Hybrid dosing of the cyclin-dependent kinase (CDK) inhibitor flavopiridol in relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma

@article{Miljkovic2019HybridDO,
  title={Hybrid dosing of the cyclin-dependent kinase (CDK) inhibitor flavopiridol in relapsed/refractory mantle cell lymphoma and diffuse large B-cell lymphoma},
  author={Milos D. Miljkovic and Mark J Roschewski and Kieron Dunleavy and Wyndham H Wilson},
  journal={Leukemia \& Lymphoma},
  year={2019},
  volume={60},
  pages={3320 - 3323}
}
Flavopiridol (alvocidib) is a semi-synthetic flavon which inhibits cyclin-dependent kinases (CDKs) 1, 2, and 4 by outcompeting adenosine triphosphate (ATP), and CDK7 and CDK9 by non-competitive binding [1]. Promising preclinical data in cell lines derived from mantle cell lymphoma (MCL) and activated B-cell subtype diffuse large B-cell lymphoma (DLBCL) led to a series of clinical trials of flavopiridol in various hematological malignancies; however, phase I and II trials in which the drug was… Expand
1 Citations

References

SHOWING 1-10 OF 20 REFERENCES
Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma.
TLDR
The results of the present study confirm CDK4/6 inhibition by PD0332991 at a well-tolerated dose and schedule and suggest clinical benefit in a subset of MCL patients. Expand
Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non‐Hodgkin's lymphoma
TLDR
The single‐agent activity of this first‐generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. Expand
A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas
TLDR
Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity in patients with Rb+ advanced solid tumors or lymphomas. Expand
Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition
TLDR
It is demonstrated that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL, and CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL- 1 targeted therapy. Expand
Seventy-Two Hour Continuous Infusion Flavopiridol in Relapsed and Refractory Mantle Cell Lymphoma
TLDR
In relapsed and refractory MCL, flavopiridol is ineffective as a single agent given by 72 h continuous infusion at 50 mg/m 2 /day, and in vitro studies of flavoporidol indicate that the agent is synergistic with DNA-damaging compounds. Expand
Preclinical and Clinical Development of the Cyclin-Dependent Kinase Inhibitor Flavopiridol
TLDR
In the majority of solid tumor cell lines and xenografts, flavopiridol induces cell cycle arrest and tumor growth inhibition, which is reflected in clinical outcomes: across multiple Phase II trials there are subsets of patients with prolonged stable disease, although few responses have been observed. Expand
A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma.
TLDR
If evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease. Expand
Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)
TLDR
It is shown that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. Expand
The CDK inhibitor AT7519M in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. A Phase II study of the Canadian Cancer Trials Group
TLDR
AT7519M was safely administered to patients with relapsed/refractory CLL and MCL and some patients had tumor reductions, but the ORR was low, and activity was noted with ORR of 27%. Expand
A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma.
TLDR
A phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma and the overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2 year progression-free survival was 59.4% and the 2-year response duration was 69.8%. Expand
...
1
2
...