Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) and immunocytoma (IC) are remarkably heterogeneous with regard to their clinical course. The current staging systems can distinguish prognostic subgroups, but do not seem to predict the risk of disease progression of an individual patient with sufficient accuracy. Given the increase of treatment options for CLL and IC, additional parameters are needed to decide which patients may benefit from early or intensified treatment. It has been shown that two biochemical markers, serum beta 2-microglobulin (s-beta 2M) and serum thymidine kinase (s-TK), might identify CLL and IC patients at high risk of disease progression. Therefore, the prognostic value of these two serum parameters was compared with a panel of several established prognostic factors in a prospective clinical trial. 113 patients with CLL and 41 patients with IC (mean age +/- SD 63.9 +/- 10.7 years) were included. The following parameters were determined: histopathological diagnosis (IC vs. CLL), age, sex, performance status (Karnofsky index), B symptoms, peripheral blood lymphocyte count, platelet count, blood hemoglobin, serum lactate dehydrogenase (s-LDH), s-beta 2M, s-TK, serum creatinine, number of lymph node areas involved, prior therapy, and the time from diagnosis to inclusion in the study. Univariate analyses showed that nine parameters (Karnofsky index, peripheral blood lymphocytosis, platelet count, blood hemoglobin, lymph node areas involved, pretreatment, s-LDH, s-beta 2M, and s-TK) significantly predicted progression-free survival. In a Cox regression model, only four of these parameters provided independent prognostic information on progression-free survival: 1. s-beta 2M, 2. Karnofsky index, 3. platelet count, and 4. s-TK. The results show that s-beta 2M and s-TK independently predict progression-free survival in patients with CLL and IC, and suggest that these prognostic factors may allow an improved prediction of progression-free survival, particularly in early disease stages.

Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma.

Of all leukemias, chronic lymphocytic leukemia (CLL) shows the highest variability in its clinical presentation and course. CLL can present as an aggressive and life threatening leukemia or as an indolent form that will not require treatment over decades. The currently available clinical staging systems for CLL are simple and inexpensive but lack accuracy to predict disease progression and survival on an individual basis. The increased understanding of the key events of molecular pathogenesis has provided a plethora of novel molecular and biological factors that correlate with the outcome of CLL. This Review provides a concise discussion of the most important discoveries and gives guidance on how to implement novel prognostic tools in the clinical management of CLL by applying the criteria of evidence, relevance, and simplicity to the selection of prognostic markers.

Prognostic factors in chronic lymphocytic leukemia-what do we need to know?

Clinical observations reveal that an augmented pace of T-cell recovery after chemotherapy correlates with improved tumor-free survival, suggesting the add-back of T cells after chemotherapy may improve outcomes. To evaluate adoptive immunotherapy treatment for B-lineage non-Hodgkin lymphoma (NHL), we expanded T cells from client-owned canines diagnosed with NHL on artificial antigen presenting cells (aAPC) in the presence of human interleukin (IL)-2 and IL-21. Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival. Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells. Therefore, chemotherapy can be used to modulate infused T-cell responses to enhance anti-tumor effects. The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches.

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Adoptive T-cell therapy improves treatment of canine non-Hodgkin lymphoma post chemotherapy.

Production and characterisation of a novel chicken IgY antibody raised against C-terminal peptide from human thymidine kinase 1.

Thymidine kinase (TK) is a cellular enzyme which is involved in a “salvage pathway” of DNA synthesis. It is activated in the G1/S phase of the cell cycle, and its activity has been shown to correlate with the proliferative activity of tumor cells. Additionally, certain viruses are able to induce cellular TK production and activity. Clinical studies have reported elevated serum TK levels in a variety of neoplasias. The majority of these studies concerned hematologic malignancies. TK seems to be a useful marker in non-Hodgkin's lymphoma, where it correlates with clinical staging and provides significant prognostic information on (progression-free) survival. Preliminary results in acute myeloid leukemia indicate that pretreatment serum TK values may predict the response to the first induction chemotherapy. Moreover, serum TK appears to have some clinical value in such solid tumors as prostate cancer, breast cancer, and small-cell lung cancer, whereas it is not a reliable marker of non-small-cell lung cancer and brain tumors.

Strohmeyer S

Papers

Thymidine kinase: a tumor marker with prognostic value for non-Hodgkin's lymphoma and a broad range of potential clinical applications.