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Flavopiridol-related Proinflammatory Syndrome Is Associated with Induction of Interleukin-6

Developmental Therapeutics Program, Radiation Oncology Branch [R. A. M., J. W., G. M., D. H., W. D. F., E. A. S.], National Cancer Institute, Laboratory of Immunology Branch [C. D. U., A. K.], National Aging Institute, and Molecular Therapeutics Unit [T. L., A. M. S.], Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892, and Department of Radiation Oncology, University of Rochester, New York [I. D.]

Background: Flavopiridol is a flavonoid with antiproliferative effects mediated, in part, by inhibition of cyclin-dependent kinases. Clinical manifestations in a previous Phase I trial in patients with refractory malignancies treated with a 72-h flavopiridol infusion included a proinflammatory syndrome consisting of fever, fatigue, and "local" tumor pain with concomitant alterations in plasma acute-phase reactant proteins.

Purpose: The aim of this study was to determine whether the proinflammatory syndrome observed in this trial was associated with modulation of plasma cytokines.

Methods: Patients receiving flavopiridol (n = 76) had serial plasma samples drawn preinfusion and during the infusion for evaluation of interleukin (IL)-6, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, basic-fibroblast growth factor, transforming growth factor-ß, and tumor necrosis factor- levels by standard ELISA assays. The Wilcoxon signed rank test was used to test the significance of the difference between the baseline (time 0) plasma cytokine levels compared with the values of each subsequent data collection time points (8, 24, 48, and 72 h).

Results: There was a significant and sustained increase in plasma IL-6 levels at all time points when compared with baseline values. Paired values were used in the statistical analysis. Median plasma (interquartile range) values of IL-6 were elevated from 15.5 (9–52) pg/ml at baseline to 23 (4–48) pg/ml (P < 0.01) at 8 h; from 15 (2–48) pg/ml at baseline to 46 (21–105) pg/ml (P < 0.001) at 24 h; from 16 (9–52) pg/ml at baseline to 61 (32–170) pg/ml (P < 0.001) at 48 h; and from 15.5 (6–48) pg/ml to 68 (40–200) pg/ml (P < 0.001) at 72 h. Significance was maintained even when adjusted for multiple comparisons. The relative increase in IL-6 concentration was dose-dependent. Moreover, IL-6 elevation had a direct correlation with flavopiridol peak plasma concentration, flavopiridol area under the curve, and plasma C-Reactive protein levels. A significant decrease in plasma granulocyte macrophage colony-stimulating factor occurred at the 8-h sampling point: 50 pg/ml (interquartile range 10–205 pg/ml, P < 0.01) when compared with baseline plasma levels and 71 pg/ml (interquartile range 5–152 pg/ml, P < 0.01). No changes in the other pro or anti-inflammatory cytokines were observed. Immunohistochemistry studies in bone marrow aspirates from a prospective group of patients in this trial demonstrated 4-fold induction of IL-6 (compared with baseline), mostly in non-T cells.

Conclusion: Biochemical analysis of plasma in patients undergoing infusional flavopiridol found a significant dose-dependent induction of IL-6. IL-6 elevation could be a marker for the process leading to the appearance of the proinflammatory syndrome observed in patients treated with infusional flavopiridol. The mechanism(s) underlying IL-6 induction and its significance are still unknown but may influence strategies to modulate flavopiridol’s clinical effects.

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