Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients

Abstract

Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stemcell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatmentrelated mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR. (Blood. 2011;118(16):4346-4352) IntroductionImmunoglobulin light chain (AL) amyloidosis is the most common form of systemic amyloidosis, with an incidence of 5-12 persons per million per year. 1 In AL amyloidosis, clonal bone marrow plasma cells produce monoclonal light chains that misfold and deposit in tissues and organs as amyloid fibrils, resulting in progressive system and organ failure, and ultimately in death. Untreated patients with this disease have a dismal outcome, with a median survival of 10-14 months from diagnosis. 2 Moreover, fewer than 5% of patients survived for Ͼ 10 years before the introduction of high-dose melphalan and stem cell transplantation (HDM/ SCT). 3 Oral melphalan and prednisone (MP) modestly increases the median survival to 16-18 months and rarely induces hematologic complete responses (CRs) or reversal of organ dysfunction. 2,4,5 The introduction of HDM/SCT in the 1990s appears to have markedly improved these results. 6 Single and multicenter studies show CR rates of 16%-67%, organ responses in 25%-45% of patients, and a median overall survival (OS) of ϳ 5 years. [7][8][9][10][11][12][13][14][15][16] A case-control study demonstrated the benefit of this procedure for patients younger than 70 years compared with nontransplant regimens, most of them alkylator-based oral chemotherapy. 17 A major issue in HDM/SCT for AL amyloidosis is the potential for high treatment-related mortality (TRM) because of underlying organ dysfunction in this disease. Some early multicenter series reported TRM as high as 40%, but recent reports from experienced single centers have reported a TRM rate in the range of 10%-15% as a result of improved selection of patients and better peritransplantation management. [17][18][19] In previous reports, we and others have shown that patients who achieve CR after HDM/SCT have ...

Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement

“…However, it is intriguing that the dose of melphalan did not affect OS, contrary to our observation in a series of all amyloid patients, including those with cardiac involvement. 13 Median EFS was 36 months and there was a trend toward shorter EFS in stage III cardiac involvement (33 months) compared with stage I and II (not reached). Univariate and bivariate analysis did not show any statistically significant prognostic variables.…”

“…In HDM/SCT, hematologic CR correlates with EFS, OS, cardiac response and reduction in cardiac biomarkers. 7,13 Patients who do not achieve a VGPR or have a less than 90% reduction in serum FLCs exhibit a much worse prognosis. 16,17 In our series, the hematologic CR rate was 27% by intention-to-treat analysis, which compares with 43% in all evaluable patients with AL amyloidosis treated with HDM/SCT in our previous series.…”

“…The dose of melphalan depended on severity of cardiac disease, performance status and other co-morbidities, as described previously. 12,13 All patients were assessed for hematologic and cardiac responses at 6 and 12 months post transplant, and annually thereafter. Death was reported by patients' family or physician or confirmed using the Social Security Death Index at http://ssdi.rootsweb.ancestry.com.…”

Not too little, not too much—just right! (Better ways to give high dose melphalan)

“…[16][17][18][19][20] However, high-dose intensity also is associated with improved disease response. 21,22 Palumbo et al 23 reported improved PFS with melphalan 200 mg/m 2 rather than melphalan 100 mg/m 2 , but increased gastrointestinal toxicity was noted.…”

Outcomes of autologous hematopoietic cell transplantation in primary amyloidosis after bortezomib-based induction therapy

“…1,2 There has been an increasing interest in using induction chemotherapy to cyto-reduce and achieve good hematologic and organ responses prior to AHCT in amyloidosis. 3,4 Bortezomib is a proteasome inhibitor with activity in plasma cell disorders that has been reported to achieve high rates of hematologic and organ response in amyloidosis.…”