RESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder driven by interferon-gamma (IFN-γ). Emapalumab, an anti-IFN-γ antibody, is approved for the treatment of patients with primary HLH. Hematopoietic stem cell transplantation (HSCT) is required for cure of HLH. Reduced intensity conditioning (RIC) HSCT is associated with improved survival but higher incidences of mixed chimerism and secondary graft failure. To understand the potential impact of emapalumab on post-HSCT outcomes we conducted a retrospective study of pediatric patients with HLH receiving a first RIC-HSCT at our institution between 2014 and 2022 after treatment for HLH, with or without this agent. Mixed chimerism was defined as <95% donor chimerism and severe mixed chimerism as <25% donor chimerism. Intervention free survival (IFS) included donor lymphocyte infusion, infusion of donor CD34-selected cells, second HSCT or death within 5-years post-HSCT. Fifty patients met inclusion criteria, 22 received emapalumab within 21 days prior to the conditioning regimen and 28 did not. Use of emapalumab was associated with a markedly lower incidence of mixed chimerism (48% vs. 77%, p=0.03) and severe mixed chimerism (5% vs. 38%, p<0.01). IFS was significantly higher in patients receiving emapalumab (73% vs. 43%, p=0.03). Improved IFS was even more striking in infants <12 months, a group at highest risk for mixed chimerism (75% vs. 20%, p<0.01). While overall survival was higher with emapalumab, this difference was not significant (82% vs. 71%, p=0.39). We show that the use of emapalumab for HLH pre-HSCT mitigates the risk of mixed chimerism and graft failure following RIC-HSCT.
RESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is most commonly treated with etoposide and dexamethasone. This standard of care therapy has improved survival, but â¼15% of patients still die in the first months after diagnosis, and poor responses prompting salvage therapy are frequent. Thus, identifying patients at risk promptly is likely to improve outcomes. We conducted a multi-institutional, retrospective study of pediatric and young adults treated per HLH-94 or HLH-2004 from 2010 to 2019 to identify patients at risk for early mortality. Biweekly data during the first 100 days of treatment were analyzed using receiver operating curves to define optimal prognostic indicators and their thresholds. The primary end point was survival to bone marrow transplant (BMT) or â¼1 year if no BMT was pursued. Eighty-nine patients met the study inclusion criteria. Pre-BMT mortality was 13% (n = 12), and overall mortality was 27% (n = 24). Laboratory markers measured on day 7 of therapy more efficiently predicted outcomes than did either pretreatment or later assessments. The most potent day 7 unfavorable marker was improvement in soluble CD25 (sCD25) of less than 25% from pretherapy levels. Absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen were also discriminatory markers (area under the curve ≥ 0.7). The presence of ≥3 of these unfavorable markers was strongly associated with pre-BMT mortality (accuracy, 0.93). Thus, serial monitoring of sCD25 and assessment of other early (day 7) response markers optimally predicts prognosis with etoposide-based therapy and may indicate the need for earlier use of alternative, response-adapted therapeutic strategies for HLH.