Background Immune reconstitution is closely associated with various transplant-related complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT), including infections, GVHD, and relapse. This complex, dynamic process is influenced by multiple factors. Existing research primarily focuses on T-cell and NK-cell reconstitution, while studies on B-cell reconstitution remain limited due to its comparatively longer recovery period. Therefore, further research is needed to fully understand the dynamics of B-cell reconstitution after transplantation and its influencing factors. Calcineurin inhibitors (CNIs), including Cyclosporine A (CsA) and Tacrolimus (FK506), are widely used immunosuppressive agents in allo-HSCT. While CsA and FK506 are considered interchangeable in many clinical contexts, they still have some differences in their mechanisms of immune suppression. Given the widespread clinical application of CsA and FK506, clarifying their impact on B-cell reconstitution may offer valuable theoretical foundations for the precise use of CNIs in clinical practice.

Methods A total of 312 patients were included in this retrospective cohort study. All patients were from the Department of Hematology, the First Affiliated Hospital of Chongqing Medical University and underwent allo-HSCT between January 2016 and June 2023. All patients underwent GVHD prophylaxis both during and post-transplantation. Prophylaxis regimens included either tacrolimus (FK506, administered at 0.05 mg/kg twice daily intravenously, adjusted to maintain a trough level of 5–15 ng/mL) or cyclosporine (CsA, administered at 3.0 mg/kg/day intravenously from day −1, adjusted to maintain a trough level of 200–300 ng/mL). Viral infection was defined as any positive detection of DNA copies for CMV, EBV, or HSV during the transplantation. The total glucocorticoid dose was defined as the sum of all types of glucocorticoids used by the patient from day 0 to day +90 post-transplant, converted to an equivalent dose of methylprednisolone. All statistical analyses were conducted by R software version 4.3.2

Results All patients received CNIs for GVHD prophylaxis after allo-HSCT, with 67.6% treated with CsA and 32.4% with FK506. After grouping patients based on the selection of CNIs, significant differences were observed in various clinical characteristics between the two groups, including the status at HSCT (p=0.049), the use of ATG (p<0.001), the dosage (p<0.001), and the duration of glucocorticoid therapy (p=0.002). To mitigate these confounding factors, propensity score matching (PSM) was employed, incorporating relevant covariates. After matching, the FK506 group exhibited elevated B-cell frequencies compared to patients with CsA at days +90 and +120 post-HSCT. Patients with higher cumulative dose of glucocorticoids combined with CsA within the first 100 days post-transplant led to poorer B-cell reconstitution. We also conducted a mediation analysis to assess the direct effect of CNI on viral infection and the indirect effects mediated by B-cell reconstitution. The model indicated a causal relationship among the three variables: compare to CsA, FK506 positively influenced B-cell proportions (95%CI [0.07, 0.32], p=0.003) at 3-month, thereby reducing the probability of viral infection (p=0.017), while no direct effect of FK506 on viral infection (p=0.526) was observed.

Conclusion Our study was the first to comprehensively investigate the effects of FK506 and CsA on B-cell reconstitution after allo-HSCT. Our findings indicated that patients in the FK506 group showed superior B-cell recovery compared to the CsA group, both in bone marrow and peripheral blood, with this difference predominantly occurring between days +90 and +120 post-transplant. Second, we conducted a detailed analysis of post-HSCT glucocorticoid use and found higher cumulative dose of glucocorticoids combined with CsA within the first 100 days post-transplant led to poorer B-cell reconstitution, whereas FK506 did not have the same effect. Additionally, we observed a potential association between bone marrow B-cell recovery around day +100 and viral infections. Through mediation analysis, we further explored the relationship between FK506, B-cell reconstitution, and viral infection, revealing that B cells played a mediating role in the impact of FK506 on post-transplant viral infection.

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2025
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