Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-MECOM positive acute myeloid leukemia with subsequent emergence of a rare KMT2A-ASXL2 fusion

Abstract

Secondary acquisition of t(9;22)(q34;q11.2)/BCR-ABL1 fusion in the context of de novo acute myeloid leukemia (AML) with inv(3)(q21q26)/GATA2-MECOM rearrangement has been rarely reported. Furthermore, t(2;11)(p23;q23)/KMT2A-ASXL2 fusion has been rarely described with only a single case reported to date. We report a 45-year-old male with a diagnosis of de novo AML harboring GATA2-MECOM rearrangement in conjunction with a related subclone with concomitant inv(3) and t(9;22). The patient was treated with a tyrosine kinase inhibitor (TKI) which lead to disappearance of the inv(3)/t(9;22) subclone and subsequent expansion of the inv(3) ancestral clone. The patient was started on a 7+3 induction regimen with TKI but had persistent disease. He was placed on several additional treatment protocols and only achieved morphologic remission with a combination of fludarabine, cytarabine and filgrastim with TKI. Approximately 11.5 months after diagnosis the patient relapsed with the inv(3) clone predominating initially, followed by return of the inv(3)/t(9;22) subclone and the emergence of a second subclone with concomitant inv(3) and t(2;11)(p23;q23). Mate-pair sequencing was performed and identified a KMT2A-ASXL2 in-frame fusion, which was only recently described in a single case of therapy-related AML. For BCR-ABL1 positive AML, which generally carries a poor prognosis, treatment with TKIs has been proposed in combination with standard chemotherapy. In our case, treatment with TKI alone led to initial response of the BCR-ABL1 positive clone, but the ancestral clone quickly expanded and subsequent standard AML therapy may have led to further clonal evolution and re-emergence of the BCR-ABL1 clone in the absence of therapeutic selection.

Keywords: Acute myeloid leukemia; BCR-ABL1; GATA2-MECOM; KMT2A-ASXL2; Mate-pair sequencing (MPseq); Next generation sequencing (NGS).