Outcomes of Hemophagocytic Lymphohistiocytosis in Acute Myeloid Leukemia: The Three-Site Mayo Clinic Experience.

• AML-associated HLH primarily affects older patients with genomically unstable AML and is independently associated with poor survival. • TP53 and DNA damage repair pathway mutations are associated with increased susceptibility to HLH in AML. Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal complication of acute myeloid leukemia (AML), and contemporary data on its clinical and genomic correlates remain sparse. We retrospectively identified 19 adults with AML who developed HLH across three Mayo Clinic sites (2020–2024) and compared them with 73 patients with AML without HLH. HLH occurred at a median of 34 days from AML diagnosis (range 0–472) and was associated with fever, multiorgan dysfunction, and rapidly rising biomarkers (ferritin, CRP, triglycerides, bilirubin; all p <0.001). Morphologic hemophagocytosis was observed in only 18% of cases, underscoring its poor sensitivity. HLH was associated with markedly inferior overall survival (median 5.7 vs. 14.8 months, p =0.005), including within adverse-risk and TP53 -mutated AML subsets. When modeled as a time-dependent covariate, HLH remained strongly associated with inferior survival (HR 3.9, p <0.001). Genomic profiling demonstrated enrichment of TP53 (58%), NF1 (16%), and RAD21 (11%) mutations, with tumor-suppressor and/or DNA damage repair pathway alterations in 68% versus 34% of controls ( p =0.009). On multivariable analysis, HLH (HR 3.1, p =0.003) and adverse-risk cytogenetics (HR 2.2, p =0.040) independently predicted worse survival. Age ≥65 years was associated with accelerated HLH onset (14 vs. 84 days, p =0.032) and higher mortality (HR 13.4, p =0.005). All patients received high-dose corticosteroids; some received tocilizumab or ruxolitinib, and none received etoposide. Despite diverse leukemia-directed therapies, only three patients achieved long-term survival. Collectively, these findings indicate that AML-associated HLH arises predominantly in older patients with genomically unstable leukemias, portends poor prognosis, and warrants biomarker-guided surveillance and improved targeted immunomodulatory strategies with antileukemic therapy.