CT-1060: Comparative Safety and Efficacy of Calcineurin Inhibitor (CNI)-Free vs CNI-Based GVHD Prophylaxis Following Allogeneic HCT: A Real-World TriNetX-Based Propensity-Matched Analysis

CNI-based regimens have long been standard for GVHD prophylaxis post allo-HCT. Emerging evidence supports the use of CNI-free strategies incorporating sirolimus and post-transplant cyclophosphamide. However, comparative data on long-term safety and efficacy remain limited. We conducted a retrospective cohort study using the TriNetX US Collaborative Network (69 healthcare organizations). Adults (≥18 years) with hematologic malignancies who underwent allo-HCT in 2017–2025 were identified using ICD-10-CM and -PCS codes. Patients were categorized into two groups: those receiving CNI-based prophylaxis (tacrolimus/cyclosporine ± methotrexate/mycophenolate mofetil [MMF]) and those receiving CNI-free prophylaxis (sirolimus + MMF + post-transplant cyclophosphamide), based on RxNormcoded medication exposure within 100 days post-transplant. Propensity score matching (1:1) was performed on 205 CNI-free and 2,899 CNI-based patients, yielding 199 patients per arm. Outcomes were assessed over 730 days post index using risk analyses and Kaplan-Meier survival methods. CNI-free prophylaxis was associated with significantly lower incidence of GVHD (rate difference [RD], –26.6%, CI, –35.6 to –17.7, P < 0.001; RR, 0.662, CI, 0.570–0.770; HR, 0.592, CI 0.462–0.759, P = 0.000) and neutropenia (RD, –15.1%, CI, –24.7 to –5.4, P = 0.002; RR, 0.712, CI, 0.569–0.890; HR, 0.767, CI, 0.569–1.033, P = 0.004). Emergency department visits were also significantly reduced (RD, –12.1%, CI, –20.1 to –4.0, P = 0.004; RR, 0.571, CI, 0.388–0.842; HR, 0.615, CI, 0.398–0.949, P = 0.027). Conversely, all-cause mortality was significantly higher in the CNI-free arm (RD, 7.0%, CI, –2.4 to 16.5, P = 0.146; RR, 1.209, CI, 0.935–1.564; HR, 1.390, CI, 1.005–1.921, P = 0.045). Febrile neutropenia was more frequent in CNI-free patients (RD, 9.5%, CI, –0.1 to 19.2, P = 0.054; RR, 1.253, CI, 0.995–1.579; HR, 1.619, CI, 1.194–2.196, P = 0.002). Renal toxicity was less frequent with CNI-free prophylaxis (RD, –24.8%, CI, –36.8 to –12.9, P < 0.001; RR, 0.499, CI, 0.344–0.724; HR, 0.441, CI, 0.280–0.693, P = 0.000). No statistically significant differences were observed for relapse of hematologic malignancies, pleural effusion, pneumonia, sepsis, anemia, ventilation assistance, or hospital dependence. CNI-free GVHD prophylaxis post allo-HCT demonstrated lower GVHD incidence and improved renal safety but was associated with higher mortality and febrile neutropenia. These findings suggest that while CNI-free regimens offer certain advantages, careful patient selection and infection surveillance are critical. Further prospective trials are warranted.