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 cell-cycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-deoxy-3[(18)F]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.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Ann S
authors.initials: AS
authors.lastname: LaCasce
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.forename: Ariela
authors.initials: A
authors.lastname: Noy
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Yu
authors.forename: Shankar
authors.initials: S
authors.lastname: Vallabhajosula
authors.forename: Heiko
authors.initials: H
authors.lastname: Schoder
authors.forename: Patricia
authors.initials: P
authors.lastname: English
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.forename: Michael M
authors.initials: MM
authors.lastname: Millenson
authors.forename: Scott A
authors.initials: SA
authors.lastname: Ely
authors.forename: Rachel
authors.initials: R
authors.lastname: Courtney
authors.forename: Naveed
authors.initials: N
authors.lastname: Shaik
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Sophia
authors.initials: S
authors.lastname: Randolph
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Selina Y
authors.initials: SY
authors.lastname: Chen-Kiang
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Yap
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013379:Substrate Specificity; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib