S244: outcome of familial hemophagocytic lymphohistiocytosis: report on 148 patients from the italian registry

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and severe hyperinflammatory syndrome caused by defects in genes of the granule-dependent cytotoxic pathway of NK or CD8 T cells. The clinical presentation is frequently complicated by multiorgan failure and the mortality rate is high. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but intensive treatments, including chemotherapy and novel targeted approaches, are required to induce remission before HSCT. Aims: To investigate the clinical presentation and outcome in a large cohort of patients with FHL diagnosed in the last 15 years and enrolled in the Italian hemophagocytic lymphohistiocytosis (HLH) Registry. Methods: Patients with a genetic diagnosis of FHL between 2007 and 2022 centralized at the Italian referral center for HLH at the Meyer Children’s Hospital IRCCS (Florence, Italy), were considered eligible for study inclusion. Patients without available data on clinical and laboratory presentation and on outcome with a minimal follow-up duration of 6 months were excluded. Results: One hundred and forty-eight patients were included in the study (males n=93, 62.8%). The median age at diagnosis was 11.5 months (IQR 2-87.3). Genetic diagnoses included: FHL2 in 48 patients (32.4%), FHL3 in 41 (27.7%), FHL4 in two (1.4%), FHL5 in 16 (10.8%), XLP-1 and -2 in 12 each (8.1%), GS2 in nine (6.1%), and CHS in eight (5.4%). One-third of patients (n=93, 62.8%) fulfilled the HLH-2004 criteria; the most frequent presenting features were: fever (n=130, 87.8%), splenomegaly (n=121, 81.8%) and hepatomegaly (n=84, 56.8%). Neurological involvement was detected in 49 patients (33.1%), bi-cytopenia in 98 (66.2%), and liver enzymes abnormalities in 73 (49.3%). The median values of ferritin, triglycerides, and fibrinogen were 2,525 ng/mL (IQR 1,004-11,550), 273 mg/dL (IQR 183.7-428.5), and 130 mg/dL (IQR 81-233.5), respectively; infectious triggers were reported in 43 patients (29.1%). Most patients received first-line chemotherapy according to the HLH-94 (n=29, 19.6%), HLH-04 (n=75, 50.7%), and Euro-HIT (n=7, 4.7%) protocols. Among the remaining patients, 18 (12.2%) received steroids and 19 (12.8%) did not receive any treatment. Out of 111 patients receiving chemotherapy, 65 (58.6%) achieved complete response (CR) and 21 (18.9%) partial response (PR). Thirty-three patients (22%) reactivated, and 91 (61.5%) received HSCT, 77 of whom survived and were alive at a median follow-up of 67 months (34-106). Overall, 98 patients (66.2%) were alive after a median follow-up of 30 months (IQR 5.5-73.5). Unadjusted predictors of non-response were age <6 months, low platelets (<20,000/uL), high ferritin values (>5,000 ng/mL) and high bilirubin levels (>2 mg/dL); predictors of pre-transplant mortality were high ferritin and bilirubin levels, while predictors of overall mortality were age <6 months and high bilirubin levels. At multivariable analysis, high bilirubin levels were confirmed as a predictor of pre-transplant mortality (OR 4.29, 95%CI 1.25-15.7; p=0.022). Summary/Conclusion: Despite recent advances in therapeutic management, FHL remains a life-threatening condition that requires additional efforts to develop novel treatments. Liver involvement is the main predictor of poor survival. Keywords: HSCT, Hemophagocytic Lymphohistiocytosis (HLH)