Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

Abstract

We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had <i>KMT2A</i> gene rearrangements; one had <i>TCF3::ZNF384</i> translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by <i>IG/TR</i> gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. <i>KMT2A</i>-r patients demonstrated very few additional mutations, while in the <i>TCF3::ZNF384</i> case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular -minimal residual disease studies can lead to reliable identification of lineage switch.