A phase I/II study of bortezomib plus CHOP every 2 weeks (CHOP-14) in patients with advanced-stage diffuse large B-cell lymphomas

Abstract Background: The mammalian target of rapamycin (mTOR), plays a major role in regulating cell growth. The activated form of mTOR (phosphorylated mTOR) mediates its effects through mitogen and nutrient dependant signal transduction that regulates mRNA translation. Levels of phosphorylated mTOR (p-mTOR) have been shown to correlate with cell proliferation and inhibition of the mTOR pathway has shown therapeutic promise in some tumors. Information on the role of p-mTOR in hematopoietic malignancies is limited. The aim of the current study is to evaluate the expression of p-mTOR in diffuse large B-cell lymphomas. Design: Formalin-fixed paraffin-embedded tissue sections from 45 DLBCLs were immunostained by an automated method (Ventana Medical Systems, Inc., Tucson, AZ) using p-mTOR rabbit monoclonal antibody (IHC specific Ser2448/49F9; Cell Signaling Technology, Inc., Danvers, MA). Immunoreactivity (cytoplasmic with membranous accentuation) was semiquantitatively assessed based on p-mTOR stain intensity (none, weak, moderate, intense) and distribution (none, focal<10%, regional 11–50%, diffuse>50%). Staining was correlated with histologic and prognostic factors. Results: Membranous/cytoplasmic p-mTOR immunoreactivity was present in 88% of DLBCLs and correlated with advanced tumor stage, with 100% advanced stage versus 73% low stage tumors expressing membranous/cytoplasmic p-mTOR protein (p=0.002). One hundred percent of cases with complete absence of p-mTOR immunoreactivity were low stage DLBCLs. Conclusion: Membranous/cytoplasmic protein expression of p-mTOR correlates with advanced stage in DLBCL. Activated mTOR may play an important role in disease progression and provide a target for therapy in DLBCL. Further studies of the m-TOR pathway in hematopoietic malignancies appear warranted.

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Expression of mTOR in diffuse large B-cell lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18535 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18535-e18535

Author(s):

Srivalli Gopaluni ◽

Neerja Vajpayee ◽

Nancy Newman ◽

Charu Thakral ◽

Juhi Husain ◽

...

Keyword(s):

B Cell ◽

Survival Data ◽

Clinical Stage ◽

Univariate Analysis ◽

B Cell Lymphoma ◽

Predictive Marker ◽

Advanced Stage ◽

B Cell Lymphomas ◽

Poor Overall Survival ◽

Large B Cell

e18535 Background: The mammalian target of rapamycin (mTOR) pathway mediates protein synthesis, cell growth and survival of normal and malignant cells. This pathway is constitutively activated in several B-cell lymphomas. We studied immunohistochemical expression of mTOR, phosphorylated mTOR (pmTOR) and bcl-2 in 55 cases of diffuse large B-cell lymphomas (DLBCL) and their association with established prognostic factors as well as treatment outcomes in a retrospective single instituition study. Methods: After IRB review, 55 cases of DLBCL were identified. Immunostains for mTOR, pmTOR and bcl-2 were performed and their expression correlated with clinical and survival data. Associations of demographic (age and gender), clinical (stage, IPI score) and chemotherapy (RCHOP or other) with marker expression as well as association with recurrence and survival were studied using chi square and t-test for univariate analysis and logistic regression for multivariate evaluation. Results: Of the 55 patients, 44% were > age 65, 65% were males and 65% had advanced stage (III or IV) disease. High IPI scores were noted in 42% and 87% received the RCHOP regimen.On univariate analysis, high mTOR expression was associated with male gender (85% vs. 46%, p<0.01), high IPI score (67% vs. 18%, p, 0.001) and higher mean age (66 vs. 53 years, p < 0.001). With high mTOR expression a trend towards higher stage ( 78% vs 54% p=0.08) and likelihood of poor overall survival (defined as survival <3 years; 41% vs 18% p =0.08) was noted. Further, on univariate analysis bcl-2 expression was associated with higher risk of recurrence (35% vs.11%, p 0.05) whereas no association with clinical factors or outcomes was noted with pMTOR expression. On multivariate analysis the only parameter found to be significant was IPI [0R 11.6 95% CI 1.4-100]. Conclusions: High mTOR expression is associated with gender, age, IPI and showed a trend towards advanced stage and shorter survival. This target needs to be investigated prospectively in DLBCL as a prognostic factor and predictive marker. Given the availability of several mTOR inhibitors, the natural history of patients with poor risk DLBCL(high IPI) with high expression of mTOR may be favorably altered.

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