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Flavopiridol Elicits Poor Response in Mantle Cell Lymphoma, DLBCL

Key clinical point: The novel CDK inhibitor flavopiridol showed minimal efficacy in patients with relapsed/refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and other B-cell lymphomas.

Major finding: Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%).

Study details: A phase 1/2 study of 28 patients with relapsed/refractory MCL and DLBCL.

Disclosures: The trial is sponsored by the National Cancer Institute, and the study authors are employees of the National Cancer Institute.

Citation:

Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.

Commentary:

At its core, mantle cell lymphoma is characterized by dysregulation of the cell cycle. The t(11;14) results in aberrant expression of cyclin D1, which combines with CDK4 to phosphorylate Rb and release the break on E2F transcription factors, promoting progression of the cell cycle through early G1 and committing the cells to enter S phase. Inhibition of the cell cycle by targeting CDK4 is a rationale therapeutic strategy. In early studies in chronic lymphocytic leukemia, the pan-CDK inhibitor flavopiridol was found to have highly complicated pharmacokinetics but also the potential to induce significant tumor lysis. Ultimately, the complicated pharmacology, challenging therapeutic index, and limited specificity led to it being eclipsed by other more specific CDK inhibitors, including the CDK4/6 inhibitors approved for breast cancer and under evaluation in mantle cell lymphoma, as well as more specific CDK2/9 inhibitors being evaluated in multiple cancers.—Peter Martin, MD