Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation

AL (primary or immunoglobulin light chain) amyloidosis (AL) differs from my eloma per se in that tissue deposits of amyloid are found, typically in ass ociation with smalt numbers of clonal plasma cells producing lambda light c hains, and also in that AL patients typically present with a predominantly dysfunctional organ-system This constellation of features - fibrillar depos its comprised of light chains, lambda light chain predominance, and organ-s ystem tropism and dysfunction - remains unexplained. Select patients with A L respond to haemopoietic stem cell transplantation (SCT) with clinical imp rovement and extended survival. particularly those who do not have cardiac involvement. In order to ascertain whether the organ-system tropism of AL w as associated with immunogloblin light chain variable region (Ig V-L) germl ine gene utilization, we attempted to clone, sequence and assign germline d onors to the clonal Ig V-L genes of 62 AL patients, all of whom were treate d with SCT. We succeeded in 39 cases, identifying clonal AL genes derived f rom donors of the lambda I (n=10), lambda II (n = 5), lambda III (n = 6), l ambda VI (n = 11) and KI (n = 7) subtypes. The majority of the donors (IGLV 6S1, DPL5, DPL2, DPL23 and LFVK431) were genes that appear in the expressed repertoire <5% of the time, suggesting an intrinsic propensity to form amy loid under certain conditions. Patients whose clones derived from the lambd a VI IGLV6S1 donor uniformly presented with dominant renal involvement whil e those with other V-lambda or unknown donors often had dominant cardiac or other organ involvement, particularly patients whose clones derived from t he XI DPL2 donor. In addition, both early (<3 months) and overall post-SCT survival were significantly better in lambda VI IGLV6S1 patients compared t o patients with other V-lambda donors. These findings indicate that there a re important associations in AL amyloidosis among Ig V-L gene utilization, organ-system tropism and post-SCT survival.