We investigated the association of plasma thrombopoietin (TPO) and overall survival in 127 patients with previously treated and previously untreated chronic lymphocytic leukemia (CLL). Higher levels ...of TPO were associated with advanced Rai stage (P < .001), higher levels of β2-microglobulin (β2-M) (P < .001), and the absence of mutation in the immunoglobulin heavy chain variable region (IgVH) (P < .001), and were inversely correlated with platelet count (P = .002). We found that TPO correlated strongly in a continuous manner with overall survival in both previously treated and untreated patients. The univariate Cox proportional hazard model demonstrated that high TPO levels were associated with shorter survival (P < .001), and multiple variable Cox proportional hazards regression analysis demonstrated that this was independent of the IgVH mutation status, β2-M, and Rai stage. Recursive partitioning showed that a cutoff point of 639 pg/mL separated the CLL patients into 2 major survival groups (P < .001). The effects of β2-M were masked by the effects of TPO in the patients with TPO levels higher than 639 pg/mL, but in the remainder, patients with β2-M level higher than 4.95 mg/L had significantly shorter survival than those with lower values. Plasma TPO and β2-M may be useful for the prediction of clinical behavior in CLL and may replace the need for the determination of IgVH mutation status.
Abstract
Effectively personalizing medicine depends upon selecting patients (pts) amenable to targeted therapies. We report the development of a custom immunohistochemistry (IHC) assay to identify ...P-cadherin positive expression in the archival biopsy of pts with solid malignancies. Validated reagents including a mAB to P-cadherin were incorporated into a custom IHC kit standardized across three Phase I sites (Seoul National University, Royal Melbourne Hospital, and Fox Chase Cancer Center).
Pts with a P-cadherin positive archival biopsy are being enrolled into an ongoing trial. Clinical results will be reported separately. P-cadherin positivity is defined by a scoring index (SI) product of the Tumor Area Positive for P-cad x Staining Intensity. Based on the literature, a SI ≥ 4 is associated with poor clinical outcome and was therefore required for pt entry into the trial. The IHC protocol was standardized across sites using positive and negative controls run in a masked fashion at each site and cross-examined and repeated by a central lab that had final decision-making authority (ApoCell, Inc., Houston, TX). Each site ran independent IHC assays and analyses by board-certified pathologists, and provided stained and unstained archival biopsy slides for independent, masked analysis by ApoCell. The turn-around time for central IHC analysis was ≤ 48 h.
Forty-four of 67 pts (65.7%) were found to be P-cadherin positive and eligible for entry into the trial. The distribution of enrolled patients by site is as follows: Australia (SI ≥ 4, n = 20), Korea (SI ≥ 4, n = 15), and USA (SI ≥ 4, n = 9). Median and mean SI values for the P-cadherin SI were 6 and 5.3 ± 2.9 (SD), respectively, with a range of 0 – 9. Clinical sites produced a SI equal to ApoCell in 56 of 67 pts (85.6% concordance rate). Among solid malignancies tested, a majority of gastric, colon and rectal cancers have demonstrated P-cadherin SI values ≥ 4. Successful execution of this IHC study demonstrates the feasibility of prospectively selecting pts based on IHC expression of P-cadherin using a custom standardized scoring index analysis across multiple clinical sites.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C16.
Several cytokines and growth factors are involved in the regulation of megakaryocytopoieses and platelet formation. Interleukin-11 (IL-11), IL-6, IL-3, IL-1b, and thrombopoietin (TPO) act ...synergistically to promote proliferation and maturation of megakaryocytes. Recombinant IL-11 and TPO are under clinical investigation as supplements to stimulate thrombopoiesis in patients with cancer. We investigated the plasma levels of TPO in 127 patients with chronic lymphocytic leukemia (CLL) and correlated these levels with platelet counts and various laboratory and clinical characteristics. TPO levels were significantly higher in patients with CLL (median, 232 pg/mL; range, 26.4–2714.5 pg/mL) than in healthy control subjects (P <0.01). More importantly, higher levels of TPO were associated with advanced Rai stage (P <0.0001), higher b-2-microglublin (b2-M) levels (P<0.001), and the presence of mutation in the IgVH gene (P <0.001). TPO levels were inversely correlated with platelet count (P = 0.002). Univariate Cox proportional hazard models demonstrated that high TPO levels in CLL patients were associated with shorter survival (P <0.0001); multivariate analysis demonstrated that this association was independent of the IgVH mutation status, b2-M levels, and Rai stage. Recursive partitioning showed that a cut-point of 639.4 pg/mL separated CLL patients into two major groups with a significant difference in survival (P <0.0001). When b2-M level was added to this model, its effect was masked by the effects of TPO in patients with TPO >639.4 pg/mL. However, among patients with TPO levels =639.4 pg/mL, those with b2-M levels >4.95 mg/L had significantly shorter survival than those with lower b2-M levels. These data not only emphasize the importance of TPO in reflecting the aggressiveness of CLL, but also suggest that TPO and b2-M can be used to predict clinical behavior in this disease and may replace the need for determining IgVH mutation status. Further studies are needed to determine if the prognostic role of TPO is due to its direct effects on the growth of the leukemic clone or simply reflects a general failure in the homeostatic regulation of various cytokines.
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Syndecan-1 (sCD138) is a transmembrane heparin sulfate-bearing proteoglycan expressed in epithelial cells as well as hematopoietic cells that demonstrate plasmacytoid differentiation. Higher levels ...of sCD138 correlate with poor outcome in myeloma. We examined the association of circulating sCD138 levels in plasma with clinical behavior in 104 patients with chronic lymphocytic leukemia (CLL). sCD138 levels were significantly higher in patients (median, 52.8 ng/mL; range, 13.4–252.7 ng/mL) than in healthy control subjects (median, 19.86; range, 14.49–33.14 ng/mL) (P <0.01). Elevated sCD138 (> median, 52.8 ng/mL) was associated with significantly shorter survival (P = 0.0004); this association was independent of IgVH mutation status, β2-microglobulin (β2-M) level, and treatment history. Patients with mutated IgVH but high sCD138 levels (>52.8 ng/mL) had significantly shorter survival than those with mutated IgVH and lower levels of sCD138. Similarly, patients with unmutated IgVH but high sCD138 levels had significantly shorter survival than those with lower sCD138 levels and unmutated IgVH (P = 0.007). In a multivariate Cox regression model, only Rai stage, β2-M, and sCD138 remained predictors of survival. These data suggest that sCD138 when combined with β2-M and Rai stage, may replace the need for testing IgVH mutation status.
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