Busulfan-based reduced toxicity conditioning regimen used in hematopoietic stem cell transplantation in HLH patients results in sustained donor chimerism

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome characterized by excessive inflammation and an ineffective immune response. This syndrome, often driven by a genetic abnormality, can ultimately be fatal if unsuccessfully controlled. Allogeneic hematopoietic stem cell transplant (HSCT) is curative. Historical studies reveal that overall survival with HSCT is variable, ranging from 40 to 66%. Myeloablative conditioning regimens utilized in patients with HLH resulted in increased transplant related morbidity and mortality. This led to reduced intensity conditioning (RIC) regimens being used in the HLH HSCT. Multiple single institutional experiences report the use of alemtuzumab, fludarabine and melphalan based regimens with significantly superior overall survival, when compared to myeloablative therapy, but with a high incidence of mixed chimerism. Graft loss was common within the first year post-transplant, necessitating donor lymphocyte infusions (DLI) or a second HSCT. Recently, Allen et al reported results of a multicenter prospective phase 2 trial, utilizing RIC of alemtuzumab, fludarabine and melphalan (NCT 01998633). Although the 1-year and 18month overall survival (OS) for patients with HLH (n1⁄4 34) was 82.4% and 68% respectively, the proportion of HLH patients alive at 1 year with sustained engraftment was only 41%, suggesting caution for this approach. Thus, it is critically important to identify a RIC regimen that is effective in sustaining long-term donor engraftment in HLH patients. The ideal conditioning regimen for HLH HSCT minimizes treatment-related morbidity and mortality, while ensuring rapid, sustained engraftment. Gungor et al reported that busulfan-based RIC regimens are safe and efficacious in patients with chronic granulomatous disease. These patients come to HSCT in an inflammatory state, similar to HLH patients. They reported a 93% overall survival, with graft-failure occurring in only 5% of the patients. On the basis of this information, we adopted this conditioning strategy for transplantation of patients with HLH at Phoenix Children’s Hospital. We report our single institution experience using a busulfan-based reduced toxicity conditioning regimen prior to HSCT for pediatric patients with HLH.