The study authors conclude that all together, their data suggest that MYC-mediated G0S2 downregulation contributes to TKI resistance and blastic transformation of CML. Restoring G0S2 expression could have clinical utility by reestablishing TKI sensitivity in TKI-resistant patients and altering mitochondrial metabolism.

The study authors conclude that a greater number of mtDNA mutations was associated with a better molecular response in imatinib-treated patients. In a small number of patients, they found that mtDNA mutations with a higher VAF were associated with impaired OXPHOS in CD34+ cells at diagnosis. The study authors hypothesize that reduced OXPHOS may sensitize the leukemic cells to imatinib. Functional studies are ongoing.

The study authors confirm with their final analysis the Molecular recurrence-free survival and MRecTFS rate at 6 months from the interim analysis. However, late relapses (15% between 6 and 36 months) occurred. Nevertheless, with 46%, almost half of the patients stayed at least in MRecTFS.

The study authors conclude that the OPTIC primary analysis demonstrates the optimal benefit: risk profile for ponatinib was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1IS; 30 mg →15 mg and 15 mg cohorts may provide benefit, especially in patients without T315I mutation (see Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in patients with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations.