Unrelated Donor Hematopoietic Cell Transplant (HCT) for Hemophagocytic Lymphohistiocytosis (HLH).

HLH is a rare immunoregulatory disorder characterized by widespread infiltration of histiocytes and T cells into organs, including the central nervous system (CNS), and is fatal in most cases without HCT. HLH can be inherited in an autosomal recessive pattern with unaffected sibling donors available for fewer than 20% of patients thus necessitating alternative donor HCT in the majority of cases. Data on 91 patients who underwent unrelated donor HCT and reported to the Center for International Blood and Marrow Transplant Research between 1989–2005 were analyzed. Fifty-one percent of patients were <1 yr at HCT and 29% had a Lansky performance score ≤80%. In a subset of patients (n=51) additional disease specific characteristics were available: 8 had a family history of HLH, of patients tested, 19 were confirmed to have either a perforin or MUNC-13 gene mutation; CNS disease was present at diagnosis in 21 patients and remained active in 4 at HCT; and 5 patients had active systemic disease at HCT. Most patients (80%) were conditioned with busulfan (BU), cyclophosphamide (CY), and etoposide (VP16) with or without anti-thymocyte globulin. Graft sources were bone marrow (86%), peripheral blood stem cells (4%) and cord blood (10%). Graft vs. host disease (GVHD) prophylaxis was cyclosporine or tacrolimus based in 89% of patients and T-cell depletion in 11%. Fifty-nine percent of grafts were matched at HLA A, B and DRB1, 34%, mismatched at 1-locus and 7%, mismatched at 2-loci. Neutrophil recovery was achieved by day 42 in 91% of patients. The probabilities of grades 2–4 acute at day-100 and chronic GVHD at 3-years were 41% and 23%, respectively. In multivariate analysis, the risk of overall mortality was 2-fold higher in patients who did not receive BU/CY/VP16 as their conditioning regimen (RR 1.99, p=0.03). In the sub-set of patients from whom disease-specific characteristics were available, overall mortality was higher in those with active systemic disease at HCT (RR 3.11, p=0.04). Early mortality was high, 35% at day-100 after HCT. Causes of early mortality included GVHD (n=5), infections (n=8), interstitial pneumonitis (n=8), organ failure (n=6), hemorrhage (n=3) and persistent disease (n=2). With a median follow-up of 49 months (range, 5–145) the 1- and 3-year probabilities of overall survival were 52% and 47%, respectively. For 46 patients with documented systemic remission at HCT, the 1- and 3-year probabilities of overall survival were 56% and 49%, respectively. These data represent the largest experience with unrelated donor HCT for HLH and demonstrate that a BU/CY/VP16 conditioning regimen provides cure in over 50% of patients. Outcome of HCT for patients with active systemic disease was poor with only 1 of 5 such patients surviving, demonstrating a need for novel therapies in patients who fail to respond to standard pre-transplant treatment. Unrelated donor HCT for HLH was associated with high early mortality and future studies should explore strategies to decrease early HCT-related mortality.