e19010 Background: AML is a disease defined by the acquisition of genetic lesions in normal hematopoietic stem cells and progenitors resulting in poorly differentiated and highly proliferative leukemic blasts. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that maintains de-differentiation and leukemogenesis. MLL rearrangements (MLL-r) occur in up to 10% of adult AML and are associated with upregulated expression of the transcription factors HOXA9 and MEIS1 and worse clinical outcomes. Entospletinib (ENTO), an oral, selective inhibitor of SYK, has been studied in clinical trials for unselected AML patients as well as MLL-r patients. ENTO plus standard induction chemotherapy in front line had a 76% (13/17) composite complete response (CR) in AML patients with high HOXA9 and MEIS1. We have 3 patients that achieved CRs with ENTO monotherapy; one patient achieved CR to 14 days of ENTO monotherapy prior to initiation of chemotherapy; 2 patients with relapsed/refractory AML with MLL-r treated with ENTO monotherapy achieved CRs. Methods: This was part of an international multicenter phase Ib/II study (NCT02343939) which evaluated the efficacy, safety, and tolerability of ENTO in subjects with AML. During dose escalation, ENTO was administered in combination with induction chemotherapy (Group A) or with a hypomethylating agent (Group B). ENTO was administered as monotherapy for R/R AML in Group C. This report includes one patient from group A (newly diagnosed AML, MLL-r, 14-day monotherapy lead-in with ENTO) and two patients from group C monotherapy (relapsed/refractory AML, MLL-r). Results: Three patients receiving ENTO monotherapy had CRs. 18-year-old male from group A, that was MLL-r, NPM1-mutant (-). Patient treated at 400 mg PO, BID, achieved a cytogenetic CR with incomplete count recovery after cycle 0 (before chemotherapy); the patient continued study with induction chemotherapy and ultimately received ASCT in CR. Two additional patients in group C (with multiple therapies), both at 400 mg bid: (i) 37-year-old male, MLL-r, NPM1(-), was on study for 28 days, achieved CR; (ii) 28-year-old female, MLL-r, NPM1(-) on study for 60 days, achieved CR, both proceeded to SCT. Conclusions: Based on the results from these three patients, the clinical activity of SYK inhibition should be explored further in AML. We are testing Lanraplenib, a next-generation SYK inhibitor with enhanced selectivity, and more favorable pharmacologic properties in combination in genetically defined subsets of AML (NCT05028751). Clinical trial information: NCT02343939 .