Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy.
Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias1-4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment.
Acknowledgements: This research is funded by the Wellcome Trust (grants 206194 and 223135/Z/21/Z). T.H.H.C. is the recipient of an EMBO long-term fellowship (ALTF 172-2022). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We are indebted to our patient and their family for participating in this research.
European Molecular Biology Organization (EMBO) (ALTF 172-2022)