Stem-Cell Transplantation for Amyloidosis: Improving Outcomes but Not for the Faint of Heart.

Immunoglobulin (Ig) light-chain amyloidosis (AL) is a multisystem disorder characterized by the deposition of misfolded immunoglobulin light chains as amyloid fibrils, leading to organ dysfunction. Prognosis of patients with AL amyloidosis is greatly impacted by the degree and pattern of organ involvement, with cardiac involvement as the key determinant of outcome. Therapy of AL amyloidosis has been largely directed toward the often indolent plasma cell clone responsible for the production of amyloidogenic Ig and inspired by advances in the therapy of multiple myeloma (MM). High-dose melphalan (HDM) with autologous stem-cell transplantation (ASCT) was introduced for the therapy of AL amyloidosis nearly 20 years ago. An attractive aspect of HDM/ASCT is the rapid reduction in amyloidogenic Ig and the depth of hematologic responses, which correlates with improvement in organ function. However, HDM/ASCT is also associated with higher rates of early transplantation-related mortality (TRM; ranging from 13% to 43%) in AL compared with the experience with this approach in MM. Nonetheless, several studies documented the feasibility of durable hematologic and organ responses and improved survival in patients treated with this approach. Another strategy that led to clinical responses was therapy with dexamethasone, initially alone, but soon combined with alkylating agents such as cyclophosphamide or melphalan. These data set the stage for a randomized clinical trial comparing HDM versus melphalan and dexamethasone (MelDex) in patients with AL amyloidosis. This trial failed to show superiority of HDM/ASCT over MelDex, but the interpretation was complicated by high rates of treatmentrelated early mortality (24%) observed in the ASCT arm. These data also dampened the enthusiasm for the use of ASCT in AL amyloidosis in recent years, particularly in Great Britain. Several hypotheses, including the role of patient selection, single-center versus multicenter nature, experience of the transplantation centers, and details of peritransplantation care, have been invoked to help understand the variance in TRM between different studies. Of these, the most objective data exist as to the importance of patient selection. Given the importance of cardiac involvement, it is not surprising that biomarkers of cardiac injury/dysfunction, such as cardiac troponin T and brain natriuretic peptide (BNP) or N-terminal pro-BNP, are important in predicting outcome and form the basis of current staging in AL amyloidosis. Although these staging systems are not optimal for selecting patients for ASCT, excluding patients with elevated cardiac biomarkers (eg, cardiac troponin T 0.06 ng/mL and N-terminal pro-BNP 5,000 ng/L) has permitted transplantation centers to reduce TRM to single-digit estimates, while permitting selected patients with cardiac AL to potentially benefit from this procedure. Whether application of such patient selection criteria will allow similarly low rates of TRM in the context of prospective multicenter studies of ASCT in AL amyloidosis remains to be demonstrated. Consideration of ASCT-based therapy for AL amyloidosis has been further complicated in recent years by the introduction of combination therapies with novel agents, particularly those using bortezomib. In single-arm studies, these regimens have been shown to mediate rapid reduction in light chains and high rates of hematologic response, with resultant improvement in organ function. Bortezomib-based regimens may also lead to improved organ function in patients who otherwise would not be candidates for ASCT at initial diagnosis because of the degree of organ dysfunction. Although the superiority of bortezomib-based therapies over MelDex has not yet been established in the context of a randomized trial, the rapid kinetics of hematologic response with these regimens raises questions about whether ASCT should be the preferred initial therapy even in ASCT-eligible patients. The ability to design larger multicenter studies with ASCT in AL amyloidosis depends on the feasibility of carrying out these studies with acceptable transplantation-related early mortality (EM). The study by D’Souza et al provides an important step in this direction. The authors analyzed data from the Center for International Blood and Marrow Transplantation Research database from 134 centers over three 5-year time cohorts between 1995 and 2012. The data demonstrate that in this real-world experience, impressive reductions in transplantation-related EM have been obtained over the past decade, and in the most recent cohort, the day 100 mortality rate of 5% is comparable to that achieved at larger centers. These data should provide reassurance when designing randomized studies comparing ASCT. Unfortunately, the lack of data about cardiac biomarkers, even in the most recent cohort, makes it difficult to evaluate the possible reasons behind the observed improvement in outcome and the contribution of better patient selection (v other possibilities) to the observed results. Centers that performed more AL transplantations a year (using a somewhat arbitrary cutoff of four or more transplantations per year) had a lower EM rate compared with centers that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 32 NOVEMBER 1