Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma Journal Article
| Authors: | Leonard, J. P.; LaCasce, A. S.; Smith, M. R.; Noy, A.; Chirieac, L. R.; Rodig, S. J.; Yu, J. Q.; Vallabhajosula, S.; Schoder, H.; English, P.; Neuberg, D. S.; Martin, P.; Millenson, M. M.; Ely, S. A.; Courtney, R.; Shaik, N.; Wilner, K. D.; Randolph, S.; Van Den Abbeele, A. D.; Chen-Kiang, S. Y.; Yap, J. T.; Shapiro, G. I. |
| Article Title: | Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma |
| Abstract: | Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11:14) translocation results in enhanced cyclin D1 expression and cyclin D1- dependent kinase activity to promote cellcycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2- [ 18F]fluoro-D-glucose (FDG) and 3-deoxy- 3[ 18F]fluorothymidine (FLT) positron emission tomography (PET) to study tumor metabolism and proliferation, respectively, in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein (Rb) phosphorylation and markers of proliferation and apoptosis. Substantial reductions in the summed FLT-PET maximal standard uptake value (SUV max), as well as in Rb phosphorylation and Ki-67 expression, occurred after 3 weeks in most patients, with significant correlations among these end points. Five patients achieved progression-free survival time of > 1 year (range, 14.9-30.1+ months), with 1 complete and 2 partial responses (18% objective response rate; 90% confidence interval, 5%-40%). These patients demonstrated > 70%, > 90%, and ≥ 87.5% reductions in summed FLT SUV max and expression of phospho-Rb and Ki67, respectively, parameters necessary but not sufficient for long-term disease control. 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. This study is registered at www.clinicaltrials.gov under identifier NCT00420056. © 2012 by The American Society of Hematology. |
| Journal Title: | Blood |
| Volume: | 119 |
| Issue: | 20 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2012-05-17 |
| Start Page: | 4597 |
| End Page: | 4607 |
| Language: | English |
| DOI: | 10.1182/blood-2011-10-388298 |
| PROVIDER: | scopus |
| PUBMED: | 22383795 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 4 June 2012" - "CODEN: BLOOA" - "Source: Scopus" |
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