Results of second allogeneic hematopoietic stem cell transplantation for graft failure after first allogeneic hematopoietic stem cell transplantation complicated by the development of macrophage activation syndrome in children with high-risk acute leukemia

Abstract

Introduction. Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a life-threatening complication, with an incidence of 5–20% in pediatric patients with acute leukemia. Macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH) represents one of the most aggressive triggers of GF, being closely associated with cytokine storm, multiple organ dysfunction, and high transplant-related mortality. In the setting of primary or secondary GF, a second allo-HSCT remains the only potentially curative treatment option; however, performing it against a background of hyperinflammation carries substantial risks of fatal complications and recurrent non-engraftment. The aim of the study – to evaluate factors influencing the rates of non-engraftment, overall survival, and relapse-free survival following second allo-HSCT in pediatric patients with acute leukemia who suffered primary or secondary GF after their first allo-HSCT. Materials and methods. This retrospective single-center study included 44 pediatric patients (median age 9.4 years) with acute myeloid leukemia (n = 11), acute lymphoblastic leukemia (n = 28), and myeloproliferative neoplasms (n = 5). Primary GF was diagnosed in 65.9% of patients, while secondary GF/rejection occurred in 34.1%. Key triggers of MAS/sHLH included viral infections (Epstein–Barr virus, cytomegalovirus, human herpes virus 6, parvovirus B19), bacterial/fungal complications, and cytokine release syndrome. Prior to the second HSCT, conditioning regimens consisted of reduced-intensity conditioning in 79.5% and anti-thymocyte globulin-based conditioning in 20.5%; a subset of patients received anti-cytokine therapy. A switch to a different HLA-matched donor was performed in 47.7% of cases. The median follow-up was 3 years. Results. The cumulative incidence of engraftment was 73% (median time to neutrophil recovery – 15 days). One-year overall survival was 64% (95% confidence interval (CI) 48–76), relapse-free survival was 57% (95% CI 41–70), and non-relapse mortality was 34% (95% CI 20–48). The main causes of death were infectious complications (n = 7), hepatic veno-occlusive disease/sinusoidal obstruction syndrome/transplant-associated thrombotic microangiopathy (n = 6), acute respiratory distress syndrome (n = 3), and cerebrovascular accident (n = 2). The incidence of grade II–IV acute GVHD was 61%, with grade III–IV occurring in 36%. HLA donor switch, stem cell source, and conditioning regimen, including anti-thymocyte globulin use, did not demonstrate a statistically significant impact on overall survival. Conclusion. A second allo-HSCT in pediatric patients with GF complicated by MAS/sHLH demonstrates acceptable engraftment and survival outcomes, remaining the only available option for long-term disease control. The high incidence of early immunological complications and non-relapse mortality necessitates exactly pre-transplant optimization, performing of weekly serum ferritin and inflammatory marker monitoring, and morphological confirmation of hemophagocytosis during the early post-transplant period (days +14 to +21), particularly in the absence of hematopoietic recovery. Optimization of targeted anti-cytokine therapy and intensified prophylaxis/management of infectious complications represent priority strategies to reduce transplant-related mortality.