Outcome of Patients with AL Amyloidosis Who Do Not Achieve Hematologic Complete Response After Treatment with High Dose Melphalan and Autologous Transplantation: Results In a Series of 421 Patients

Treatment of AL amyloidosis with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) results in hematologic complete response (CR) in 40% of patients and a median survival of about 5 years. Hematologic CR is associated with improved organ function and long survival. Whether patients who fail to achieve CR have any benefit from HDM/SCT has not been examined in a large series of patients. OBJECTIVE: The aim of this study was to investigate the outcome of patients with AL who do not achieve a CR after HDM/SCT and assess the transplant-related mortality (TRM) at a single specialized referral center. DESIGN and PATIENTS: Retrospective analysis of 421 patients with AL amyloidosis treated with HDM/SCT (100 to 200 mg/m²) in the Amyloid Treatment and Research Program at Boston Medical Center between July 1994 and December 2008. The subgroup of patients who did not achieve a CR at 1 year after transplant was analyzed in detail to assess their outcome in terms of organ response, event-free survival (EFS) and overall survival (OS). The median follow-up was 4 years (range, 0 to 15.6) for the entire cohort and 6.3 years (range, 1 to 15.6 years) for surviving patients. RESULTS: Three hundred and forty patients out of 421 included in the study (81%) were evaluable for response at 1 year post-HDM/SCT. The CR rate among the 1-year survivors was 43% while 195 patients (57%) did not achieve a CR, defined as disappearance of all signs of monoclonal gammopathy and bone marrow plasmacytosis. By consensus criteria, organ response rate in the non-CR group was 53.3%, compared to 78.6% for CR-patients (p<0.0001). Hematologic and/or clinical progression was observed in 68% (133/195) of non-CR patients, with a median time to progression of 1.5 years (range, 0.13 to 11.3). More than half of these patients (68/133) received second line therapy with melphalan (4), thalidomide (21), bortezomib (8), lenalidomide (24), dexamethasone (8), a second HDM/SCT (2), and a reduced-intensity allogeneic SCT (1). Fifty (26%) of the non-CR patients are alive and clinically stable, although 12 of them received further treatment due to persistence of clonal disease without evidence of clinical/organ progression. Median EFS in the non-CR population was 2 years (CI95% 1.6–2.7), as compared with 8.3 years for patients in CR (p<0.0001). Outcome of non-CR patients in terms of event rate and EFS was not influenced by the light chain isotype. The OS was significantly longer for evaluable patients who achieved a CR compared with those who did not (13.2 versus 5.9 years, p<0.0001). The estimated probability of survival for patients in CR was 86% (CI95% 79–91%) at 5 years and 67% (CI95% 57–76%) at 10 years, while it was 58% (CI95% 50–65%) and 24% (CI95% 16–32%) at 5 and 10 years, respectively, for those who did not achieve CR. At the time of this analysis, 234 (55.5%) of the 421 patients have died, 81 (19.2%) of them within the first year after HDM/SCT. Transplant-related mortality was 11.4%, decreasing to 5.6% for the 124 patients who received HDM/SCT in the last 5 years, despite the fact that the patients' clinical characteristics were similar in the two time periods. CONCLUSIONS: Treatment of selected AL patients with HDM/SCT resulted in durable hematological responses, high organ response rate and a median OS of almost 6 years even in those who do not achieve a CR after HDM/SCT.

Supported by NIH HL-68705 and Instituto de Salud Carlos III (grant CM07/00108).

Sanchorawala: Celgene corp: Research Funding.