The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Abstract

Key Points• Donor chimerism .20%-30% usually protects against late disease reactivation after day 180 post stem cell transplantation for primary HLH.• Lower levels do not inevitably result in reactivations. The risks of intervention must be weighed against the risk of reactivation.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 (2000HLH ( -2013 and DC permanently or transiently <75% (overall, CD3 1 , CD56 1 ) 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 central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n 5 11, partial flare n 5 3, isolated central nervous system reactivation n 5 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3 1 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 second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second 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 second HSCT must be based on a thorough risk assessment. (Blood. 2016;127(25):3281-3290)

Relationship between Mixed Donor–Recipient Chimerism and Disease Recurrence after Hematopoietic Cell Transplantation for Sickle Cell Disease

“…Many patients with nonmalignant disorders are symptom-free long-term after hematopoietic cell transplantation (HCT) despite mixed donor–recipient chimerism [1–6]. It is difficult to (1) distinguish between patients with adequate/stable donor chimerism with continued long-term disease control and those with unstable engraftment that results in disease recurrence and (2) predict the level at which donor chimerism is too low to sustain a disease-free state.…”

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

“…4 Based on the outcomes of HSCT in FHL patients, T-cell chimerism of at least 10% to 15% is required for efficient remission of HLH. 5,6 Hence, the T cells' transduction efficiency is a key parameter in this strategy. We demonstrated that, by using a new lentiviral pseudotype (such as the H/F-envelope), high levels of T-cell transduction can be achieved.…”

Gene-corrected human Munc13-4–deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice

“…The post-HSCT outcome in HLH patients shows that remission is maintained as long as the level of T-cell donor chimerism reaches 10% to 15%. 15,16 The conventional VSVG-LV strategy must therefore be tested in a preclinical murine model, in order to establish whether or not poor in vitro T-cell transduction prevents the achievement of this level of chimerism in vivo. Another limitation relates to the availability of T cells as a result of pancytopenia and the manifestations of HLH.…”