Urinary Excretion of Epinephrine and Dopamine Correlates with Efficiency of G-CSF Mobilized Stem Cells in Patients with AL Amyloidosis

Hematopoietic stem cell migration out of the bone marrow is essential for effective and successful stem cell transplantation. Sympathetic nervous system signaling has been shown to regulate hematopoietic stem cell egress from bone marrow. Ablation of adrenergic neurotransmission in animal models indicates that norepinephrine signaling controls granulocyte colony stimulating factor (G-CSF) -induced osteoblast suppression, CXCL-12 (or stromal derived factor-1 (SDF-1)) down regulation and hematopoietic progenitor cell mobilization (Katayama Y, et al. Cell 2006). In addition, β adrenergic agonists and antagonists enhance and reduce stem cell mobilization, respectively. High dose therapy and stem cell rescue following G-CSF mobilization is a standard approach to the treatment of patients with light chain (AL) amyloidosis. In patients with AL amyloidosis, we prospectively studied the relationship between catecholamine levels and the efficiency of stem cell collection. Methods: In AL amyloidosis patients enrolled on a phase II clinical trial using G-CSF mobilization and high dose melphalan conditioning, 24 h urine samples were collected and analyzed for epinephrine, norepinephrine and dopamine excretion before G-CSF administration and after stem cell collection was completed. Statistical analysis included the Spearman Rank Coefficient (r), Wilcoxon Rank Sum test and Signed rank test. Results: In 39 patients with AL Amyloidosis collected on study, median CD34+ cells collected per kg was 8.3 × 10⁶ (IQR 5,12.3) in a median of 2 (IQR 2,3) collections. The median number of CD34+ cells infused on day 0 was 4.7 × 10⁶ (IQR 3.8, 6) per kg and time to neutrophil engraftment (ANC > 500 × 2 days) was 9 (IQR 9, 11) days. Baseline urinary excretion of epinephrine and dopamine correlated with total number of CD34+ cells per kg collected (r = 0.33, P = 0.005; and r = 0.47, P = 0.05, respectively). An optimal collection outcome defined as > 5 × 10⁶CD34+ cells in 2 collections was achieved by 25/39 patients and was associated with higher baseline epinephrine (median 7 versus 4mcg/24h, P = 0.02) and dopamine (median 220 versus 156mcg/24h, P = 0.05) but not norepinephrine levels. When comparing baseline and post collection catecholamine levels, only dopamine values changed significantly from before to after stem cell collection (P = <0.0001). Patients with renal involvement as the only site of disease (N= 16) collected greater total CD34+ stem cells per kg (median 11.4 versus 6, P = 0.002) than patients with other sites or more than one site of disease (N=23). There was no correlation between the number of stem cells infused and the time to engraftment. Conclusion: Consistent with the notion that the sympathetic nervous system regulates the egress of progenitor cells from their niche, we found that baseline epinephrine and dopamine excretion is associated with greater total and more efficiently collected CD34+ stem cells following G-CSF mobilization in patients with AL amyloidosis. In mouse models G-CSF-induced mobilization requires peripheral adrenergic signals and reduces norepinephrine in the bone (Katayama Y, et al. Cell 2006). Reduced dopamine excretion following G-CSF administration in this study may indicate that circulating catecholamines may provide a marker for the overall sympathetic tone that could predict mobilization efficiency in humans. Further, this study supports other results on the role of dopamine in progenitor migration (Spiegel A, et al. Nat Immunol. 2007) and suggests an important role of dopamine in G-CSF-induced mobilization in patients with AL amyloidosis. Together, these data suggest that modulation of the sympathetic nervous system to enhance hematopoietic stem cell mobilization should be explored and that approaches such as the one we describe may guide G-CSF mobilization with respect to the need for Plerixafor.

No relevant conflicts of interest to declare.