While we have never been as spoiled for treatment choice as we are now, PI3K inhibitor safety is being very closely monitored by the FDA.
So, it's timely that Sigrid S Skanland and Jennifer R Brown have written a peer-reviewed Haematologica early view paper that discusses "the current status of PI3K inhibitors in CLL, factors limiting the use of currently approved PI3K inhibitors in CLL, current strategies to overcome these limitations, and where to go next."
"Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective in chronic lymphocytic leukemia (CLL). However, the severe toxicity profile associated with the first-generation inhibitors idelalisib and duvelisib, combined with the availability of other more tolerable agents, have limited their use."
Not all of us do well on a BTKi drug or venetoclax but we may do brilliantly on a PI3K drug, provided the risk is acceptable. If we've exhausted approved treatments there's a reasonable risk gap between PI3K inhibitors and some of the more experimental treatments, which can also be much harder to access than an oral (tablet) medication. Additionally, some with severe renal or heart disease or significant risk of tumor lysis might be well served by treatment with a PI3K inhibitor.
"It is therefore of interest to optimize the administration of currently approved PI3K inhibitors and to develop next-generation agents to improve tolerability, so that this class of agents will be considered an effective and safe treatment option when needed."
"Optimizing their use by developing more specific next-generation inhibitors, reducing toxicity and defining the ideal sequence or combination of therapies are therefore necessary to further improve CLL outcomes."
"Current strategies to overcome treatment limitations include intermittent dosing, which is established for copanlisib and zandelisib and under investigation for duvelisib and parsaclisib. A second strategy is to combine the PI3K inhibitor with another novel agent, either as a continuous regimen or a fixed-duration regimen, to deepen responses."
The authors note that 'there are a large number of emerging clinical trials with PI3K inhibitors in CLL'.
'Although the implementation of PI3K inhibitor-based regimens in CLL management has faced various challenges, efforts remain high to optimize its use and identify tolerable schedules and combinations. Both patient selection and optimized patient management can reduce risk. . . . Importantly also, new clinical trial designs better reflect current recommendations by including patients who have been exposed to several lines of therapy, including targeted therapies and in some cases even a PI3K inhibitor.'
The authors conclude by explaining ways to facilitate precision medicine that will "maximise efficacy and minimise toxicity by matching the right therapy to the right patient at the right time". These measures include:
"Higher-resolution patient stratification made possible if biomarkers identified in pre-clinical studies can be validated in biomarker-driven clinical trials and implemented in routine practice . . . clinical trials of novel therapies should biobank samples dedicated to functional analyses such as cell signalling profiling, immune phenotypes, and ex vivo drug sensitivity testing, in addition to genetic profiling, to allow for the identification of molecular signatures predictive of treatment responses including tolerability. To develop truly predictive prognostic markers in this heterogeneous disease, sharing of comprehensive clinical, genetic, and functional data from both clinical trials and real-world cohorts is necessary. Based on these data, maximally predictive models and minimal biomarker signatures can be developed to inform personalised treatment decisions. This approach to precision medicine is exemplified in the EU funded CLL-CLUE consortium."
Sigrid S. Skanland, Jennifer R. Brown, 'PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?' Haematologica, 2022 July 28, doi.org/10.3324/haematol.20... [epub ahead of print]
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