Study links beta blocker use to mortality after stem cell transplantation
Key takeaways:
- Taking beta blockers may raise mortality risk for HSCT recipients due to suppression of signals from nerves that promote bone marrow regeneration.
- More validation is needed but the findings may change practice.
Taking prescribed beta blockers during hematopoietic stem cell transplantation may increase mortality risk due to suppression of signals from nerves that promote bone marrow regeneration, according to study results.
The study — conducted by investigators at Children’s Medical Center Research Institute at UT Southwestern — built upon prior research in mice that showed peripheral nerves stimulate mouse bone marrow regeneration by activating beta-2 and beta-3 adrenergic receptor signaling.
That finding introduced the possibility that nonselective beta blockers could suppress engraftment after HSCT.
Researchers subsequently determined beta blockers had no effect on steady-state mouse hematopoiesis, but that mice treated with a nonselective beta blocker — but not a beta-1 selective inhibitor — showed impairments to hematopoietic regeneration after syngeneic or allogeneic HSCT.
Sean J. Morrison, PhD, director of Children’s Medical Center Research Institute at UT Southwestern and a Howard Hughes Medical Institute investigator, along with Stephen Chung, MD, assistant professor of internal medicine at UT Southwestern, and colleagues then retrospectively evaluated data from patients on a beta blocker regimen who underwent HSCT at UT Southwestern and Vanderbilt University Medical Center.
Results showed patients who underwent allogeneic HSCT while being treated with nonselective beta blockers — but not beta-1 selective beta blockers — demonstrated delayed platelet engraftment and poorer survival.
The finding appeared particularly pronounced among patients who underwent post-transplant chemotherapy for graft-versus-host disease.
“Our data suggests that people who get an allogeneic transplant — particularly if they get post-transplant chemotherapy and are getting lower doses of CD34-positive cells — are delayed in terms of engraftment, and much more likely to die after transplant,” Morrison told Healio. “For those people, our data suggests that they should stop taking their nonselective beta blockers while they are waiting to engraft or — if they can’t tolerate coming off beta blockers — they should transition to a beta-1 selective inhibitor.”
Healio spoke with Morrison about the rationale for this study, the key results and how the findings can be applied to clinical practice.
Healio: What motivated you to study the effects of previously prescribed beta blockers in this patient population?
Morrison: It started as a result of basic science experiments done in mice. There are peripheral nerves in the bone marrow, and those nerves are necessary for bone marrow regeneration after chemotherapy or radiation therapy. However, nobody knew what the mechanism was.
In a 2023 paper, we determined that sympathetic nerves secrete catecholamines that activate beta-adrenergic receptor signaling in bone marrow stromal cells responsible for producing the growth factors necessary for bone marrow regeneration. That beta-adrenergic receptor signaling is necessary to increase the production of those growth factors during bone marrow regeneration.
Because beta-adrenergic receptors are the target for beta blockers, that predicted that if someone happens to be on a beta blocker when they undergo HSCT, the engraftment would be delayed and they could have a bad outcome.
We showed in the mouse experiments that beta-2 and beta-3 were the important beta-adrenergic receptors, not beta-1. Once we had that result, we predicted that people who happened to be on a nonselective beta blocker that would inhibit beta-2 and beta-3, but not a beta-1 selective inhibitor, would show delayed engraftment after HSCT.
Healio: What did your retrospective review of patient data show?
Morrison: We started going through clinical data to analyze two independent patient populations. We compared time to engraftment after transplant among people who were on a nonselective beta blocker, those on a beta-1 selective inhibitor and those who were not taking any beta blocker.
Consistent with what we predicted from the mouse experiments, people who received allogeneic transplants and were on a nonselective beta blocker had substantially delayed engraftment and were much more likely to die than those who were on beta-1 selective inhibitors or no beta blocker. This was particularly observed among patients who received post-transplant chemotherapy for graft versus host disease prophylaxis.
Healio: What did your study reveal in terms of CD34-positive cell dosage in this patient population?
Morrison: Our data suggest people who get an allogeneic transplant and are on a nonselective beta blocker are more likely to experience engraftment delays and death, if they are also getting lower doses of CD34-positive cells. Our data showed we can overcome this effect by transplanting higher doses of CD34-positive cells. We saw that both in mice and in humans.
Healio: How might your findings change clinical practice?
Morrison: Our data suggest that allogeneic transplant patients on a non-selective beta blocker should either discontinue the beta blocker until they engraft or transition onto a beta-1 selective blocker, particularly if they receive post-transplant chemotherapy for graft-versus-host-disease prophylaxis.
Healio: What are the next steps in research?
Morrison: The number of patients in our study was not huge, and we’ve now shown this in mice and in two cohorts at two different institutions. However, it’s conceivable that as additional data come in from more institutions, it will refine our understanding of the risk factors and help us identify exactly which patients are at risk. We are trying to get data from additional institutions to further assess this. If we do get additional data that corroborate these findings, my sense is that this should truly be a generalized change in clinical practice.
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For more information:
Sean J. Morrison, PhD, can be reached at sean.morrison@utsouthwestern.edu.
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