Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy

Tim H H Coorens; Grace Collord; Taryn D Treger; Stuart Adams; Emily Mitchell; Barbara Newman; Gad Getz; Anna L Godfrey; Jack Bartram; Sam Behjati

doi:10.1038/s43018-023-00604-0

Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy

Nat Cancer. 2023 Aug;4(8):1095-1101. doi: 10.1038/s43018-023-00604-0. Epub 2023 Jul 20.

Authors

Tim H H Coorens¹, Grace Collord², Taryn D Treger^{3

4

5}, Stuart Adams², Emily Mitchell^{3

4}, Barbara Newman⁴, Gad Getz^{6

7

8}, Anna L Godfrey⁴, Jack Bartram², Sam Behjati^{9

10

11}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. tcoorens@broadinstitute.org.
² Great Ormond Street Hospital for Children, London, UK.
³ Wellcome Sanger Institute, Hinxton, UK.
⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Department of Paediatrics, University of Cambridge, Cambridge, UK.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA.
⁹ Wellcome Sanger Institute, Hinxton, UK. sb31@sanger.ac.uk.
¹⁰ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. sb31@sanger.ac.uk.
¹¹ Department of Paediatrics, University of Cambridge, Cambridge, UK. sb31@sanger.ac.uk.

Abstract

Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias^1-4 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Bispecific* / therapeutic use
Child
Female
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
T-Lymphocytes

Substances

blinatumomab
Antibodies, Bispecific

Grants and funding

WT_/Wellcome Trust/United Kingdom