Arnyloidosis of the AL type, due to depositions of clonal immunoglobulin (1g) light chains, is a rare plasma cell neoplasm (2,500 new cases annually in the USA) and a rapidly progressive orphan disease with a poor prognosis. Death usually occurs 2 to 3 years after diagnosis due to organ failure despite oral therapy with melphalan and prednisone. Since July 1994, in our multidisciplinary Amyloid Program that is dedicated to finding an effective therapy forthis disease, we have treated patients in Phase I and 11 trials with intravenous (IV) melphalan (FDA END #41,776) and mobilized blood stem-cell support. Results indicate feasibility and efficacy; indeed, the therapy is so much more effective than any current treatment that it is ethically difficult to design a clinical trial to evaluate it. We are testing, therefore, in a stratified randomized prospective Phase II clinical trial, the hypothesis that treating patients within I year of diagnosis with IV melphalan and blood stem-cell support is as effective as treating patients with 2 cycles of oral therapy followed by IV melphalan. Patients are followed at 3-month intervals to assess progressive amyloidosis, plasma cell response to therapy and quality of life. In order to test thehypotheses that clonal malignant cell contamination in stem-cell collections increases with mobilization and correlates inversely with duration of response to therapy, all patients have serial marrow and blood specimens, pre- and post-mobilization blood specimens and stem-cell collections, evaluated by PCR for rearranged Ig heavy chain genes. After cloning and sequencing, responding patients amplified genetic material, tumor-specific primers are constructed in order to quantitate with competitive PCR the tumor burden in patient samples. The significance of this work lies in defining an effective therapy for this rare and rapidly fatal disease. MALDI and ESI mass spectrometry are being utilized to characterize the Ig light chain material excreted in patient urine, in order to assist in definition of the biochemical consequences of the disease and treatment.
Showing the most recent 10 out of 253 publications
