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Cardiotoxicity of the BCR-ABL1 tyrosine kinase inhibitors: Emphasis on ponatinib.

ABSTRACT: The advent of tyrosine kinase inhibitors (TKIs) targeted therapy revolutionized the treatment of chronic myeloid leukemia (CML) patients. However, cardiotoxicity associated with these targeted therapies puts the cancer survivors at higher risk. Ponatinib is a third-generation TKI for the treatment of CML patients having gatekeeper mutation T315I, which is resistant to the first and second generation of TKIs, namely, imatinib, nilotinib, dasatinib, and bosutinib. Multiple unbiased screening from our lab and others have identified ponatinib as most cardiotoxic FDA approved TKI among the entire FDA approved TKI family (total 50+). Indeed, ponatinib is the only treatment option for CML patients with T315I mutation. This review focusses on the cardiovascular risks and mechanism/s associated with CML TKIs with a particular focus on ponatinib cardiotoxicity. We have summarized our recent findings with transgenic zebrafish line harboring BNP luciferase activity to demonstrate the cardiotoxic potential of ponatinib. Additionally, we will review the recent discoveries reported by our and other laboratories that ponatinib primarily exerts its cardiotoxicity via an off-target effect on cardiomyocyte prosurvival signaling pathways, AKT and ERK. Finally, we will shed light on future directions for minimizing the adverse sequelae associated with CML-TKIs.

SUBMITTER: Singh AP

PROVIDER: S-EPMC8095092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.

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Cardiotoxicity of the BCR-ABL1 tyrosine kinase inhibitors: Emphasis on ponatinib.

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