Development and targeted use of nilotinib in chronic myeloid leukemia

The development of imatinib has resulted in sustained hematologic and cytogenetic remissions in all phases of chronic myeloid leukemia (CML). Despite the high efficacy, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired resistance has been traced to Bcr-Abl kinase domain mutations. Several strategies have been developed to overcome the problem of imatinib resistance, including imatinib dose escalation, novel targeted agents and combination treatments. A second generation of tyrosine kinase inhibitors was developed, which displays increased potency towards Bcr-Abl and is able to target the majority of CML mutant clones. Nilotinib (Tasigna®, AMN107, Novartis) is a close analog of imatinib with approximately 20-fold higher potency for BCR-ABL kinase inhibition. Preclinical and clinical investigations demonstrate that nilotinib effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML post imatinib failure, with a good tolerance. Nilotinib has been approved for CML patients in chronic and accelerated phases, post imatinib failure

Meir Wetzler, MD

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111978/1/cncr29391.pd

Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.

PurposeDasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit-risk profile of dasatinib 100 mg once daily, exposure-response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).Patients and methodsDasatinib exposure in patients with chronic myeloid leukemia in chronic phase was determined by population pharmacokinetic analysis of data from seven dasatinib clinical studies (N = 981), including the Phase III dose-optimization study (n = 567). Data from the Phase III study were then used to characterize exposure-response relationships for the four dasatinib treatment regimens investigated (100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily).ResultsMajor cytogenetic response was significantly (P < 0.01) associated with weighted average steady-state dasatinib plasma concentrations, and pleural effusion was significantly associated with trough concentration. Major cytogenetic response was also significantly associated with maintenance of uninterrupted dosing. The 100 mg once daily arm had the lowest steady-state trough concentration of the four dose arms investigated in the Phase III study, and although this arm also had the lowest weighted average steady-state dasatinib plasma concentration, it had the highest dose maintenance.ConclusionDasatinib dose optimization to 100 mg once daily from 70 mg twice daily significantly minimizes adverse events while maintaining efficacy by exploiting differences in the measures of exposure associated with efficacy and safety

Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations

<p>Abstract</p> <p>Background</p> <p>The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).</p> <p>Results</p> <p>Simulation results are consistent with all currently available clinical/experimental evidence. The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.</p> <p>Conclusion</p> <p>The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches. Together with recent mutation profiling results demonstrating the breadth of clinically observed JAK2 mutations, our findings suggest that molecular testing/diagnostics of JAK2 should extend beyond V617F and exon 12 mutations, and perhaps should encompass most of the pseudo-kinase domain-coding region.</p

Targeting DNA methylation

Abstract Two nucleoside inhibitors of DNA methylation, azacitidine and decitabine, are now standard of care for the treatment of the myelodysplastic syndrome, a deadly form of leukemia. These old drugs, developed as cytotoxic agents and nearly abandoned decades ago were resurrected by the renewed interest in DNA methylation. They have now provided proof of principle for epigenetic therapy, the final chapter in the long saga to provide legitimacy to the field of epigenetics in cancer. But challenges remain; we don&apos;t understand precisely how or why the drugs work or stop working after an initial response. Extending these promising findings to solid tumors faces substantial hurdles from drug uptake to clinical trial design.We do not know yet how to select patients for this therapy and how to move it from life extension to cure. The epigenetic potential of DNA methylation inhibitors may be limited by other epigenetic mechanisms that are also worth exploring as therapeutic targets. But the idea of stably changing gene expression in vivo has transformative potential in cancer therapy and beyond

The organic arsenic derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML