Serum Thymidine Kinase (TK) Distinguishes Grade of Non Hodgkins Lymphoma (NHL) and Predicts Complete Response Rate (CRR) and Progression Free Survival (PFS).
Authors: Rajan Sandeep K. 
Published: April 2020

Background: International Prognostic Index (IPI) based on clinical plus lab criteria help determine CRR and prognosis in lymphoma patients. However drawbacks exist and new markers to improve prognostication are sought for. TK is an enzyme involved in the DNA synthesis salvage pathway and can serve as a proliferative marker.

Methods: Serum TK enzyme activity was determined using the Prolifigen TK radioenzymatic assay (Sangtec Medical,Sweden) in 58 consequetive NHL patients. All cases had conventional histopathologic and staging procedures and evaluation of IPI. Treatment was per institutional standards. For intermediate grade NHL: Low IPI and limited stage-non-bulky NHL received 3 cycles CHOP + IFRT; 6–8 CHOP-R for higher stage or bulky disease. For Burkitt’s NHL, HYPERCVAD chemotherapy was given and CVP for low grade NHL (all were high stage). All patients had CT scanning after 3-cycles and at end of planned therapy. CRR was noted at end of therapy. Patients were followed up every 2-m for the first year and PFS noted. TK assay was done baseline, after 2-cycles (TK-2c), at end of planned therapy (TK-endRx) and every 2m thereafter. Statistical analysis was done by Sigmastat (v.2) software.

Results: Histological subtypes of 58 NHL were: 6 aggressive (Burkitt’s NHL), 46 Intermediate grade(41 DLBCL, 1 mantle cell, 2 ALCL & 2 NK-T) and 6 low grade (5 follicular and 1 marginal zone). Stage distribution was, I=3, II=25, III=9 and IV=21. For DLBCL, IPI risk was 25 Low, 10 Low-Intermediate, 4 Hi-intermediate and 2 High. Baseline TK was distinct in low grade, intermediate and high grade NHL by Kruskal-Wallis One Way ANOVA (median value 5.7mU/μg, 14.5 and 88.1; P &lt; 0.05). 19 patients did not reach CR with planned therapy. 6 of these reached CR with IFRT. TK value &gt; 10mU/μg after 2-cycles (TK-2c) predicted failure to reach CR (Table-1, P&lt;0.001 by Fisher exact test). Patients with TK &gt; 10mU/μg at end of planned chemotherapy (TK-endRx) were more likely to have a relapse within 1-y (Table 2, Fisher exact test P&lt;0.001). In DLBCL, CRR was correlated with Stage, IPI, B-symptoms, high LDH and TK-2c, the highest correlation coefficient by Pearson product moment correlation was with TK-2c. Correlation coefficient (CC) for IPI was 0.36 and that for TK-2c was 0.56 (CC &gt; 0.5 is statistically significant). By multiple linear regression TK-2c was independent predictor of CRR (P =0.002) and IPI status was not significant predictor. With median follow-up of 16m (range 14–22m), 10 patients in CR had a relapse, in all TK value showed a raise at least 2m before clinical relapse.

Conclusions: In this study TK distinguished grade of NHL, TK-2c predicted CRR and TK-endRx &gt;10mU/mcg predicted PFS &lt;1y. At least in our predominantly low and low-intermediate IPI risk group patients, TK-2c was better predictor of CRR and prognosis than conventional clinical factors. Further studies are needed to confirm this in all risk categories.

TK after 2-cycle predicts CRrate (CRR)

CR Yes No Fisher exact test p&lt;0.001 TK &lt;10mU/mcg 36 3 TK &gt; 10mU/mcg 3 16

TK-endRx and Progression free at 1-y.

Progression free at 1y Yes No Fisher exact test P&lt; 0.001 TK &lt; 10mU/mcg 43 1 TK &gt; 10mU/mcg 6 8