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  • br Use of CDK inhibitors in

    2019-08-22


    Use of CDK inhibitors in CLL today There has been explosive development of novel therapeutics for CLL in the last decade and a massive transformation of practice is underway [75]. Most of this development and excitement revolves around B-cell receptor (BCR) signaling inhibitors: the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3k-delta inhibitor idelalisib have both shown remarkable response rates among patients with relapsed and refractory CLL, are conveniently available as daily or twice daily oral medications, and have relatively minimal toxicities when compared to chemotherapy or even other 3\'-O-(2-nitrobenzyl)-2\'-dATP of targeted agents [76], [77]. Their approval and commercial availability has been unquestionably beneficial for patients. Still, amidst this excitement, other promising agents may have fallen by the wayside. Development of CDK inhibitors, drugs capable of producing responses even in high-risk refractory CLL (Table 3) has stagnated in this disease. Today, there are no open trials of alvocidib in any disease despite that patients with very advanced disease could still achieve a CR with this therapy. This likely stems from early difficulties establishing efficacy while minimizing the toxicity of life-threatening tumor lysis; this narrow therapeutic window begets reluctance, but more recent experience demonstrates that with due care toxicities are both manageable and largely preventable. Dinaciclib is under investigation only in multiple myeloma and advanced solid tumors. TG02 remains under investigation for CLL at a handful of sites in the United States: Dana-Farber Cancer Institute in Boston, The Ohio State University James Comprehensive Cancer Center, and The University of Texas MD Anderson Cancer Center. Palbociclib, as discussed, has shown promise in ibrutinib-resistant MCL, a disease with BCR-driven biology in some ways similar to CLL, and, although not actively under investigation for CLL, merits consideration.
    Potential uses for CDK inhibitors in CLL We can envision many potential uses for CDK inhibitors in CLL today and in the future. For patients without high-risk cytogenetics, front-line treatment still consists of traditional chemo-immunotherapy like fludarabine, cyclophosphamide, and rituximab, a regimen that despite a response rate of up to 95% is still not curative [78]. Whether detected or not, by virtue of the fact that CLL inevitably returns, minimal residual disease (MRD) is present after both initial chemo-immunotherapy as well as after some targeted or novel therapies despite achievement of a CR. CDK inhibitors could be used after other therapy when the patient is in an MRD-positive CR state to try to deepen the response and lengthen the time to next therapy, or—perchance to dream—even to eradicate any remaining clone to effect a cure. Emerging evidence that CDK inhibitors might be able to target ultra quiescent leukemia stem cells (through alternative targets like Egr2 and ERK5) provides a further basis for this strategy. Another potential use for CDK inhibitors in CLL is in the context of lymphocytosis that has plateaued during treatment with a BCR pathway inhibitor. Although it has recently been shown that patients with prolonged lymphocytosis following achievement of PR with lymphocytosis (PR-L) do not fare more poorly than patients achieving a standard CR or PR in terms of PFS [79], the N (17 with PR-L) and follow-up period leave room for further study with longer-term follow-up of a larger number of patients to see if this pool of anergic CLL cells provides a reservoir from which to develop ibrutinib-resistant clones. Should this be the case, an anti-antiapoptotic (ie, BCL2, MCL1 targeting) CDK inhibitor might be an ideal agent to deplete this pool of quiescent CLL prior to the development of resistance. Similarly, as ibrutinib-resistant clones harboring a BTK p.C481S or PLCG2 mutation may be able to be identified by deep sequencing prior to clinically resistant disease in the way 3\ a BCR-ABL transcript emerges prior to relapse in chronic myeloid leukemia, we suggest that CDK inhibitors should be studied as suppressive therapy to spot-treat emerging clones in order to maximize the duration and value of ibrutinib and potentially other similar BCR-targeting therapies. Selinexor, a potentially more toxic agent has demonstrated the ability to kill ibrutinib-resistant primary CLL [80]. Palbociclib has demonstrated this ability in BTK p.C481S-mutated MCL [74], although it is not clear if this result extends to CLL. More agents, including CDK inhibitors, should be tested in this way so that we have as diverse an armamentarium as possible before patients in the soon large population receiving commercial ibrutinib begin to form resistance.