Outcomes of Autologous Hematopoietic Stem Cell Transplantation in Patients with Light-Chain Amyloidosis: A Systematic Review and Meta-Analysis

Background: Light-chain (AL) amyloidosis is a rare plasma cell disorder involving the deposition of misfolded light-chain proteins in various tissues, leading to organ dysfunction. For patients with AL amyloidosis and preserved organ function, high-dose chemotherapy followed by autologous hematopoietic cell transplantation (ASCT) is considered the mainstay of the treatment. However, the outcomes after ASCT for AL amyloidosis remain heterogeneous due to the patient selection, the pattern of organ involvement, and therapy-related complications. This systematic review/meta-analysis aimed to investigate the outcomes of ASCT in patients with AL amyloidosis.

Methods: Eligible articles were retrieved from Embase, CENTRAL, Clinicaltrials.gov, Medline, and Pubmed databases following PRISMA guidelines using search terms related to "AL amyloidosis" and "autologous hematopoietic cell transplantation." Inclusion criteria included studies reporting outcomes of patients with AL amyloidosis who received ASCT. We screened 1326 articles for eligibility, and 28 studies met the inclusion criteria for pooled analysis. The inter-study variance was calculated using the Der Simonian-Laird Estimator. We assessed heterogeneity in the meta-analysis with the I2 statistics. Patient characteristics were reported descriptively. Twelve- and 24-month overall survival (OS) and progression-free survival (PFS), along with 100-day mortality and treatment-related mortality (TRM) rates, were extracted and combined for pooled rates. Proportions with 95% confidence intervals (CI) were computed using the inverse variance method with the random-effects model. All statistical analyses were performed using R version 4.3.2 and "meta" package version 7.0.

Results: We included 6987 patients from 31 studies in the systematic review. The median age was 64.7 (23-83) years, and 3206 (46%) of patients were male. Concomitant multiple myeloma was observed in 23% of the patients (n=1601). Cardiac, renal, gastrointestinal/hepatic and neurologic involvement was found in 1363 (31.7%), 2096 (48.8%), 536 (12.5%), and 302 (7%) patients, respectively. The median follow-up was 40.4 (0.4-223) months. The median time from diagnosis of AL amyloidosis to ASCT was 17.8 (0-146 months) months. The median ECOG performance status was two or less, and Karofsky's performance status was 80% or lower (60-100%). Most of the patients (77%, n=4033) had a melphalan-based conditioning regimen, 1019 (20%) patients had a bortezomib-based regimen, and 164 (3%) patients had other regimens such as an immune-modulatory drugs-based regimen. Melphalan dose was 200 mg/m2 in 3152 (80.7%) patients and less than 200 mg/m2 in 753 (19.3%) patients. Complete response (CR) was seen in 551 (41%) of patients, and partial response (PR) was noted in 807 (59%) patients. The pooled 12-and 24-month OS rates were 84% (95% CI 79-89%, I2 87%) and 76% (95% CI 62-86%, I2 84%), while the pooled 12-and 24-month PFS rates were 86% (95% CI 77-91%, I2 54%) and 69% (95% CI 57-79%, I2 62%), respectively. The pooled 100-day mortality and TRM rates were 6% (95% CI: 4-9%, I2 57%) and 6% (95% CI: 4-9%, I2 55%), respectively. The most common causes of mortality were multi-organ failure due to sepsis (n=28), cardiac involvement (n=27), hemorrhage (n=8), pneumonia (n=1), splenic rupture (n=1), and engraftment syndrome (n=1).

Conclusion: This systematic review confirms ASCT as a curative and feasible therapeutic option for AL amyloidosis patients. However, it also highlights the concern of complications, particularly multi-organ failure. Careful patient selection, including adequate renal and cardiac function, can optimize outcomes. An ongoing Blood and Marrow Transplant Clinical Trials Network randomized clinical trial will evaluate the role of high-dose chemotherapy and autologous stem cell transplant in the Daratumumab era. There could be a role of chimeric antigen receptor T-cell therapy in relapsed/refractory AL amyloidosis patients. We strongly encourage enrollment in the clinical trials.