Clonal T-cell Receptor γ and δ Gene Rearrangements in T-cell Acute Lymphoblastic Leukemia at Diagnosis: Predictor of Prognosis and Response to Chemotherapy

Abstract

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict clinical outcome. Junctional regions of T-cell receptor (TCR) genes provide the best tool to study clonality, lineage association and minimal residual disease (MRD) in T-ALL. In this study, we have analyzed the suitability of clonal TCR gamma and delta junctional gene rearrangement status of T-ALL patients at diagnosis as a prognostic marker for T-ALL. We studied peripheral blood samples of 50 newly diagnosed patients with T-ALL in India for incidence of clonal TCR gamma and delta junctional region gene rearrangements by PCR-coupled heteroduplex analysis. Of these, 17 T-ALL patients uniformly treated on MCP 841 protocol were followed for more than 40 months (range: 41.26-55.82 months; mean: 49.26) and their clonal TCRgammadelta genotype was correlated with clinical outcome with respect to duration of complete remission, disease-free survival (DFS) and event-free survival. We also compared the clinical and biological features of TCRgammadelta + T-ALL and TCRalphabeta + T-ALL for their relative order of significance. Thirty per cent (15 of 50) of Indian T-ALL patients exhibited clonal rearrangements of both TCR gamma and delta genes. A significant proportion of these patients (73.3%, 11 of 15 P < 0.005) showed predominant usage of VgammaI-Jgamma1.3/2.3 with Vdelta1-Jdelta1 genes. A statistically significant association of L2 and L1 FAB blast morphology with TCRgammadelta + T-ALL and TCRalphabeta + T-ALL, respectively was observed (P = 0.001 by Fisher's Exact Test). The survival rate in DFS group was higher for TCRgammadelta + T-ALL compared to TCRalphabeta + T-ALL (P = 0.1378 by Log rank test). Thus we have identified clonal TCR gamma and delta junctional gene rearrangement status of T-ALL patients at diagnosis as a prognostic marker and predictor of response to chemotherapy. In future, this may help in designing tailored and risk-adjusted (less aggressive and less toxic) therapies for subset of T-ALL patients.