Abstract

A “2-hit” model of leukemogenesis has been proposed in which one class of mutations confers a proliferative or survival advantage to the cells and the second class serves primarily to interfere with hematopoietic cell differentiation. In support of this, FLT3 receptor mutations have been frequently reported in patients with t(8;21) and inv(16) acute myeloid leukemia (AML), otherwise known as core-binding factor (CBF) leukemias, whose fusion gene products (AML1-ETO and CBFB-MYH11) contribute to impaired differentiation of leukemic cells. In CML, enhanced kinase activity of BCR-ABL confers a proliferative and survival advantage to the leukemic cells and clonal evolution is a common event at the time of disease acceleration. However, the acquisition of CBF fusion genes has not been commonly reported during the clonal evolution of CML. We report 4 patients with CML who developed CBF type rearrangements [inv(16)(n=2) and t(8;21)(n=2)] at the time of disease progression. Patient #1, a 61 year old female, presented with myeloid blast phase disease with 46,XX,t(9;22)(q34;q11.2),inv(16)(p13q22) and was treated with imatinib achieving a hematological but not cytogenetic response. Patient #2, a 48 year old male, presented with chronic phase disease and received imatinib for 2 years, achieved a complete cytogenetic remission (CG CR) but progressed to blast phase with development of 46,XY,t(9;22)(q34;q11.2),inv(16)(p13q22). Both patients had elevated and abnormal marrow eosinophils at the time of clonal evolution. Patient #3, a 54 year old female, presented in chronic phase, received imatinib and achieved CG CR after 3 months. Blast transformation occurred after one year with 48, XX,+8,t(8;21)(q22;q22),t(9;22;19;10)(q34;q11;p13.1;q22),+der(22)t(9;22;19;10). Patient #4, a 47 year old male, presented with an extramedullary myeloid mass on his arm and features of chronic phase in the marrow examination. He was treated with troxacitabine with resolution of the mass. He was then treated with imatinib. Ten months later he developed a recurrent mass with cytogenetic studies of both the mass and marrow showing 47,XY,+8,t(8;21)(q22;q22),del(9)(q13q32),t(9;22)(q34;q11.2). To our knowledge, eleven other patients with CML with inv(16)(n=10) or with t(8;21)(n=1) have been previously reported in the literature, none treated with imatinib. Patients with inv(16) had features of AML with eosinophilia (FAB M4Eo) demonstrating dysplastic eosinophils in the bone marrow examination. Development of the CBF rearrangement was invariably associated with disease progression into the myeloid blast phase with the exception of one patient, reported to develop lymphoid blast phase, based on surface markers. CBF rearrngements occur rarely at the time of disease progression in CML and may contribute to disease transformation based on the “2-hit” hypothesis for leukemogenesis.