Pediatric ALL Relapse May Be Caused by Mutations From Chemotherapy

Although chemotherapy is the standard treatment for pediatric acute lymphoblastic leukemia (ALL), and has made it one of the most survivable childhood cancers, the chemotherapy drug class thiopurines can cause mutations that result in relapse. The findings were published in Nature Cancer.

Previously, it was unknown if acquired drug-resistant mutations in ALL are present at diagnosis or induced by treatment. The present findings are the first evidence in pediatric cancer that mutations may be induced by chemotherapy.

“The findings offer a paradigm shift in understanding how drug resistance develops,” Jinghui Zhang, PhD, Department of Computational Biology chair at St. Jude Children’s Research Hospital, said in a statement. “The results also suggest possible treatment strategies for ALL patients who relapse, including screening, to identify those who should avoid additional thiopurine treatment.”

The study used samples from pediatric patients with ALL who relapsed in the United States, China, and Germany. More than 1000 samples were collected from different times in treatment. Samples from 181 patients were collected at diagnosis, remission, and relapse.

The authors identified a mutational signature, which reflects the history of genetic changes in a cell, to decipher the process. Thiopurine-induced mutations were linked to genes that become mutated in leukemia and rendere ALL resistant to thiopurines through mismatch repair.

A mutation to the tumor suppressor gene TP53 promoted resistance to multiple chemotherapy drugs, on-treatment relapse, and poor treatment response. The researchers were able to replicate the thiopurine-induced TP53 mutations and chemotherapy resistance. They noted that this could be reversed by pharmacological p53 reactivation.

They estimate that treatment-induced mutations play a role in 25% of pediatric ALL relapse. In the study, 8% of the patients had evidence of thiopurine-associated mismatch repair.

“This study not only changes our ALL treatment considerations, but also opens the door to study mechanistically how defective repair generates drug-resistant mutations,” said Bin-Bing Zhou, PhD, of Shanghai Children’s Medical Center.

Despite the findings, the benefits of the thiopurine class continue to outweigh the risks, with most patients being unaffected by the thiopurine-induced mutations, the researchers noted.

“In the future, it may be possible to monitor bone marrow during treatment as a way to detect these mutational signatures early enough to help identify at-risk patients who may be candidates for emerging therapies like CAR T cells,” Zhang said.

Initial findings were originally presented at the 2021 annual meeting of the American Association for Cancer Research.

Reference

Yang F, Brady SW, tang C, et al. Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse. Nat Cancer. Published online July 22, 2021. doi:10.1038/s43018-021-00230-8