Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party

Abstract

Background: We analyzed a nationwide registry of pediatric patients with hemophagocytic lymphohistiocytosis (HLH) in Korea to assess the clinical and genetic features and treatment outcomes in pediatric HLH.

Methods: The Korea Histiocytosis Working Party retrospectively analyzed data on 251 pediatric patients diagnosed with HLH between 1996 and 2011.

Results: In the study cohort, 25 cases were categorized with familial HLH, 64 with presumed secondary HLH, and 162 with unspecified HLH. Of 217 evaluable patients, 91 (42%) had concomitant Epstein-Barr virus infection. Of 238 evaluable patients, central nervous system (CNS) involvement, which was more frequent in the familial group, was evident in 81 cases (34%). Genetic tests revealed a predominant UNC13D mutation with a high incidence of two recurrent splicing mutations (c.118-308C>T and c.754-1G>C). The 5-yr overall survival rate was 68% (38% in the familial group and 81% in the presumed secondary group). The 5-yr overall survival rate among 32 patients who underwent allogeneic hematopoietic stem cell transplantation was 64%. In multivariate analysis, a younger age at diagnosis, severe transaminasemia, and a coagulation abnormality were independent prognostic factors for survival. Responses during initial treatments were also significant indicators of outcome.

Conclusion: Our study showed the unique predominance of a UNC13D mutation and vulnerability to Epstein-Barr virus infection in Korean children with HLH and emphasizes the prognostic significance of age, liver dysfunction, and treatment responses in this disease. A multicenter prospective trial that builds on the present results is warranted to identify subgroups of patients with a poor prognosis and identify optimal treatments.

Keywords: allogeneic hematopoietic stem cell transplantation; genetic mutation; hemophagocytic lymphohistiocytosis; prognostic factors; survival.

Figure 1

Distribution of familial and presumed secondary HLH by age for 89 classifiable patients.

Figure 2

The 5‐yr overall survival rate of 251 patients with HLH in the overall group (A) and according to the type of disease (B).

Figure 3

The 5‐yr overall survival rate of 32 patients who received allogeneic HSCT in the overall group (A), according to the type of donor (B), graft source (C), and the intensity of conditioning regimen (D). MRD, matched related donor; URD, unrelated volunteer donor; PB, granulocyte colony‐stimulating factor‐mobilized peripheral blood; BM, bone marrow; UCB, unrelated cord blood; MAC, myeloablative conditioning; RIC, reduced‐intensity conditioning.