Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents

      Background:  AL is characterized by the production of monoclonal light chains which misfold, deposit in various organs, including the heart, and cause early death. High dose melphalan with SCT results in high hematologic response (HR) rates and is standard treatment for eligible patients.  Achieving a CR to SCT results in extended EFS and OS.  We have studied novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve HR rates and outcomes.  In this report we examine long-term outcomes of pts who received initial therapy with RA-SCT followed by consolidation for HR < CR. 

Methods:  We performed a retrospective study to assess the HR rates, incidence of hematologic relapse and progression (R/POD) and OS of AL pts enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822).  OS was calculated from SCT to death or last follow up (f/u).  Median EFS and OS were estimated by the method of Kaplan Meier.  Cumulative incidence function was used to estimate the incidence of R/POD and death. 

Results:  Between 2002 and 2011, 83 pts were enrolled and underwent RA-SCT on these trials.  Following RA-SCT, pts with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first, and bortezomib and dexamethasone (BD) in the second trial.  36 pts had cardiac AL (43%) and all had free light chain (FLC) measurements used to score HR and R/POD using consensus criteria. The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. CR rates increased at 1 yr compared to 3 mos post-SCT from 21% to 36% with TD and from 28% to 62% with BD.  With a median f/u of 5.1 yrs, the EFS is 4.5 yrs (95% CI: 2.6 to NR) and the OS of all pts has not been reached (Figure 1).  16 pts died prior to R/POD and 26 pts have R/POD with a cumulative incidence of R/POD of 8%, 18%, and 29% at 1, 2 and 3 yrs, respectively.  31% (8/26) of relapsed pts have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR.  Median OS following R/POD was 5 yrs (95% CI: 2.6-5.8). 

Conclusions:  Half of the AL pts on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 yr post-SCT.  At 3 yrs post-SCT the cumulative incidence of R/POD was 29% and 1/3 of relapsed pts did not require therapy, likely due to the very sensitive FLC assay that detects low level R/POD in the absence of organ progression.  Almost 80% of pts requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 yrs. These results indicate that initial therapy with RA-SCT and consolidation is effective for patients with AL in the era of novel agents, and even relapsing pts have excellent outcomes. With over 5 ys of f/u, median OS has not been reached.

Figure  SEQ Figure \* ARABIC 1. EFS and OS following SCT and consolidation