Lineage switch is a rare phenomenon in which acute leukemia transforms from lymphoid to myeloid lineage, or vice versa. It is typically seen following therapy or at the time of relapse. 1 Among the chromosomal aberrations associated with lineage switch, the t (4; 11)(q21; q23) rearrangement with KMT2A/AFF1 fusion protein (formerly, MLL/AFF1 or MLL/AF4) is the most common. 2 In general, lineage switch disease is often refractory to therapy and portends a poor prognosis. 3, 4

Blinatumomab is a monoclonal antibody with bispecificity for both CD19 on B cells and CD3 on cytotoxic T cells. Following simultaneous binding to both epitopes, normal and neoplastic B cells are lysed by the host cytotoxic T cells. 5 Recent reports have documented lineage switch of acute leukemias following CD19-targeted therapy; 6–9 however, the underlying mechanism and management of these events are unclear. Herein, we present a case of refractory B lymphoblastic leukemia (B-ALL) with t (4: 11)(q21; q23) KMT2A/AFF1 transforming to acute myeloid leukemia (AML) shortly following blinatumomab therapy. We studied both molecular and cytogenetic abnormalities at the initial diagnosis of B-ALL and at the time of lineage switch, thereby providing insights into the underlying biology.