Thymidine Kinase Levels Correlate With Prognosis In High Grade Lymphoma, and Can Discriminate Patients With a Clinical Suspicion Of Low Grade To High Grade Transformation
Authors: Gatt Moshe E. , Goldschmidt Neta , Friedman Moran , Kalichman Ina , Charlotte Arronson Anne , Barak Vivian 
Published: October 2019

Abstract

Introduction
Hematologic malignancies accounts for about 10% of all cancers. Of these, the lymphoid tumors are most prevalent, cells transforming at various stages of the lymphoid lineage differentiation. The lymphoid tumors can further be divided into low grade, slow growing diseases, and rapidly growing high grade diseases.
Measurement of total cell division activity using serum thymidine kinase 1 (TK1) has been evaluated previously for these diseases. It correlates with disease progression, stage and grade. The prognostic utility of pretreatment TK1 activity has been only partially investigated. In addition, its ability to differentiate the subset of patients where a transformation from low grade to high grade is suspected, has never been investigated.

Study Aims
In this study, the new TK chemiluminescence immunoassay was used to assess serum TK1 levels in patients with various hematologic neoplasms. Serum TK1 levels were correlated with baseline clinical and laboratory parameters and overall survival. In addition, we hypothesized that serum TK1 levels may discriminate the transformation from low grade to high grade lymphoma in the context of a clinical suspicion.

Patients and Methods
At the first phase of the study, we analyzed a total of 194 patients using DiaSorin TK1 elisa kit (Stillwate, MN, USA). All levels were taken during the initiation of treatment at diagnosis or relapse, except for TK kinetics along time. Most had lymphoid neoplasms of various origins. Most patients had DLBCL (60 including transformation) and low grade NHL (46). We analyzed in addition patients with HL, MM and CLL, as well as patients with very aggressive tumors such as Burkitt's Ly/Leukemia, ALL and AML (the latter for control purposes). At the second phase we collected, assessed and compared a cohort of patients with transformation of low to high grade lymphoma, and patients with low grade lymphoma with suspected transformation, whom eventually had other diagnoses (i.e. infections, low grade related symptoms, large low grade-related masses etc.).

Results
Measurements of TK and B2M in Normal samples: Considering the relatively new use of the TK levels,measurement method by ELISA, we first verified its values in normal subjects.
38 subjects, male and female adults were tested. The average reading revealed normal levels to be 4.06 u/L +/- 1.83. We therefore set the upper limits of normal to be 7.7 u/L (average + 2 standard deviations). Low grade lymphomas had significantly (p<0.03) lower readings mean 12.8 u/L (± 21.5) as compared with 32.8 (± 36.6) u/L for high grade diseases. In low grade diseases TK levels did not correlate with survival. However, in high grade diseases normal TK levels correlated with a significantly better long term survival (p=0.04). Of note were six patients with transformations who had a TK level of 48.8 u/L (± 29.73). We thus further analyzed another cohort of 60 patients with a base line low grade lymphoma and suspected transformation. Of these, 36 patients had a suspicion eventually proving to be low grade disease or infection related (i.e.-no evidence of transformation), and 24 with biopsy proven transformations. The TK level differed significantly (p<0.01) between the two groups. After censoring for 3 CLL patients with very high WBC count in the non-transforming group, and 5 patients with stage 1 in-situ transformations in the transformation group, these differences became striking (P<0.0001) with a median level of 7.6 versus 48.6 u/L, respectively (figure). Having a TK level of > 14.1 u/L had a sensitivity of 95% and a specificity of 76% for having a low to a high grade lymphoma transformation, with a negative predictive value of 96% and a positive predictive value of 69%, respectively.

Conclusions
TK levels are useful in assessing prognosis, especially in high grade lymphomas. Moreover, TK levels were able to discriminate low grade patients suspected of a high grade transformation, but eventually having none, and patients with proven transformations.

Disclosures:
No relevant conflicts of interest to declare.