Abstract Acquired aplastic anemia (AA) is a life-threatening disorder caused by an autoreactive T-cell mediated destruction of hematopoietic stem cells resulting in the inability to produce adequate red blood cells, white blood cells and platelets. Acquired AA is extremely rare, occurring in 2-6 patients per million. There are between 600- 900 new cases each year in the United States. While AA can occur at any age there is a bi-modal distribution with peaks in late childhood/early adolescence and in older adults. Patients with AA are susceptible to potentially fatal opportunistic infections, clonal hematopoiesis/leukemogenesis, and chronic transfusion burden. The workup of a patient with suspected AA takes several weeks during which time the patient receives only supportive care. Immune suppression therapy (IST) and bone marrow transplant (BMT) are the two therapies available for patients once a diagnosis is definitive. For patients with an available matched related donor (MRD), BMT is the standard of care (SOC). Patients lacking a MRD traditionally received IST although many institutions are now prioritizing alternative donor transplant. IST has a 50% response rate over time with the other half of patients requiring additional therapy. BMT has a higher disease-free survival rate but increased potential toxicities including graft versus host disease, infertility and graft rejection. The decision of which therapy to pursue is often the most anxiety-provoking time for families with children that have newly diagnosed AA. This Phase 2a/2b Trial Emapalumab: A Window of Opportunity in Pediatric Aplastic Anemia leverages data showing that the Interferon-gamma (IFNγ) pathway is associated with the pathogenesis of AA. Pediatric patients with newly diagnosed AA will receive a prophase of an IFNγ neutralizing monoclonal antibody called emapalumab. This prophase will not add time to curative therapy and will occur during the workup period between presentation and start of definitive therapy. At the conclusion of the prophase, patients that have a hematologic response will be consolidated with IST while those that do not will receive institutional SOC. In this way we create an algorithm to try and identify patients that are most likely to have a favorable response to IST. This data-driven identification of which patient should receive IST will help alleviate parental anxiety in making these decisions without sufficient information. Aim 2 of this project seeks to extend our previous findings that distinct patterns of pediatric clonal hematopoiesis are associated with poor outcomes after IST. Conversely, lack of these markers aligned with favorable IST responses. We will prospectively validate these findings and assess if these specific clonal changes can be used as predictive biomarkers for response to IST. We will also examine if an early upfront prophase with emapalumab can prevent and/or minimize emergence of clonal hematopoiesis by preserving larger re...