A rare case of high-risk M4 Acute Myeloid Leukemia with ETV6::ABL1 rearrangement in a young adult with preceding chronic idiopathic thrombocytopenia: Insights and implications Free

Background:

ETV6::ABL1 rearrangement is exceptionally rare in acute myeloid leukemia (AML), particularly in pediatric and adolescent/young adult (AYA) cases, with most literature limited to ALL or CML. Its presence is associated with high-risk features, resistance to first-generation tyrosine kinase inhibitors (TKIs), and a lack of standardized therapy regarding TKI or hematopoietic stem cell transplantation (HSCT) use. In addition, persistent idiopathic thrombocytopenia preceding the onset of AML raises questions about early hematopoietic alterations in the pathogenesis and potential transition from an indolent to a malignant phenotype.

Case Presentation:

An 18-year-old female with a three-year history of idiopathic thrombocytopenia who presented with hyperleukocytosis (WBC 218×10^3/μL) at which time she was diagnosed with AML. Bone marrow aspirate demonstrated a myelomonocytic M4 phenotype with approximately 70% blasts. Cytogenetics identified 46,XX,t(9;12)(q34;p13) with an ETV6(12p13.2)::ABL1(9q34) rearrangement. She was also found to have a PHF6 mutation with a variant allele frequency of 37% (c.346C>T and p.Arg116*). PHF6 encodes a tumor suppressor that is mutated in approximately 3% of de novo AML patients and 15% of patients with AML with myelodysplasia-related changes. Notably, serial bone marrow exams and genetic testing during the thrombocytopenic phase showed no evidence of dysplasia, clonal evolution, or germline thrombocytopenia-associated mutations. In addition, there was no clinical evidence of myelodysplastic syndrome (MDS) prior to leukemic transformation.

Treatment Course:

The patient was treated per the AAML1831 protocol for high-risk disease, with the addition of Dasatinib due to potential Imatinib resistance in ETV6::ABL1-positive disease. Morphologic remission was attained following induction I, but minimal residual disease (MRD) persisted. MRD negativity was achieved after induction II and she then received intensification I prior to proceeding to HSCT. The patient received a 10/10 HLA-matched unrelated donor allogeneic HSCT in May of 2024 with a Busulfan and Cyclophosphamide conditioning regimen. Post-HSCT, she experienced several complications including veno-occlusive disease, engraftment syndrome, acute and chronic Graft vs Host Disease (GvHD), transplant-associated thrombotic microangiopathy (TA-TMA), and several infectious plus orthopedic sequelae; all were managed successfully. She is over one year post HSCT with negative MRD, donor only chimerism, and no active GvHD with improving quality of life.

Discussion:

This case represents a unique presentation of AML in an AYA with an ETV6::ABL1 rearrangement and preceding chronic idiopathic thrombocytopenia. The presence of ETV6::ABL1 is not only rare but also confers an adverse prognosis, indicating the need for HSCT and the use of second-generation TKIs like Dasatinib. Somatic rearrangements in ETV6 disrupt normal megakaryopoiesis that could be linked to her longstanding thrombocytopenia prior to AML diagnosis. However, in the absence of confirmed MDS or germline mutations, her case could suggest a possible insidious clonal evolution not detectable by conventional studies, raising the need for molecular surveillance in cytopenic patients even in cases with negative cytogenetic screening. The detected PHF6 mutation, although of unclear risk category, is observed in some de novo and myelodysplasia-transformed AML, further supporting the probability of stepwise clonal evolution.

Conclusion:

This report highlights an extremely rare case of AML with ETV6::ABL1 rearrangement in a young adult with prior idiopathic thrombocytopenia, successfully treated with a combination of AAML1831-based chemotherapy, Dasatinib, and allogeneic HSCT. Her disease course emphasizes the vital importance of advanced cytogenetic and molecular diagnostics in cytopenic patients, the tailored use of targeted therapies, and HSCT for rare high-risk rearrangements. Broader study of ETV6::ABL1 driven AML in children and adults is needed to establish the optimal management strategies and to better understand the significance of preceding cytopenias in leukemogenesis.