A retrospective study on beta-blocker use and outcomes in hematopoietic stem cell transplant patients

Introduction

Allogeneic hematopoietic stem cell transplant (allo-HCT) is an effective treatment for hematological malignancies, but its success is often complicated by graft-versus-host disease (GVHD). GVHD arises from a dysregulated immune response, where donor T cells attack host tissues. It is intricately connected to a cascade of pro-inflammatory signals through both cytokine release and immune cell activation, which leads to sustained tissue damage and inflammation (Ferrara, Cooke & Teshima, 2003; Holler, 2002; Piper & Drobyski, 2019; Jankovic et al., 2013). Approximately 30–60% of allo-HCT recipients develop acute GVHD (aGVHD) and the Center for International Blood and Marrow Transplant Research (CIBMTR) estimated that 12–14% of all deaths among HLA-matched allo-HCT recipients from 2018–2020 were due to GVHD (Bolon et al., 2022). In severe cases, patients with a grade III–IV acute GVHD (aGVHD) suffered a 29% transplant-related mortality rate (Jagasia et al., 2012; Khoury et al., 2017). Beyond its impact on mortality, aGVHD is also associated with increased hospital length of stay (LOS) and overall healthcare costs (Yu et al., 2019). Current first-line treatment for GVHD consists of immunosuppression with corticosteroids; however, this approach is only effective in 55–65% of cases, particularly with patients with severe GVHD (Flowers & Martin, 2015; Axt et al., 2019; Calmettes et al., 2015). Given the significant impact GVHD has on patients and the lack of a more reliable treatment, there is a need for improved prophylaxis to mitigate GVHD severity or incidence.

Beta-blockers (BB) are pharmacologically safe medications commonly used clinically for cardioprotection by modulating the beta-adrenergic receptor (b-AR) (Gorre & Vandekerckhove, 2010; Oliver, Mayor Jr & D’Ocon, 2019). However, recent research has highlighted their immunomodulatory effects in various clinical settings, including critical illness (Wilson et al., 2013; Morelli et al., 2013), burn injury (Herndon et al., 2001; Kopel et al., 2021) and cancer (Grytli et al., 2014; Hochberg, Cairo & Friedman, 2014; Jansen et al., 2014; Wang et al., 2013; Hwa et al., 2017). BB use in critically ill patients is associated with improved outcomes due to reduced systemic inflammation and attenuation of excessive immune activation (Wilson et al., 2013; Morelli et al., 2013). In oncology, BBs are associated with improved outcomes in various solid tumors and hematologic malignancies, including overall survival and disease-specific mortality, potentially due to mechanisms related to immune surveillance and inflammatory signaling (Grytli et al., 2014; Hochberg, Cairo & Friedman, 2014; Jansen et al., 2014; Wang et al., 2013; Hwa et al., 2017). These findings suggest that BBs may play a role in regulating inflammatory responses, which are central to GVHD pathogenesis.

BBs have previously been investigated in the setting of allo-HCT. One study on propranolol demonstrated a potential survival benefit, as well as underscored its feasibility and tolerability in allo-HCT patients (Knight et al., 2018). Another phase two randomized controlled trial found that propranolol inhibited stress-related pathways, suggesting potential benefits in reducing relapse and improving disease-free survival (Knight et al., 2020). Different b-AR receptor subtypes may have distinct role in modulating immune responses. In previous studies, B1-selective BBs have shown protection against catecholamine-induced injury in critical illness (Kuo et al., 2021; Heliste et al., 2022), while b2-AR has been implicated in enhancing the graft-versus-tumor (GVT) effect (Mohammadpour et al., 2018), and b3-AR is involved in modulating oxidative stress in hematopoetic stem cell redox homeostasis (Pasha, Calvani & Favre, 2021).

Since b-AR signaling impacts a wide variety of immune responses, including pro-inflammatory pathways (Ferrara, Cooke & Teshima, 2003; Holler, 2002; Piper & Drobyski, 2019; Jankovic et al., 2013; Powell et al., 2013), hematopoesis (Maestroni, 2020; Méndez-Ferrer, Battista & Frenette, 2010), and hematopoietic reconstitution after allo-HCT (Wang & Cao, 2019), BBs may have a beneficial role in allo-HCT. Blockade of b-AR signaling and the associated pro-inflammatory pathway could be a promising strategy to mitigate GVHD and improve post-HCT outcomes. Thus, we hypothesize that BB use prior to allo-HCT may be associated with decreased GVHD and improved survival outcomes.

Methods

Results

Demographics were compared between patients who were on a BB before and after allo-HCT (Yes BB) (n = 105) and those who were not (No BB) (n = 669). The Yes BB group had a greater proportion of participants with an HCT-CI of 4 or greater (p = 0.010). However, there were no significant differences between the two cohorts by race, sex, median age, conditioning regimen, or donor type (all p > 0.05) (Table 1).

Patients in the Yes BB group had a significantly lower incidence of acute GVHD (55.2% vs. 65.8%, p = 0.036) (Table 2). Median albumin levels were lower in the Yes BB group at D-10 (p = 0.042) and D+90 (p = 0.014) than in the No BB group; however, the change in Albumin between D-10 and D+90 was not significant (p = 0.101). There were no observed differences in cGVHD occurrence or grade or other survival outcomes such as OS, NRM, relapse occurrence, and LOS (all p > 0.05) (Table 2, Figs. S1A–S1E). We performed multivariate analysis to further examine associations between BB use and other co-variates on aGVHD (Table 3). We included covariates that were associated with aGVHD on univariate analysis, as well as age at transplant and type of GVHD prophylaxis. Albumin at D+90 was excluded from MVA to avoid post-hoc confounding since aGVHD commonly occurs before D+90. None were statistically significant (Table 3).

Additionally, we subdivided the Yes BB group by BB Mechanism (Table 4). Use of a non-selective BB (propranolol, sotalol, nadolol) was associated with lower pre-transplant weight compared to vasodilating BB (carvedilol, labetalol) and selective BB (atenolol, metoprolol, nebivolol) (136 lbs vs. 165 lbs vs. 174 lbs, respectively, p = 0.034). The use of vasodilating BB trended towards reduced LOS, however this just missed the cut-off for statistical significance (p = 0.054). There were no other significant differences in either primary or secondary outcomes for the mechanism-based subgroups (all p > 0.05) (Table 5).

Discussion

Our study found an association with decreased incidence of aGVHD in allo-HCT patients that had peri-transplant BB exposure on univariate analysis (p = 0.036); though this association did not remain significant on multivariate analysis (p = 0.150), suggesting that other factors may contribute to this trend, or that covariates may have overshadowed the BB effect. Therefore, we are hesitant to fully support a role for BBs as a prophylactic intervention to prevent aGVHD. One clinical study evaluated the risk of developing cGVHD for patients on a non-selective BB during the time of allo-HCT. While their results trended towards significance, that BBs were protective against cGVHD, they lacked sufficient power to detect a definitive difference. In our study, we found no association between BB and cGVHD occurrence (p = 0.947) or severity (p = 0.988). However, it is possible that a few days of peri-transplant BB exposure was insufficient to exert a lasting impact on this long-term outcome, given the median time to onset of cGVHD was 244 days (approximately 7.7 months) in our cohort. Future studies should include BB dosage and duration to better examine the impact of BB intake on long-term outcome evaluation of survival outcomes, including cGVHD.

The broader literature supports BB use as a potential adjunct in the care of cancer patients (Jansen et al., 2014; Wang et al., 2013; Hwa et al., 2017; Heliste et al., 2022; Patel et al., 2023; Tan et al., 2019). Additionally, previous studies have documented the role of b-AR signaling in influencing proinflammatory pathways and immune cell function (Ferrara, Cooke & Teshima, 2003; Holler, 2002; Piper & Drobyski, 2019; Jankovic et al., 2013; Knight et al., 2020; Kuo et al., 2021; Heliste et al., 2022; Mohammadpour et al., 2018; Pasha, Calvani & Favre, 2021; Powell et al., 2013; Maestroni, 2020; Méndez-Ferrer, Battista & Frenette, 2010; Wang & Cao, 2019). Recent laboratory studies in murine models have explored the b-AR role in GVHD modulation, specifically b2-AR signaling, in the modulation of GVHD from allo-HCT. A single study demonstrated that b2-AR activation ameliorated aGVHD, which opposes our hypothesis (Mohammadpour et al., 2020). The same team found that blockade of b2-AR improved GVT without impacting GVHD (Mohammadpour et al., 2018). Another team demonstrated that cold stress increased norepinephrine production, leading to excessive b-AR signaling and suppression of GVHD, which was reversed with b2-AR antagonists, supporting a role of b2-AR signaling in modulating GVHD severity (Leigh et al., 2015). Thus, there exists some data that there is potential impact in the allo-HCT population by modulating the adrenergic receptor; however, our results would not support the use of BB for survival benefits in allo-HCT. Possible explanations for the discrepancy between our findings and prior studies include differences in sample size, patient population, or BB dosing regimens. Additionally, variations in cGVHD diagnostic criteria and clinical management strategies across institutions may contribute to differing results. It is important to note that the lack of statistical significance in survival outcomes suggests neither benefit nor harm from BBs, consistent with current data on their pharmacological safety.

While BB use did not impact post-HCT weight overall (p = 0.753), subgroup analysis revealed that patients receiving non-selective BBs were associated with lower post-HCT weight compared to vasodilating and selective BBs (p = 0.034). The use of vasodilating BB trended towards reduced LOS (p = 0.054). Vasodilating BBs have been shown to reduce LOS in heart failure patients and those undergoing cardiothoracic surgery, likely due to their effects on hemodynamic stability and adrenergic modulation (Butler et al., 2006; Coleman et al., 2004; Fowler et al., 2001; Packer et al., 2002). While this relationship between BBs and LOS has not been explored in all HCT patients, our preliminary findings from our subgroup analysis suggest that BB types might variably impact a patient’s weight, and possibly LOS, during the peri-HCT period. Although further studies would need to substantiate these results and elucidate the underlying mechanism.

Several limitations of our study must be acknowledged. Our study is limited by the retrospective nature of the data collection. There are also underlying differences between the Yes BB and No BB groups, especially since the reasoning for being on a BB prior to allo-HCT is generally a co-morbidity that would increase HCT-CI and the potential risk of adverse events. While balanced in terms of demographics (except for HCT-CI), the Yes BB and No BB groups were unbalanced in terms of sample size, which could have contributed to the lack of statistical power to see a difference in additional outcome measures. While we attempted to control for confounding variables through multivariate analysis, residual confounding cannot be entirely excluded. Another limitation is the change in the use of cyclophosphamide during our cohort, where GVHD outcomes drastically improved, which could diminish the overall power we are able to detect. Lastly, the limited sample sizes in our subgroup analysis reduced the statistical power to detect differences, underscoring the need for larger prospective or randomized studies to strength any inference.

In conclusion, our study suggests that BB use does not significantly affect outcomes in allo-HCT patients, including aGVHD; however, subgroup analysis suggest that BB type may differentially affect post-HCT weight. While our study demonstrates that BBs remain pharmacologically safe in this population, our results do not support their routine use for modification of allo-HCT outcomes. Future prospective studies are necessary to substantiate these preliminary findings and explore the role of BBs in peri-HCT management to better understand their clinical implications and therapeutic potential.

Supplemental Information