Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma

被引：249

作者：

Leonard, John P. ^{[2
]}

LaCasce, Ann S. ^{[3
,4
,5
]}

Smith, Mitchell R. ^{[6
]}

Noy, Ariela ^{[7
]}

Chirieac, Lucian R. ^{[5
,8
]}

Rodig, Scott J. ^{[5
,8
]}

Yu, Jian Q. ^{[9
]}

Vallabhajosula, Shankar ^{[10
]}

Schoder, Heiko ^{[11
]}

English, Patricia ^{[12
]}

Neuberg, Donna S. ^{[13
,14
]}

Martin, Peter ^{[2
]}

Millenson, Michael M. ^{[6
]}

Ely, Scott A. ^{[15
]}

Courtney, Rachel ^{[12
]}

Shaik, Naveed ^{[12
]}

Wilner, Keith D. ^{[12
]}

Randolph, Sophia ^{[12
]}

Van den Abbeele, Annick D. ^{[1
]}

Chen-Kiang, Selina Y. ^{[15
]}

Yap, Jeffrey T. ^{[1
,5
,16
]}

Shapiro, Geoffrey I. ^{[4
,5
,17
]}

机构：

[1] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA

[2] Weill Cornell Med Coll, Div Hematol Oncol, Dept Med, New York, NY USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02215 USA

[4] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Boston, MA USA

[6] Fox Chase Canc Ctr, Dept Med Oncol, Lymphoma Serv, Philadelphia, PA 19111 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, New York, NY 10021 USA

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Fox Chase Canc Ctr, Dept Diagnost Imaging, Nucl Med Serv, Philadelphia, PA 19111 USA

[10] Weill Cornell Med Coll, Dept Radiol Radiochem & Radiopharm, New York, NY USA

[11] Mem Sloan Kettering Canc Ctr, Dept Radiol, Nucl Med Serv, New York, NY 10021 USA

[12] Pfizer Inc, Pfizer Global Res & Dev, La Jolla, CA USA

[13] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[14] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[15] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA

[16] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA

[17] Dana Farber Canc Inst, Dept Med Oncol, Early Drug Dev Ctr, Boston, MA 02215 USA

来源：

BLOOD | 2012年 / 119卷 / 20期

关键词：

DEPENDENT KINASE INHIBITOR; CYCLIN D1; PD; 0332991; CENTROCYTIC LYMPHOMA; PHASE-II; IN-VITRO; CANCER; PROLIFERATION; OVEREXPRESSION; PATHOGENESIS;

D O I：

10.1182/blood-2011-10-388298

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-[F-18]fluoro-D-glucose (FDG) and 3-deoxy-3[F-18]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 (SUVmax), 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 SUVmax 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. (Blood. 2012; 119(20): 4597-4607)

引用

页码：4597 / 4607

页数：11

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