Publication
Examining treatment responses of diagnostic marrow in murine xenografts to predict relapse in children with acute lymphoblastic leukaemia
Publisher:
Springer Science and Business Media LLC
Date:
15-06-2020
DOI:
10.1038/S41416-020-0933-4
Abstract: While current chemotherapy has increased cure rates for children with acute lymphoblastic leukaemia (ALL), the largest number of relapsing patients are still stratified as medium risk (MR) at diagnosis (50–60%). This highlights an opportunity to develop improved relapse-prediction models for MR patients. We hypothesised that bone marrow from MR patients who eventually relapsed would regrow faster in a patient-derived xenograft (PDX) model after induction chemotherapy than s les from patients in long-term remission. Diagnostic bone marrow aspirates from 30 paediatric MR-ALL patients (19 who relapsed, 11 who experienced remission) were inoculated into immune-deficient (NSG) mice and subsequently treated with either control or an induction-type regimen of vincristine, dexamethasone, and L -asparaginase (VXL). Engraftment was monitored by enumeration of the proportion of human CD45 + cells (%huCD45 + ) in the murine peripheral blood, and events were defined a priori as the time to reach 1% huCD45 + , 25% huCD45 + (TT25%) or clinical manifestations of leukaemia (TTL). The TT25% value significantly predicted MR patient relapse. Mutational profiles of PDXs matched their tumours of origin, with a clonal shift towards relapse observed in one set of VXL-treated PDXs. In conclusion, establishing PDXs at diagnosis and subsequently applying chemotherapy has the potential to improve relapse prediction in paediatric MR-ALL.