Novel juxtamembrane FLT3 in-frame insertion in a child with refractory AML: a case report of durable remission following allogeneic HSCT and FLT3 inhibitor therapy

Background FLT3 gene mutations, particularly internal tandem duplications ( FLT3 -ITD), are present in approximately 25%–30% of patients with acute myeloid leukemia (AML) and are important drivers of leukemogenesis; less frequently, FLT3 mutations occur as tyrosine kinase domain (TKD) variants. Non-canonical variants, such as juxtamembrane domain (JMD) in-frame insertions, are rare and their pathogenic mechanisms and therapeutic sensitivities are less defined. Case description We report a 13-year-old female patient with refractory AML harboring a novel in-frame insertion in the FLT3 JMD NC_000013.11(NM_004119.3):c.1780_1781insGGGTCCCTCCGCCTACCC; p.(Phe594delinsTrpValProProProThrLeu) identified by next-generation sequencing (NGS). The disease was resistant to standard intensive chemotherapy but showed marked sensitivity to the FLT3 inhibitor sorafenib. Following relapse upon sorafenib discontinuation due to cardiac toxicity, the patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) while in active disease (M3 marrow). A sequential myeloablative conditioning regimen consisting of melphalan, fludarabine, and fractionated total body irradiation (TBI-8 Gray) was employed. Post-transplant, sorafenib maintenance was resumed for 2 years. Outcomes The patient achieved sustained complete remission and remains disease-free 63 months post-HSCT, despite significant pre-transplant comorbidities including fungal pneumonia and a pulmonary artery pseudo-aneurysm. Conclusion This case suggests that non-canonical FLT3 JMD insertions may be actionable molecular alterations and highlights the need for further investigation of FLT3 inhibitor efficacy and the therapeutic relevance of these rare mutations in AML.