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Secondary acute lymphoblastic leukemia (ALL) is a rare disease that has not been well characterized compared with secondary myelodysplastic syndrome or secondary acute myeloid leukemia. We present a report of two patients who developed ALL following complete remission of diffuse large B-cell lymphoma (DLBCL). The first case is more consistent with a therapy-related ALL as a PCR analysis of bone marrow aspirate revealed a distinct clone and the mixed-lineage leukemia gene rearrangement, commonly associated with exposure to topoisomerase II inhibitors. The second case is more consistent with clonal evolution given positive MYC and BCL2 fusion signals in the original diagnosis of DLBCL and the secondary ALL.