Mobilization of Blood Stem Cells with G-CSF in Systemic Light-Chain Amyloidosis: Dominant Organ Involvement Significantly Affects Stem Cell Collection.

Abstract

Systemic light-chain (AL) amyloidosis is both a protein deposition disorder and a monoclonal plasma cell dyscrasia. Effective treatment depends on reduction of the clonal plasma cells that produce the toxic light chains. Although high-dose melphalan with autologous stem cell transplant (MEL SCT) is effective for AL patients, the mobilization and collection of peripheral blood stem cells with G-CSF can be problematic despite their lack of prior chemotherapy and minimal marrow infiltration with plasma cells. In addition, unusual toxicities of G-CSF mobilization such as hypotension have been noted in AL patients. As new therapies show efficacy in AL, the role of stem cell mobilization and MEL SCT will likely be re-evaluated, increasing the importance of understanding the variability in stem cell mobilization. Recent work has shown that the mechanism of G-CSF mobilization likely involves the sympathetic nervous system (Cell 2006; 124:407). Interestingly, amyloid is well known to cause autonomic neuropathy. In addition, involvement of the heart in amyloidosis has also been shown to cause cardiac adrenergic denervation. If G-CSF mobilization depends upon the sympathetic nervous system, then the type of organ involvement could predict the yield of stem cell collection in AL patients mobilized with G-CSF. With these concerns in mind, we retrospectively assessed the results of stem cell mobilization and collection in all patients with AL mobilized with G-CSF (6ug/kg bid) for 4 days, with collections beginning on day 5 with a collection target of 10x106 CD34+ cells per kg in up to 4 leukaphereses. At initial evaluation, we assessed patients using standard criteria to identify the dominant organ of involvement (Am J Hematol 2005; 79:319) and to determine candidacy for risk-adapted MEL SCT (Blood 2002; 99:4276). Over a 7-year period 105 patients with AL were mobilized and collected as described, including 40 with kidney (K), 21 with liver/GI or soft-tissue (L/GI/ST), 31 with cardiac (H) and 13 with peripheral nervous system (PNS) involvement. We recorded the number of leukaphereses per patient and the dose of CD34+ cells/kg collected per leukapheresis. There were no significant differences in the number of leukaphereses per group. The K, L/GI/ST and H groups had a median of 2, and the PNS group of 3, collections. There were significant differences in CD34+ cells/kg collected based on dominant organ involvement: patients with H or PNS involvement had significantly fewer CD34+ cells/kg collected (see figure below; K vs H p=0.03, K vs PNS p=0.02, L/GI/ST vs H p=0.07, L/GI/ST vs PNS p=0.04; two tailed Mann-Whitney). Moreover, 15/44 H+PNS patients failed to collect at least 4x106 CD34+cells/kg compared to 7/61 K+L/GI/ST patients (p<0.01). These observations provide a basis for directed studies of the sympathetic nervous system in AL, particularly in association with stem cell mobilization with G-CSF. [Display omitted]