MEASURING OF TOTAL CELL DIVISION (THYMIDINE-KINASE) ACTIVITY WITH NOVEL SENSITIVE NON-RADIOMETRIC METHOD IN NHL AND CLL: STRONG CORRELATION WITH DISEASE STAGE AND ACTIVITY

Sborník

Background. Thymidine-kinase-1 (TK1) is a key enzyme expressed in the G1- S cell division stage to supply thymidine triphosphate necessary for cell division. Recent data show that pretreatment TK1 levels are predictive for survival of patients with non- Hodgkin´s lymphoma (NHL) or chronic lymphocytic leukemia (CLL). However, until now results are obtained with radioactive assays (TKREA) with lower sensitivity and narrow detection range. Aims. To analyze the clinical-laboratory correlations of pretreatment TK1 levels analyzed with a novel non-radioactive high-sensitive method in unselected cohort of newly diagnosed patients with NHL and CLL and Hodgkin´s lymphoma (HL). Methods. Samples were obtained at time of diagnosis in 80 patients: 73 of them were diagnosed as lymphoma (diffuse large B-cell n=24, follicular n=3, marginal zone n=3, T-cell n=3 and Hodgkin lymphoma n=3, respectively) and 35 as CLL. In seven cases reactive (benign) lymphadenopathy was diagnosed. All samples were analyzed both with conventional TK-REA method and with a novel technique based on thymidine incorporation mediated by serum TK1 (DiviTum from Biovica Int AB, Uppsala, Sweden). Using novel method was mean TK1 value 590. 6±1260. 7 Du/L, median TK1 value was 195. 3 Du/L, TK-REA method assessed mean TK1 value 20. 4±22. 2 U/L (median 11. 8 U/L), both methods showed strong correlation (r=0. 90, p<0. 001). We further analyzed patients with malignant lymphomas: median age was 64 years (range 22-89) with male predominance (M:F = 47:26), most of the patients (67%) had limited-stage disease (Ann Arbor stage I/II or Binet A/B), systemic symptoms were present in 43% and bulk >7cm in 30% of them. Beta-2-microglobulin (B2M) level was elevated >3mg/L in 21% and LDH in 32% of the cases. Results. Patients with reactive lymphadenopathy had significantly lower mean TK1 levels (163. 0±182 Du/L), compared to those with NHL, HL and CLL (631. 6±1312. 1 Du/L, p=0. 006). Mean TK1 level was significantly higher in patients with advanced disease stage (366. 8 vs 971. 0, p=0. 002), bulky disease (434. 4 vs 1036. 1, p=0. 006), systemic symptoms (335. 4 vs 979. 9, p<0. 001). Serum TK1 level was more than 3-fold higher in patients with high grade lymphoma than in low grade subtypes (317. 6 vs 1015. 0, p=0. 06) and 7-fold higher TK1 in patients with elevated LDH (209. 8 vs 1477. 7, p<0. 001). TK1 showed close correlation with LDH level (r=0. 79, p<0. 001). Trend was observed in correlation between maximum FDG avidity (SUV max.) on PET scan and TK1 level (r=0. 46, p=0. 07). On the other hand we found no correlation between TK1 and sex, age, B2M level and Ki-67 proliferating index. We found higher TK1 in CLL patients with unmutated IgVH status compared to those with mutated IgVH (607. 0 vs 166. 6, p=0. 002). Conclusions. The TK1 activity in specimens covers an extreme span - novel analytic method extends the detection range. It means that we are able to quantify higher levels than the conventional TK-REA method at time of diagnosis. We found a strong correlation between pretreatment TK1 levels and lymphoma stage and its aggressiveness.

Haematologica, 2012; 97(s1):  645