Mutations Associated With Arsenic Resistance in Acute Promyelocytic Leukemia
In a letter to The New England Journal of Medicine, Zhu et al described identification of resistance mutations in acute promyelocytic leukemia patients receiving arsenic trioxide (Trisenox) and all-trans retinoic acid (ATRA) therapy. The direct-binding targets of arsenic trioxide in the promyelocytic leukemia protein (PML) B2 domain are necessary for induction of molecular response in acute promyelocytic leukemia.
Mutation in PML–retinoic acid receptor alpha (RARA) had previously been found to be associated with arsenic trioxide resistance in an ex vivo model, but this association had not been observed in acute promyelocytic leukemia patients. Mutations at PML A216V and L218P previously had been detected in two patients with clinical resistance to arsenic trioxide.
PML-RARA Mutations
In the study, direct sequencing was used to screen PML-RARA transcripts from 35 patients with relapsed acute promyelocytic leukemia who had received arsenic trioxide. A total of 13 patients with arsenic-resistant disease (no remission after arsenic-based induction therapy) received ATRA plus chemotherapy induction therapy, chemotherapy consolidation therapy, and ATRA and arsenic trioxide as maintenance therapy before relapse.
PML mutations were found in nine of these patients, including three with the A216V mutation and four with A216T, S214L, L217F, and S220G mutations, and one with both the S214L and A216T mutations. In addition, seven patients had RARA mutations. No PML mutations were found in the 22 patients without clinical resistance to arsenic treatment.
Effect on Subsequent Response
Evaluation of samples obtained from an additional 13 patients before their most recent relapse showed that second remission could be achieved with arsenic and ATRA in patients with only a RARA mutation but not in those with both PML and RARA mutations. PML mutations were usually detected after RARA mutations and were rarely detected before first relapse.
Overall, death occurred in 5 of 22 patients with disease that was not resistant to arsenic and 11 of 13 patients with arsenic-resistant disease, including 8 of the 9 patients with PML mutations and 3 of 4 patients without PML mutations.
The investigators stated, “The presence of a mutation in the arsenic-binding domain of PML-RARA led to arsenic resistance in patients in an ex vivo model. Our clinical observations provide evidence to substantiate this finding in vivo and validate the presence of a PML mutational hot-spot domain (C212-S220). Detection of PML-RARA mutations may be helpful in guiding treatment choices.”
Xiao-Jun Huang, MD, of Peking University People’s Hospital, Beijing, is the corresponding author. Hong-Hu Zhu, MD, and Ya-Zhen Qin, MD, of Peking University People’s Hospital contributed equally to The New England Journal of Medicine letter.
The study was supported by grants from the National Natural Science Foundation, 100 Leading Talents Training Project of Science and Technology of Beijing, and Beijing Municipal Science and Technology Commission.
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