Single Center, Retrospective Study on the Effect of Mirabegron, a Beta3-Adrenergic Receptor Agonist, on Total Lymphocyte Numbers in the Peripheral Blood

Introduction

Physiologic hematopoiesis is dependent on adrenergic signals, relayed by the peripheral nervous system to the bone marrow niche. Murine studies by other groups have shown that neural activation of the beta3-adrenergic receptor (B3-AR) on specific mesenchymal stromal cells is necessary to regulate the balance between myelopoiesis and lymphopoiesis (Morrison et al., 2004; Maestroni,2020; Maryanovich et al., 2018). In aged mice, sympathetic neuropathy impairs B3-AR activity, which in turn induces myeloid biased hematopoiesis and lymphocytopenia, while activation of the B3-AR preserves lymphopoiesis (Drexler et al., 2019; Maryanovich et al., 2018). The regulatory effect of B3-AR activity on human blood cell production has not been determined.

In 2012, the FDA approved Mirabegron, a B3-AR agonist, for the treatment of overactive bladder in adults. We performed a retrospective comparison of absolute lymphocyte and neutrophil counts (ALC and ANC, respectively) prior to and after initiation of Mirabegron in order to test our hypothesis that activation of the B3-AR in a clinical population could prevent age-associated lymphocytopenia (Serati et al., 2017; Chapple et al., 2017).

Methods

TriNetX, a global health research network, was used to identify and run descriptive analytics on patients treated at Froedtert and the Medical College of Wisconsin who had been prescribed Mirabegron between 2012-2022. Additional inclusion criteria included a complete blood cell count with differential (CBC) within 12 months prior to Mirabegron initiation, (pre-CBC), and a second CBC with differential between 2-12 months after initiation of Mirabegron therapy (post-CBC). Patients with a hematologic malignancy or prior exposure to CD20-directed antibody therapy were excluded. De-identified clinical data was extracted from MCW's Clinical Research Data Warehouse. All statistical analyses were done using R version 4.0.3. Paired t-tests were used to compare pre-CBCs and post-CBCs and generalized linear regression models were created for the CBC outcomes.

Results

We identified 674 patients meeting all inclusion and exclusion criteria. Patients were then further divided into either cohort 1 (n=126) if they remained on Mirabegron at the time of their post-CBC, or cohort 2 (n=503) if Mirabegron was discontinued prior to their post-CBC lab draw. Table 1 includes additional demographic descriptors of both cohorts. In cohort 1, neither ALC, ANC or ALC:ANC changed significantly during the 24-month period of our analysis, while ALC and ALC:ANC were both significantly reduced in cohort 2 (Table 2). Cohorts were further divided into age-defined subgroups, which allowed us to identify an age-associated decline in ALC and ALC:ANC in cohort 1 that was not observed in cohort 2 (Table 2).

Conclusion This study provides initial clinical data to support the hypothesis that B3-AR activation maintains physiologic blood cell production. In cohort 2, individuals greater than 60 years of age, who were not taking Mirabegron at the time of their post-CBC, experienced the expected, albeit subtle, drift towards myeloid biased hematopoiesis (i.e. significantly reduced ALC and ALC:ANC), while those who remained on Mirabegron did not experience this in terms of significance (Table 2). Data from cohort 2 confirms the widely described lymphocytopenia and myeloid biased hematopoiesis of advanced age (Table 2). Limitations of our study include its short time frame of analysis, and retrospective design. Furthermore, neither the immunologic sequelae of B3-AR activation nor the impact of B3-AR activation on B- or T-lymphocytes could be obtained from this retrospective clinical data set. Nevertheless, analysis of this real world data suggests merit for prospective examination of Mirabegron as a modifier of age-associated lymphocytopenia and immunosenescence. Equally as important, our data bridges murine studies of the hematopoietic niche to the clinical world.

No relevant conflicts of interest to declare.