Long-Term Outcome Of Patients With AL Amyloidosis Treated With High-Dose Melphalan and Stem Cell Transplantation: 19 Year Experience At a Single Center

Aggressive treatment of AL amyloidosis with high dose intravenous melphalan followed by autologous stem cell transplant (HDM/SCT) is effective in inducing hematologic and clinical remissions associated with prolonged survival. We have performed 593 transplants from July 1994 to December 2012 in the Amyloidosis Center at Boston Medical Center/Boston University School of Medicine. Patients were enrolled in several sequential institutional review board–approved protocols during the 19-year study period. Eligibility criteria for all protocols required biopsy proof of amyloid disease; evidence of a plasma cell dyscrasia and exclusion of other types as appropriate; at least one major affected organ; and adequate measures of cardiac and pulmonary function, and performance status. Functional measures included cardiac ejection fraction 40% or greater, absence of symptomatic pleural effusions, absence of heart failure or arrhythmias resistant to medical management, oxygen saturation of 95% or greater on room air, lung diffusion capacity of 50% or more of predicted, supine systolic blood pressure of 90 mm Hg or greater, and Southwest Oncology Group performance status score of 2 or less unless limited by peripheral neuropathy. Age, renal function, time from diagnosis, prior therapy, and details of the conditioning regimen varied among the trials.

Overall, the median age of patients treated with HDM/SCT was 57 years (range, 28-80). Treatment-related mortality (TRM) defined as death occurring within 100 days after SCT occurred in 51 patients, leading to overall TRM of 9% (n=51/593). Additionally, there were 11 deaths during stem cell mobilization and collection phase. No death has occurred since 2005 during stem cell mobilization and collection and TRM has improved to 5% (n=11/235). Total of 324 patients (55%) received full dose melphalan at 200 mg/m² and 269 (45%) received modified dose melphalan at 100-140 mg/m² per protocol, based upon age and organ function. Hematologic CR, as defined by international consensus criteria, occurred in 40% (n=202/508) of evaluable patients measured at 6-12 months post SCT; by intention-to-treat the CR rate was 34%. Hematologic CR occurred in 44% (n=129/291) patients who received 200 mg/m² of HDM compared to 34% (n=73/217) patients who received 100-140 mg/m² of HDM (chi square p=0.015). Hematologic relapse occurred in 40 patients (20%) with CR at a median of 3.9 years (range, 1.6-12.4). The median overall survival (OS) is 6.7 years with a median follow-up of 4.5 years. The median OS has not been reached for patients achieving a hematologic CR but exceeds 12.4 years, compared to 5.9 years for those not achieving CR (log-rank p<0.001). The median OS for patients following hematologic relapse is 3.5 years. Twenty-five % of patients are alive, up to 19 years after undergoing HDM/SCT.

These data highlight the remarkable long-term survival results that can be obtained in patients with AL amyloidosis treated with HDM/SCT. While survival is strongly dependent upon achieving a hematologic CR, the survival of patients who do not achieve a CR and of those who relapse after CR also is notable, suggesting a benefit of treatment. Strategies to improve risk-stratification of patients and reduce TRM, as well as using sequential or combination therapies to increase the CR rate, will likely improve outcomes in the future for patients who just a few years ago were considered to have a rapidly fatal diagnosis.