Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
College of Applied Medical Science, Medical Laboratory Department, Qassim University, Qassim, Saudi Arabia.
Br J Cancer. 2020 Sep;123(5):742-751. doi: 10.1038/s41416-020-0933-4. Epub 2020 Jun 15.
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 samples 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.
虽然目前的化疗已经提高了儿童急性淋巴细胞白血病（ALL）患者的治愈率，但仍有最大数量的复发患者在诊断时被归类为中危（MR）（50-60%）。这为开发用于 MR 患者的改良复发预测模型提供了机会。我们假设，在诱导化疗后，最终复发的 MR 患者的骨髓在患者来源的异种移植（PDX）模型中会比长期缓解患者的样本更快地重新生长。
从 30 名儿科 MR-ALL 患者（19 名复发，11 名缓解）的诊断性骨髓抽吸物中接种到免疫缺陷（NSG）小鼠中，然后用对照或诱导型长春新碱、地塞米松和 L-天冬酰胺酶（VXL）方案进行治疗。通过计数小鼠外周血中人类 CD45 细胞的比例（%huCD45）来监测植入情况，并预先定义事件为达到 1%huCD45、25%huCD45（TT25%）或白血病临床表现（TTL）的时间。
TT25%值显著预测了 MR 患者的复发。PDX 的突变谱与其起源肿瘤相匹配，在一组接受 VXL 治疗的 PDX 中观察到向复发的克隆转移。
总之，在诊断时建立 PDX 并随后应用化疗有可能改善儿科 MR-ALL 的复发预测。
