Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation

Abstract

Primary systemic amyloidosis results due to deposition of clonal immunoglobulin light chains in various organs resulting in organ failure and subsequent death. Melphalan and Prednisolone has been the standard first line therapy until late 1990's when aggressive treatment with high dose chemotherapy (HDT) followed by peripheral blood stem cell transplantation (PBSCT) showed higher response rate and improved overall survival. In the present study , authors at Boston Medical Center, USA studied the longterm outcome of HDT followed by PBSCT. Between July 1994-July1997, 80 patients with a median age of 56 years (range, 29 to 71) diagnosed to have primary systemic amyloidosis and SWOG (South Western Oncology Group) performance status of 1 (0 to 3) entered the study. 48% had cardiac involvement and on an average two organs (range=1-5) were involved with amyloid. All patients met eligibility criteria: confirmed tissue diagnosis of amyloidosis, clear evidence of clonal plasma cell dyscrasia, age > 18 years, performance status (SWOG 0-2), cardiac function >40%, pulmonary function (O 2 saturation >=95% on room air), hemodynamic stability (baseline systolic blood pressure >=90 mm Hg). Patients on peritoneal or hemodialysis for renal failure were not excluded if they met eligibility criteria. Stem cell mobilization was done with G-CSF (granulocyte colony stimulating factor) and HDT included intravenous melphalan (100-200 mg/m 2 ) followed by stem cell transplant 24-72 hours after completion of chemotherapy. Response evaluation included-hematological assessment and was defined as absence of monoclonal protein in serum and urine by immunofixation electrophoresis together with a bone marrow biopsy showing less than 5% plasma cells without clonal dominance of k or l light chain isotypes and was done at end of one year. Transplant related mortality (TRM) was defined as death within 100 days of transplant including mobilization and collection days. 17 patients could not be evaluated as they died within 1 st year of study (14% due to transplant related mortality and 8% due to disease per se). Statistical analysis of survival was done using Kaplan-Meier method. Among 63 evaluable patients, 32 (51%) achieved complete hematological response (CHR) with a relapse rate of 34% within 2.5 years and survival at 10 years being 53% in this subgroup. Median survival has not reached yet. Relapses occurred in 34% within 2.5 years and were treated with second line therapy. 31 (49%) patients who did not achieve hematological CR formed the other subgroup and had median survival of 50 months and probability of survival at 10 years being 6%. The survival at 10 years in both these subgroups was statistically significant (p<0.001). The median survival was higher (p=0.20) in the patients receiving full dose melphalan (200 mg / m 2 ) versus modified dose. In patients who achieved CR, 15/32 (47%) have died compared to mortality rate of 97% (30 of 31) in patients who did not achieve CR. Causes of death in the subgroup achieving CHR were progressive disease (n=6), therapy related myelodysplastic syndrome and acute myelogenous leukemia (n=1), solid tumours (n=2) and organ dysfunction despite CHR (n=6). Overall, the median survival for these 80 patients was 57 months and long-term survival beyond 10 years was achieved in 18 patients (23%) of which 17 belonged to group who achieved CHR and 1 belonged to the non CHR group. Thus, achievement of complete hematologic remission following high dose chemotherapy and stem cell transplantation was the most powerful predictor of long term survival.