FLT3 (CD135) expression in pediatric AML is associated with distinct features and worse outcomes with sorafenib therapy

Menssen AJ, Ashango AB, Alonzo TA, Gerbing RB, Pardo L, Hsu FC, Lott LL, Dai F, Cooper TM, Pollard JA, Tarlock K, Aplenc R, Meshinchi S, Brodersen LE, Wells DA, Loken MR, Hudson CA. FLT3 (CD135) expression in pediatric AML is associated with distinct features and worse outcomes with sorafenib therapy. Blood Neoplasia. 2026 Jul 7;3(3):100268. doi: 10.1016/j.bneo.2026.100268. PMID: 42602269; PMCID: PMC13474013.

FLT3/CD135 (also known as FLK2) is a membrane-bound receptor tyrosine kinase expressed on hematopoietic progenitor and monocytic cells, where it promotes proliferation, differentiation, maturation, and survival.1, 2, 3 FLT3 is expressed in acute myeloid leukemia (AML), and its activation by FLT3 ligand (FLT3L) enhances leukemic cell proliferation and survival, demonstrating a key role in leukemia pathogenesis.2 FLT3 is frequently mutated in AML, including internal tandem duplications (FLT3-ITD), which are associated with poor prognosis. However, the significance of FLT3/CD135 cell surface expression levels remains unclear, particularly in the context of FLT3-targeted therapies. Given its role in leukemogenesis, FLT3 has become a common therapeutic target, leading to the development of tyrosine kinase inhibitors including sorafenib. In combination with standard chemotherapy, sorafenib appears to improve event-free survival (EFS), disease free survival (DFS), and relapse risk (RR) in pediatric patients with AML with high FLT3-ITD allelic ratios (AR).4,5 Although there have been promising findings, resistance to FLT3 inhibitors has been observed, posing a significant challenge to long-term success.6,7. Children’s Oncology Group protocol AAML1031 for de novo pediatric AML included a treatment arm (arm C) with the FLT3 inhibitor sorafenib in combination with standard chemotherapy for patients with high-AR FLT3-ITD. Details of AAML1031 have been described previously, including an outcome analysis of arm C.8,9 Patients who submitted diagnostic bone marrow samples and consented to correlative studies were included (n = 1024). CD135 expression was prospectively measured by multidimensional flow cytometry and quantified as mean fluorescence intensity (MFI), as previously described.9, 10, 11, 12 We hypothesized that high CD135 expression may be associated with clinical features and outcomes, particularly in the context of sorafenib therapy. CD135 expression varied across the cohort, with linear MFI ranging from 2.981 to 73.139 (Figure 1A; supplemental Figure 1A). To investigate clinical associations, patients were stratified into quartiles based on expression levels. Patients in the top quartile (Q4; n = 256) showed increased expression of surface markers associated with monocytic differentiation, including CD45 (P < .0001), CD11b (P = .002), CD14 (P < .0001), CD36 (P < .0001), and CD64 (P < .0001), compared with patients in quartiles 1 through 3 (Q1-Q3; Figure 1B-F). Conversely, CD34 expression was significantly decreased in Q4 (P = .001; Figure 1G), suggesting that in pediatric AML higher CD135 surface expression is associated with a more mature monocytic phenotype and indicating a correlation between expression and differences in disease biology and maturation state.