Chemotherapy has made the most common childhood cancer one of the most curable, but researchers have evidence that it may also cause some patients to relapse. Results published in the journal blood report that treatment-induced mutations cause drug resistance in some patients with relapsed acute lymphoblastic leukemia (all).
“Our study reveals the evolutionary dynamics of pediatric all, which shows for the first time that chemotherapy, especially thiopurine, can cause mutations leading to drug resistance in patients,” said Dr. Zhang Jinghui, co-author of the study. Director, Department of computational biology, St Jude’s children’s research hospital. Thiopurine is a kind of drug used in most stages of all treatment.
The study involved 103 young patients with recurrent all. Most recurred nine months or more after diagnosis. Analysis showed that about 20% of these patients had treatment-related mutations at the time of recurrence, some of which were related to drug resistance. “These mutation features are specific and treatment-related, because they only exist in the genome of patients with recurrent all and not in the genome of other pediatric or adult cancers,” Zhang said
The findings highlight the need for less toxic therapies and precise medical methods, said co-author Dr. Pei QingHan, head of St. Jude’s Oncology Department. Candidates in development include immunotherapy, such as car-t cells and bispecific antibodies.
Dr. Jun J. Yang, CO corresponding author of St. Jude’s Department of oncology and Pharmaceutical Sciences, said: “this study shows that when drug-resistant mutations occur in all, individualized treatment may be needed.” Another corresponding author is Dr. Zhou binbing from Shanghai Children’s Medical Center, National Children’s medical center and medical school of Shanghai Jiaotong University. All is the most common childhood cancer. With current treatment, more than 90% of pediatric patients become long-term survivors. For patients with relapsed leukemia, the prognosis is depressing. Recurrence accounts for 70% to 80% of all deaths.
Although previous studies have identified relapse specific drug resistance mutations, the origin of these mutations remains unclear. Some researchers suggest that relapse of all is driven by the presence of drug-resistant leukemia cells at the time of diagnosis. The children in the study were treated in China. They sequenced the whole genome of leukemia cells and normal DNA collected at the time of diagnosis and recurrence. The analysis also included targeted deep sequencing of leukemia cells collected regularly during treatment in 16 patients.
The researchers identified relapse specific acquired mutations in 12 genes involved in drug response, including FPGS, a novel relapse related gene. The analysis also revealed two novel mutation patterns or characteristics. Researchers have shown that thiopurine causes one of the new mutation features. Further studies have shown that mutations lead to multidrug resistance. This study provides insight into the timing of relapse and the presence of relapse specific mutations in 12 genes involved in drug response.
Most patients (55%) relapsed 9 to 36 months after diagnosis but before the end of treatment. This group of patients had the most recurrence specific mutations in the 12 drug resistance genes, especially compared with patients with earlier recurrence. Mathematical models, mutation analysis and other evidence suggest that early recurrence is likely caused by drug-resistant tumor cells present at the time of diagnosis.
The researchers proposed a two-step process to explain the recurrence later. This model shows that relapse occurs when the partially drug-resistant tumor cells at the time of diagnosis acquire treatment-related mutations. Now resistant cells divide and eventually lead to relapse. “This shows that drug resistance is not a foregone conclusion,” Yang said“ It can be prevented by changing the dose or time of treatment. ” Based on these findings, it may be necessary to screen for drug resistance mutations in patients with relapse, Bei said.