Treatment of AL Amyloidosis with Tandem Cycles of High Dose Melphalan and Autologous Stem Cell Transplantation: Final Analysis of a Prospective Trial.

AL amyloidosis is caused by a clonal plasma cell dyscrasia and is characterized by widespread, progressive amyloid deposition leading to multisystem organ failure and death. In this disease, amyloid protein deposits are derived from monoclonal immunoglobulin light chains. Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. Furthermore, we have observed in over 300 patients treated with HDM/SCT that achievement of a hematologic complete response (CR), i.e. disappearance of monoclonal gammopathy and clonal plasma cell dyscrasia, is a critical determinant of clinical improvement and prolonged survival. Because of the importance of hematologic CR in treatment outcome, we conducted a prospective trial to determine whether a second cycle of HDM/SCT would induce a hematologic CR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Additional objectives of the trial were to determine the feasibility and tolerability of tandem cycles of HDM/SCT in AL amyloidosis. Eligibility for entry into the trial required evidence of plasma cell dyscrasia, age < 65 years, ≤ 300 mg of prior oral melphalan, and minimal measures of performance status (SWOG ≤ 2) and cardiopulmonary function (LVEF > 45%, DLCO > 50%). Peripheral blood stem cells were collected by leukapheresis following G-CSF mobilization, with minimum yields of 7.5 x 10⁶ CD34+ cells/kg required for participation in the trial. From 11/2000 to 6/2005, 62 patients, median age 55.5 (range 32–65), M: F ratio 1.8:1.0, were enrolled. Of the 62 patients enrolled, 9 (15%) were removed from the protocol either because of an inadequate stem cell collection (7) or because of complications during stem cell mobilization and collection that precluded treatment with HDM/SCT (2). Of the 53 patients who received the first cycle of 200 mg/m² HDM, 4 patients died within 100 days of treatment (8%), and 27 (55%) were found to have achieved a hematologic CR 6 months after HDM/SCT. Of the 22 patients who did not achieve a CR after initial treatment, 17 patients received a second HDM/SCT with 140 mg/m² of IV melphalan. Mortality within 100 days after this second treatment was 6% (1/17), while 27 % (4/15) of surviving patients achieved a hematologic CR by 6 months following the second cycle of HDM/SCT. Therefore, for the patients treated with one or two cycles of HDM/SCT on this study, the ultimate hematologic CR rate was 63% (31/49). With a median follow up of 38 months (range, 14–69 months), the median survival for all patients enrolled has not yet been reached. Moreover, improvements in amyloid related organ dysfunction, particularly in nephrotic syndrome, liver involvement, neuropathy and/or performance status, were evident in all patients who achieved a hematologic CR. In conclusion, tandem cycles of HDM/SCT are tolerable for selected patients with AL amyloidosis and can increase the proportion of patients who ultimately achieve a hematologic CR.