Blood cancers

ALL thiopurine study a ‘paradigm shift’ in understanding of how drug resistance develops

The question of whether acquired drug-resistance mutations in relapsed paediatric acute lymphoblastic leukaemia (ALL) pre-exist or are induced by treatment has been answered in part by an international study.

Researchers in the US, Germany and China say their collaboration has found evidence of a specific mechanism by which thiopurine chemotherapy induced drug-resistance-associated mutations leading to relapse.

Using genomic and functional analysis of relapsed ALL they showed that thiopurine treatment in mismatch repair (MMR)-deficient leukaemias induced hotspot TP53 R248Q mutations through a specific mutational signature (thio-dMMR).

The researchers analysed more than 1,000 samples collected from the patients at different times in treatment, including samples from 181 patients collected at diagnosis, remission and relapse.

The study showed sequential MMR inactivation was followed by TP53 mutation in some patients with ALL.

The mutation promoted resistance to was associated with on-treatment relapse, poor treatment response and resistance to multiple chemotherapeutic agents, including vincristine, daunorubicin and cytarabine.

However it could potentially be reversed by pharmacological p53 reactivation, the researchers suggested in their paper published in Nature Medicine.

“The findings offer a paradigm shift in understanding how drug resistance develops,” said study investigator Dr Jinghui Zhang (PhD) St. Jude Children’s Research Hospital in Memphis.

“The results also suggest possible treatment strategies for ALL patients who relapse, including screening to identify those who should avoid additional thiopurine treatment.”

The researchers noted that 94% of patients with ALL become five-year survivors, but relapse remains the leading cause of death worldwide for children and adolescents with ALL.

They estimated that treatment-induced mutations played a role in 25% of paediatric ALL relapse. About 8% of ALL patients had evidence of the thiopurine-associated mismatch-repair signature.

The study findings study would not only change ALL treatment considerations, but also opens the door to study mechanistically how defective repair generates drug-resistant mutations, the authors suggested.

“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,” Dr Zhang said.

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