Nonselective β-Adrenergic Receptor Inhibitors Impair Hematopoietic Regeneration in Mice and Humans after Hematopoietic Cell Transplants

Abstract

Peripheral nerves promote mouse bone marrow regeneration by activating β2-and β3-adrenergic receptor signaling, raising the possibility that nonselective β-blockers could inhibit engraftment after hematopoietic cell transplants (HCT). We observed no effect of β-blockers on steady-state mouse hematopoiesis. However, mice treated with a nonselective β-blocker (carvedilol), but not a β1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received nonselective, but not β1-selective, β-blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received posttransplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, nonselective β-blockers were associated with little or no delay in engraftment. The inhibitory effect of nonselective β-blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells. Significance: Patients who receive allogeneic HCTs followed by posttransplant chemotherapy for graft-versus-host disease prophylaxis may be at risk of delayed engraftment and increased mortality if administered nonselective β-blockers after transplantation. Transient discontinuation of nonselective β-blockers or transitioning to β1-selective inhibitors after HCT may accelerate engraftment and improve clinical outcomes.