Risk factors for mixed chimerism after stem cell transplantation with treosulfan or melphalan based conditioning regimens in children and adolescents with primary hemophagocytic lymphohistocytosis

Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a genetic hyperinflammatory syndrome that can currently only be cured by stem cell transplantation (SCT). Reduced toxicity conditioning results in favorable survival rates at the expense of higher rates of mixed chimerism. Donor chimerism >25% allows for long-term disease-free survival. Factors predisposing to mixed chimerism remain to be determined. Methods: The retrospective multicenter analysis included patients from the German and Austrian HLH registry transplanted since 2009 with a treosulfan or melphalan based regimen for hereditary disease predisposing to HLH (familial HLH 2–5, X-linked lymphoproliferative syndrome 1 and 2, Griscelli-Syndrome 2, Chediak-Higashi syndrome). Patients were analyzed for survival, engraftment, donor chimerism, and serious adverse events. Recipient chimerism was considered substantial if additional post-SCT cell therapy was administered at the discretion of the treating physician (secondary HSCT, donor lymphocyte infusion, or stem cell boost) and/or if mixed chimerism decreased to < 25% donor chimerism. A multivariate analysis of 5 potential risk factors for the appearance of substantial recipient chimerism was performed, applying a logistic regression model: (1) donor type (matched related or unrelated vs. mismatched), (2) graft source (peripheral stem cells vs. bone marrow), (3) type of alkylating agent (melphalan vs. treosulfan, both mostly with additional thiotepa), (4) serotherapy (alemtuzumab vs. ATG (Fresenius/Grafalon® or Thymoglobulin®)), and (5) remission (remission vs. non-remission). Haploidentical SCT were excluded for the risk analysis. Results: In total, 61 consecutive patients were analyzed, with a median follow up of 721 days post SCT (range 4 days - 8.2 years). Overall survival was 77%. Primary engraftment was successful in 95% of patients. Occurrence of donor chimerism < 95% was 46%. Substantial recipient chimerism (i.e. post SCT cell therapy and/or chimerism < 25%) was recorded for 31% of patients. Secondary post-SCT cell therapy was administered in 28% of all patients (of which 75% DLI, 25% boost, 46% 2° SCT). Donor type was the only significant risk factor for the occurrence of substantial recipient chimerism (p = 0,013). A mismatched donor (8 or 9/10; n = 26) increased the risk in comparison to a related or unrelated matched donor (10/10, n = 27) by 6.3 (OR, CI95% 1.6–31). The type of alkylating agent was not a significant risk factor. Mild or moderate veno-occlusive disease occurred in 10 patients. Acute GvHD ≥3° was diagnosed in 11% of patients, and limited chronic GvHD in one patient. Conclusions: Outcomes after treosulfan or melphalan based conditioning regimens are favorable, however the occurrence of mixed chimerism is frequent. A mismatched donor is a significant and relevant risk factor for the development of substantial mixed chimerism. Conflict of interest: nothing to disclose