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High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial



High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial



Bone Marrow Transplantation 33(4): 381-388



AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by progressive, widespread amyloid deposition leading to multisystem organ failure and death. Aggressive treatment with high dose IV melphalan and autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. We conducted a prospective randomized trial designed to study the timing of HDM/SCT in the treatment of AL amyloidosis with survival as a principal end-point. Newly diagnosed, untreated patients were randomized to receive HDM/SCT as initial therapy (Arm I) or following 2 cycles of oral melphalan and prednisone (Arm II). From 10/1996 to 12/2000, 100 patients, median age=56 (range 37-80), M:F=1.8:1, were enrolled. Eligibility required diagnosis within 1 year of enrollment, no prior chemotherapy, and minimum measures of performance status (SWOG 0-3), cardiac function (LVEF>40%), and baseline systolic blood pressure >90mm Hg. Peripheral blood stem cells were collected by leukapheresis following G-CSF mobilization, with minimum yields of 2.5X106 CD34+ cells/kg required for HDM/SCT. Depending on age and clinical status, patients received total IV melphalan doses of 200 or 140 mg/m2 over 2 days. Fifty-two patients were randomized to Arm I and 48 to Arm II. Median age and M:F were very similar in each group. The predominant visceral site of amyloid involvement was renal in 56% of patients in both groups. A substantial proportion of patients also had evidence of cardiac involvement by ECG and ECHO: 34 patients in Arm I (65%) and 23 patients in Arm II (48%). Of the 52 patients on Arm I, 9 (17%) did not proceed to HDM/SCT because of disease progression/death (n=1), complications during stem cell mobilization and collection (SCMC) (n=4), or patient withdrawal (n=4). Of the 48 patients on Arm II, 16 (33%) did not proceed to HDM/SCT because of progression of disease/death prior to SCMC (n=8), complications or death during SCMC (n=6), or patient withdrawal (n=2). With 12-58 mos of follow-up, median overall survival has not been reached for either treatment arm by Kaplan-Meyer analysis. However,overall survival of patients 1 year after randomization was significantly higher for patients in Arm I (70%) than for those in Arm II (58%) when the distribution of patients with cardiac involvement was taken into account (p=0.04). For the subgroup of patients with cardiac involvement, median survival was reached and was significantly longer for those in Arm I (19.6 mos) than for those in Arm II (5.3 mos)(p=0.02). On the other hand, there was no significant difference in survival after HDM/SCT for the 43 patients in Arm I and 32 patients in Arm II who completed treatment (79% survival 1 year after HDM/SCT in Arm I, 81% in Arm II). There was also no difference in complete hematologic responses (35% of patients in Arm I, 30% in Arm II, 1 year after HDM/SCT). Hence, newly diagnosed patients with AL amyloidosis, eligible for aggressive treatment with HDM/SCT, did not benefit from initial treatment with oral melphalan and prednisone prior to HDM/SCT. Indeed, for patients with cardiac involvement, there was a survival disadvantage if HDM/SCT was delayed by initial treatment with the evidently less effective therapy.

Accession: 035037148

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PMID: 14676787

DOI: 10.1038/sj.bmt.1704346


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