Abstract
Hematopoietic stem cell transplantation (HSCT) serves as a therapeutic intervention for various pediatric diseases. Acute and chronic graft-versus-host disease (GVHD) are decisive determinants for allogeneic HSCT success. The immunosuppressive agent, ciclosporin A, is most often used to prevent GVHD in pediatric patients, but is known to be nephrotoxic. Acute kidney injury afflicts 21-84% of pediatric HSCT cases, compromising clinical outcomes. This retrospective single-institution analysis scrutinized the practice of substituting nephrotoxic ciclosporin A with an everolimus/mycophenolate mofetil combination as GVHD prophylaxis in 57 patients with acute kidney injury (n=53) or central nervous system side effects due to calcineurin inhibitor treatment (n=4) following first allogeneic HSCT. This retrospective cohort study analyzes clinical courses in 57 children switched from calcineurin inhibitor-based GVHD prophylaxis (ciclosporin A or tacrolimus in single cases) to the everolimus/mycophenolate mofetil combination (n=48) or everolimus alone (n=9) after first allogeneic HSCT at the Charité University Medicine Berlin. Serving as control cohort were 74 patients undergoing first allogeneic HSCT during the same period, who did not receive everolimus at any date post-transplantation. Patients undergoing mismatched family donor transplantation without subsequent calcineurin inhibitor treatment for GVHD prophylaxis were excluded. Study endpoints encompassed the retention parameter course subsequent to GVHD prophylaxis switch, overall survival, incidence of underlying disease relapse and acute and chronic GVHD in both treatment groups. Renal function significantly improved after switching from ciclosporin A treatment to the everolimus/mycophenolate mofetil combination. Crucially, the transition to everolimus did not adversely affect overall survival following HSCT (HR 1.6; 95% CI: 0.74 - 3.5; p=0.23), especially for patients afflicted with non-malignant diseases (HR 1.4; 95% CI: 0.34 - 5.9; p=0.64). Incidences of grade 3-4 acute GVHD (HR: 1.82; 95% CI: 0.45 - 7.4; p=0.40) and severe chronic GVHD (HR 2.76, 95% CI: 0.69 - 11.0; p=0.15) in patients treated with the everolimus/mycophenolate mofetil combination were comparable to standard ciclosporin A treatment in patients in the control group. Overall survival in patients with malignant underlying diseases was lower in the everolimus cohort (HR: 2.7; 95% CI: 1.1 - 6.9, P=0.03), however, event-free survival was similar in patients with an underlying malignant disease, who were treated with either the everolimus/mycophenolate mofetil combination or ciclosporin A (HR 0.87, 95% CI: 0.39-1.9, p=0.73). Among patients who switched immunosuppression regimen from cyclosporin A to everolimus, with or without mycophenolate mofetil co-treatment after diagnosis of AKI, renal function significantly improved. Patient outcomes in the everolimus cohort were comparable to those in the control cohort. This study provides compelling real-world clinical evidence to replace ciclosporin A with the everolimus/mycophenolate mofetil combination in the management of acute kidney injury following HSCT in children.
Published Version
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