Certain Chemo May Cause Mutations in ALL Recurrence

Chemotherapy helps about 90% of pediatric patients with acute lymphoblastic leukemia (ALL) to achieve long-term survival; however, recurrence of the disease can often be deadly. Now, a new study published in Blood finds that a subset of the relapses may be triggered by the very chemotherapy which helped patients beat the cancer the first time.

“Our study reveals the evolution dynamics of pediatric ALL, which suggest, for the first time, that chemotherapy treatment, particularly thiopurines, can cause mutations that lead to drug resistance in patients,” said corresponding author Jinghui Zhang, PhD, chair of the department of computational biology at St. Jude Children’s Research Hospital.

The subject pool included 103 children with relapsed ALL in China. The genomic look showed 20% of the patients had treatment-related mutations at the time of their relapse. The patients underwent whole genomic sequencing of the leukemia cells, as well as their other reference samples of DNA. 

Further and deeper testing was conducted on 16 patients: regular collection of the leukemia cells was conducted over the course of treatment and relapse, and were also whole-genome sequenced.

The relapse-specific mutations were isolated in 12 genes-and they were identified in drug response, especially to the thiopurine compound, according to the study. Among the genes is FPGS, a gene previously identified with relapse. 

“Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response,” the authors wrote. “Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups.” 

Earlier relapse was caused by drug-resistant tumor cells which had already been there at diagnosis. The drug-response mutations were tied to later relapse, instead.

Fifty-five percent of the patients with recurrence had the cancer reemerge between 9 and 36 months after diagnosis, but before treatment ended. 

“This suggests drug resistance is not a foregone conclusion,” said study author Jun Yang, PhD, of the oncology department at St. Jude Graduate School of Biomedical Sciences. “It may be preventable through changes in the dosage or timing of the treatment.”

REFERENCES

Li B, Brady S, Ma X, et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood. doi:10.1182/blood.2019002220.