Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000-2013) and DC permanently or transiently <75% (overall, CD3(+), CD56(+)) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations (≥5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated CNS reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n=11, partial flare n=3, isolated CNS reactivation n=4). Ten events occurred during profound immune suppression before day 180 (median DC 10%, range 1-100%; CD3(+)if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC 13%, range 0-30%). In 5 patients, overall and lineage-specific DC were ≤10% for >6 months (median 5.1, range 1.1-10 years) without reactivation. A 2nd HSCT was performed in 18 patients (median DC 4%; range 0-19%). Death due to reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a 2nd HSCT (33% of 2nd HSCT). We conclude that a DC >20-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against 2nd HSCT must be based on a thorough risk assessment.
