Advances in the treatment of chronic myeloid leukemia

Abstract

Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance.

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias

“…1,4,7,9 In fact, high levels of BCR-ABL1 expression/activity in Ph 1 acute leukemias aberrantly enhances genomic instability that, together with unfaithful DNA repair machinery, leads to an accumulation of molecular and chromosomal abnormalities, some of which result in the inactivation of tumor 4 Moreover, we also provide evidence that KPT-330 potentiates the effect of imatinib, suggesting that KPT-330 might be used in combination with TKIs, especially in those cases in which TKI resistance is due to BCR-ABL1 amplification and blastic transformation. 39,47 In fact, the first XPO1 inhibitor discovery LMB, which shares the same XPO1-interacting surface with the SINEs but because of its lack of specificity is severely toxic when used in patients with cancer, 31,48 was elegantly shown to induce apoptosis of BCR-ABL1 1 cells when used in combination with imatinib through a mechanism involving the LMB-induced nuclear entrapment and inactivation/degradation of BCR-ABL1.…”

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

“…Resistance can occur because of mutations that render the drug target insensitive to the inhibitor or when cancer cells change their dependency on the pathway that is targeted. In the first example, resistance can be overcome by developing new drugs that effectively inhibit resistance-associated mutants, as in the example of dasatinib and nilotinib, which are effective on BCR/ABL mutants that confer resistance to imatinib (1). Another approach is to target multiple signaling pathways simultaneously, and thus prevent the cancer cell from changing its dependency to another signaling pathway.…”

Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells

“…In CML-CP patients, ABL1 tyrosine kinase inhibitors (TKIs)-such as imatinib, dasatinib and nilotinib-may induce complete cytogenetic response (CCR), major molecular response (MMR), or even complete molecular response (CMR), but it is unlikely that any TKI will eradicate CML. 2 While most LPCs are eventually eliminated by TKIs, LSCs are intrinsically insensitive and thus usually survive treatment. 3 CML-CP cells display genomic instability and may acquire additional genetic changes that cause disease relapse due to TKI resistance and/or induce more advanced CML accelerated phase (CML-AP) or blast phase (CML-BP).…”

“…4 Genomic instability results from an aberrant cellular response to enhanced DNA damage. The primary candidates that cause DNA damage are reactive oxygen species (ROS) such as superoxide anion (·O 2 2 ), hydrogen peroxide (H 2 O 2 ), and hydroxyl group (·OH). 5 ROS can damage DNA bases to produce 7,8-dihydro-8-oxo-29-deoxyguanosine (8-oxoG) and other oxo-base derivatives, which may lead to a variety of point mutations.…”