The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint

Richardson, Nicholas C.; Kasamon, Yvette L.; Pazdur, Richard; Gormley, Nicole

doi:10.1016/s1470-2045(22)00200-5

Cited by 65 publications

(54 citation statements)

References 3 publications

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“…For example, in the ASCEND R/R study of idelalisib and rituximab (vs. acalabrutinib), 65% of patients discontinued idelalisib due to adverse events at 3 years 34 . A recent U.S. Food and Drug Administration briefing heavily commented on the toxicity profile of PI3Ki as a class, including the recommendations for box warnings and limitations of use 35 . While several ongoing R/R randomized studies in BTKi and/or venetoclax pre‐exposed CLL patients utilize PI3Ki as the standard of care control arm, there remains an open question as to whether this class of agents is appropriate at all as a standard of care for comparison in this patient population.…”

Section: Clinical Practice In 2022: Management Of the Double Refracto...mentioning

confidence: 99%

Approach to a patient with “double refractory” chronic lymphocytic leukemia: “Double, double toil and trouble” (Shakespeare)

et al. 2022

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As patients continue to live longer with chronic lymphocytic leukemia, it has become evident that there is an unmet treatment need for patients who have progressed on multiple lines of therapy. In this article, we attempt to define the "double refractory" patient as resistant to both Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.

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Section: Clinical Practice In 2022: Management Of the Double Refracto...mentioning

confidence: 99%

Approach to a patient with “double refractory” chronic lymphocytic leukemia: “Double, double toil and trouble” (Shakespeare)

et al. 2022

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“…Through the usage of high-throughput RNA sequencing, a large number of circRNAs were found to be able to regulate cancer-related signaling pathways by affecting host gene expressions such as, circ-PTEN increased its particular parental gene PTEN (phosphatase and tensin homolog) expression by acting as the molecular sponge for miR-155 and miR-330-3p, resulting in non-small cell lung cancer cells growth inhibition and the inactivation of the carcinogenic PI3K/AKT signalling pathway, an important regulatory pathway of signalling and intracellular vesicular trafficking ( 32 , 67 ). In addition, circ-ITCH also played an important inhibitory role in colorectal cancer through functioning in the Wnt/β-catenin pathway by affecting host gene expression and Wnt/β-catenin pathway had key regulatory role in many tumor malignant biological behaviors such as cell proliferation, metastasis and epithelial-mesenchymal transition ( 33 , 68 ).…”

Section: The Role and Molecular Mechanisms Of Circrnas Regulating Par...mentioning

confidence: 99%

Circular RNAs regulate parental gene expression: A new direction for molecular oncology research

Wang

Gao

et al. 2022

Front. Oncol.

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CircRNAs have been the focus of research in recent years. They are differentially expressed in various human tumors and can regulate oncogenes and tumor suppressor genes expression through various mechanisms. The diversity, stability, evolutionary conservatism and cell- or tissue-specific expression patterns of circRNAs also endow them with important regulatory roles in promoting or inhibiting tumor cells malignant biological behaviors progression. More interestingly, emerging studies also found that circRNAs can regulate not only other genes expression, but also their parental gene expression and thus influence tumors development. Apart from some conventional features, circRNAs have a certain specificity in the regulation of parental gene expression, with a higher proportion affecting parental gene transcription and easier translation into protein to regulate parental gene expression. CircRNAs are generally thought to be unable to produce proteins and therefore the protein-coding ability exhibited by circRNAs in regulating parental gene expression is unique and indicates that the regulatory effects of parental gene expression by circRNAs are not only a competitive binding relationship, but also a more complex molecular relationship between circRNAs and parental gene, which deserves further study. This review summarizes the molecular mechanisms of circRNAs regulating parental gene expression and their biological roles in tumorigenesis and development, aiming to provide new ideas for the clinical application of circRNAs in tumor-targeted therapy.

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“…2 ). However, analyses of six randomized controlled trials with PI3Ki in indolent NHL or CLL led to concerns about inferior overall survival in the PI3Ki arms and subsequent voluntary withdrawal of umbralisib from the market for approved indications and of the application for the combination of umbralisib plus ublituximab for CLL and SLL [ 33 , 34 ]. A comment by the FDA emphasized the need for careful dose selection for PI3Ki, preferably in randomized trials [ 33 ].…”

Section: Dose-finding Studies Of Targeted Therapies In Cllmentioning

confidence: 99%

Determining drug dose in the era of targeted therapies: playing it (un)safe?

Skånland

Tjønnfjord

2022

Blood Cancer J.

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Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.

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The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint

Cited by 65 publications

References 3 publications

Approach to a patient with “double refractory” chronic lymphocytic leukemia: “Double, double toil and trouble” (Shakespeare)

Approach to a patient with “double refractory” chronic lymphocytic leukemia: “Double, double toil and trouble” (Shakespeare)

Circular RNAs regulate parental gene expression: A new direction for molecular oncology research

Determining drug dose in the era of targeted therapies: playing it (un)safe?

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