid deposits are being turned over or mobilized in some fashion.
There is precedent for this mechanism, as we highlighted here three years ago. Gianni and colleagues1 serendipitously discovered that iododeoxydoxorubicin-an experimental anthracycline being developed to bypass drug resistance mechanisms-was capable of binding to amyloid fibrils and promoting reabsorption. In that first small series, patients with amyloidosis survived nearly four years. It remains unclear whether therapy directed at amyloid deposit turnover will be as effective as therapy directed at the malignant cell that produces the amyloid.
Reference
1. Gianni L, et al. Blood 1995;86:866-61.
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