Abstract 5302: Early prediction of response to therapy in malignant lymphoma using non-invasive [18F]FLT-PET imaging from animal to human model
Authors: Li Zhoulei , Herrmann Ken , Graf Nicolas , Dechow Tobias , Junger Alexandra , Weh Daniel , Schwaiger Markus , Buck Andreas K. 
Published: June 2012

Purpose: Preclinical and clinical studies have recently shown that the thymidine analogue [18F]fluorothymidine (FLT) accumulates in tumor tissue and enables non-invasive imaging of tumor proliferation, using positron emission tomography (PET). The aim of this study is to establish FLT-PET as an adequate and robust surrogate marker for very early response assessment to therapy in malignant Lymphoma.

Methods: In animal models we assessed the thymidine metabolism in SCID mice bearing SUDHL-1 or Karpas 299 lymphoma prior to and early in the course of therapy with Hsp90 inhibitor NVP-AUY922 or mTOR inhibitor RAD001, using a small animal PET system. Tumor-to-background ratios (TBR) of FLT-PET were compared to that of FDG-PET. PET findings were correlated with histopathology and in vitro data comprising cellular tracer uptake, cell cycle related protein expression, cell cycle distribution and viability assessment. In human models, FLT-PET was performed additionally to routine staging procedures in 66 patients with malignant lymphoma undergoing R-CHOP chemotherapy. FLT-uptake was correlated with response and survival.

Results: SUDHL-1 cells proved to be sensitive to both inhibitors whereas Karpas299 showed relative resistance to NVP-AUY922. Tumor volume in treated animals bearing SUDHL-1 lymphomas showed modest increase within the first week (median increase = + 25%, range -30% to + 80%, n=8) as opposed to a 3.8-fold increase in control mice. After 14 days a clear reduction of tumor mass was observed (median = – 25%, range -40% to + 30%, n=4). Median TBR of FLT-PET decreased significantly to 40% compared to baseline as early as 5d after therapy (range 32-67%, n=8, p=0,008). In contrast, TBR in FDG-PET did not show any clear tendency (median TBR 79%, range 36%-161%, n=8, p=0.73). According to our in vitro results, less effect was seen during treatment with AUY299 resulting in an increase of median TBR in FLT-PET to 154% (p=0,008, n=11) on day 2. In contrast, mice receiving RAD001 showed a stronger inhibition of tumor development and early FLT-PET imaging indicated a decrease of TBR to 78% (n=9, p=0.008). In human data, the initial SUVmesn in complete responders was significantly lower than in patients with progressive disease or partial response (p=0.049).

Conclusion: FLT-PET has a high specificity for the detection of malignant lymphomas, both in animal xenotransplants model and in human disease. Compared with FDG-PET, FLT-PET is able to predict response to specific inhibitors treatment very early in the therapeutic course. Our human data indicate that high initial FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell NHL.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5302. doi:10.1158/1538-7445.AM2011-5302