NT-proBNP Levels after First-Dose Post-Transplant Cyclophosphamide Predict Early Cardiac Events and Mortality in Allogeneic Stem Cell Transplantation

Abstract

Post-transplant cyclophosphamide (PTCy) is an effective method for preventing graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (HSCT). However, PTCy is associated with significant toxicities, including a higher incidence of early cardiac events (ECEs). This study aimed to investigate whether the dynamic response of N-terminal pro-B-type natriuretic peptide (BNP) levels to PTCy administration can predict the occurrence of ECEs and clinical outcomes in patients receiving PTCy. We conducted a retrospective analysis of 134 patients who underwent haploidentical peripheral stem cell transplantation at our institution between December 23, 2017, and January 3, 2024. For GVHD prophylaxis, all patients received PTCy at a dose of 50 mg/kg on days +3 and +4, 4.5 mg/kg of rabbit antithymocyte globulin on days -4 to -2, cyclosporine, and mycophenolate sodium. BNP levels were measured within 24 hours after the initial administration of day +3 PTCy and before the second dose on day +4. Univariate and multivariate analyses were used to evaluate the association of BNP levels with cumulative incidence of ECEs, relapse, nonrelapse mortality (NRM), acute GVHD (aGVHD), chronic GVHD (cGVHD), graft-versus-host disease-free, relapse-free survival (GRFS) and overall survival (OS). The cumulative incidence of ECEs was 17.9% (95% CI: 11.9% to 24.9%) in this cohort. Elevated BNP levels (>530 pg/mL) were significantly associated with a higher incidence of ECEs (cumulative incidence: high versus low BNP levels: 63% [95% CI: 43% to 77%] versus 3.9% [95% CI: 1.3% to 9%], P < .001). Patients with high BNP levels also exhibited higher NRM (3-year NRM: 67% [95% CI: 43% to 83%] versus 28% [95% CI: 19% to 37%], P < .01) and inferior OS (3-year OS: 12% [95% CI: 3% to 39%] versus 39% [95% CI: 29% to 53%], P < .01). Patients with high BNP levels had significantly inferior GRFS (3-year GRFS: 5% [95% CI: 1% to 30%] versus 28% [95% CI: 19% to 41%], P = .012). No significant differences were observed in the incidence of acute or chronic GVHD between groups. Multivariate analysis revealed significant associations between ECEs and high BNP levels (hazard ratio [HR]: 19.0; 95% CI: 7.36 to 49.00; P < .01) and hypertension history (HR: 3.48; 95% CI: 1.54 to 7.85; P < .01). Additionally, high BNP levels were significantly associated with increased NRM (HR: 2.54; 95% CI: 1.37 to 4.69; P < .01) and worse OS (HR: 1.70; 95% CI: 1.02 to 2.82; P = .042). Elevated BNP levels are significantly associated with increased ECEs, higher NRM, and inferior OS in haploidentical HSCT patients receiving PTCy. BNP levels measured after the first dose of PTCy may serve as a predictive biomarker for subsequent cardiotoxicity, potentially guiding dose modification of the second PTCy administration to prevent ECEs.

Keywords: Cardiotoxicity; N-terminal pro-B-type natriuretic peptide; Post-transplant cyclophosphamide.