Early response markers predict survival after etoposide-based therapy of hemophagocytic lymphohistiocytosis.

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 approximately 15% of patients still die in the first months after diagnosis and poor responses prompting salvage therapy are frequent. Thus, identifying at-risk patients 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 2010-2019 to identify patients at risk for early mortality. Biweekly data during the first 100 days of treatment was analyzed using receiver operating curves to define optimal prognostic indicators and their thresholds. The primary endpoint was survival to bone marrow transplant (BMT) or approximately one 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 either pre-treatment or later assessments. The most potent day 7 unfavorable marker was improvement in sCD25 of less than 25% from pre-therapy levels. Absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen were also discriminatory (area under the curve >0.7) markers. 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 utilization of alternative, response-adapted therapeutic strategies for HLH.