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.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
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Supplementary data

Supplementary Table 1

Supplementary Table S1. Characteristics of UTSW autologous transplant patients. Continuous measures are shown as mean (SD) and categorical measures as percentages. A one-way ANOVA was used to compare continuous variables, and a χ2 test was used to compare categorical measures.

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Supplementary Table 2

Supplementary Table S2. Characteristics of UTSW allogeneic transplant patients. Abbreviations: Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), mixed-phenotype acute leukemia (MPAL), severe aplastic anemia (sAA), myeloablative conditioning (MAC), nonmyeloablative conditioning (NMA), reduced-intensity conditioning (RIC), matched related donor (MRD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), haploidentical (Haplo), graft-versus-host disease (GvHD), post-transplant cytoxan (PTCy), methotrexate (MTX), and cytomegalovirus (CMV). Continuous measures are shown as mean (SD), and categorical measures as percentages. A one-way ANOVA was used to compare continuous variables and a χ2 test was used to compare categorical measures.

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Supplementary Table 3

Supplementary Table S3. Characteristics of Vanderbilt autologous transplant patients. Continuous measures are shown as mean (SD), and categorical measures as percentages. A one-way ANOVA was used to compare continuous variables, and a χ2 test was used to compare categorical measures.

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Supplementary Table 4

Supplementary Table S4. Characteristics of Vanderbilt allogeneic transplant patients. Abbreviations: Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), mixed-phenotype acute leukemia (MPAL), myeloablative conditioning (MAC), non-myeloablative conditioning (NMA), reduced-intensity conditioning (RIC), matched related donor (MRD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), haploidentical (Haplo), graft-versus-host disease (GvHD), post-transplant cytoxan (PTCy), methotrexate (MTX), and cytomegalovirus (CMV). Continuous measures are shown as Mean (SD), and categorical measures as proportions. A one-way ANOVA test was used to compare continuous variables, and a χ2 test was used to compare categorical measures.

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Supplementary Table 5

Supplementary Table S5. Related to Fig. 1-4 and Supplementary Fig. S3. Cell populations analyzed by flow cytometry in this study.

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Supplementary Table 6

Supplementary Table S6. Related to Fig. 1-7. Key Resources Table.

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Supplementary Figure 1

Supplementary Figure S1. Carvedilol and metoprolol do not affect steady-state hematopoiesis.

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Supplementary Figure 2

Supplementary Figure S2: Metoprolol treatment did not significantly affect hematopoietic regeneration after syngeneic or allogeneic transplantation in mice.

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Supplementary Figure 3

Supplementary Figure S3: Propensity matched analysis of the effect of non-selective b adrenergic receptor inhibitors on hematopoietic regeneration in Vanderbilt patients undergoing autologous and allogeneic transplantation.

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Supplementary Figure 4

Supplementary Figure S4: Clinical variables associated with time to hematopoietic regeneration after autologous transplantation at UTSW.

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Supplementary Figure 5

Supplementary Figure S5: Clinical variables associated with time to hematopoietic regeneration after allogeneic transplantation at UTSW.

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Supplementary Figure 6

Supplementary Figure S6: Clinical variables associated with time to hematopoietic regeneration after autologous transplantation in Vanderbilt patients.

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Supplementary Figure 7

Supplementary Figure S7: Clinical variables associated with time to hematopoietic regeneration after allogeneic transplantation at Vanderbilt.

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Supplementary Figure 8

Supplementary Figure S8: Hematopoietic stem and progenitor cell frequencies after allogeneic transplantation.

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Supplementary Figure 9

Supplementary Figure S9: The inhibitory effect of carvedilol on hematopoietic regeneration after syngeneic transplantation can be overcome by transplanting larger doses of bone marrow cells.

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Supplementary Figure 10

Supplementary Figure S10: Post-transplant chemotherapy or use of non-selective b blockers was not associated with changes in neutrophil engraftment after allogeneic transplantation in Vanderbilt allogeneic HCT patients.

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Supplementary Figure 11

Supplementary Figure S11: Infection, graft-versus-host disease, and causes of death in UTSW allogeneic HCT recipients.

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Supplementary Figure 12

Supplementary Figure S12: Infection, graft-versus-host disease, and causes of death in Vanderbilt allogeneic HCT recipients.

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Supplementary Figure 13

Supplementary Figure S13: Discontinuation of b blockers around the time of transplantation rescues hematopoietic regeneration.

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