PB1944 EARLY CYTOTOXIC IMMUNE RESPONSE INCLUDING TUMOR SPECIFIC CYTOTOXIC T LYMPHOCYTES CAN BE OBTAINED IN CHRONIC PHASE CHRONIC MYELOID LEUKEMIA PATIENTS TREATED WITH DASATINIB.
Authors: Jo T. , Kaneko Y. , Noguchi K. , Hayashi S. , Shioya H. , Horio K. , Taguchi J. 
Published: June 2019

Background:Generation of BCR‐ABL fusion gene by reciprocal translocation of chromosomes 9 and 22 immortalizes hematopoietic stem cells, thereby leading to chronic myeloid leukemia (CML). Significant improvement in the prognosis of CML has been achieved since the introduction of tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib and nilotinib. However, to date, no consensus about the cessation of TKIs in CP‐CML patients has been obtained. We recently reported the case of a CP‐CML patient with long‐term complete molecular response (MR) after cessation of dasatinib, who has been maintaining memory cytotoxic T lymphocytes (CTLs) with T cell receptor (TCR) clonality (Jo et al. Oncology Letters 15: 2935‐2938, 2018).[A1]Abbreviations should be introduced at the first occurrence of the term.Aims:We planned to examine effector and memory CTLs in CP‐CML patients treated with TKIs. We also investigated CML specific cellular immune response.Methods:We examined the TCR Vb gene repertoire to analyze TCR clonality of CD8‐positive T cells in CP‐CML patients treated with TKIs using flow cytometry. We defined a TCR Vb gene percentage of 10% and above as being positive for monoclonality in this study. Tumor antigen specific CTLs were also analyzed using WT1‐, human TERT‐, and PR‐1‐tetramers by flow cytometry in CP‐CML patients having HLA‐A∗02:01:01/02:06:01 and/or HLA‐A∗24:02 treated with dasatinib.Results:We analyzed 15 patients treated with TKIs including dasatinib (Dasa group) and 8 patients treated with TKIs without dasatinib (non‐Dasa group). No significant statistical difference was observed in the median age at first TKI administration, the MR at the time of TCR clonality assay, and the NK cell percentages between the 2 groups. The time of TCR clonality assay was significantly earlier in tghe Dasa group than in the non‐Dasa group (P = 0.0013). Approximately 73% and 87% positivity of effector and memory CTL clonality was observed in the Dasa group; while approximately 38% and 50% positivity of effector and memory CTL clonality was observed in the non‐Dasa group, although the TKI exposure time for this group was significantly longer. Notably, the positive percentages of effector and memory CTL clonality in the non‐Dasa group are quite similar to the overall probabilities of maintenance of deep MR reported in various imatinib‐stop studies such as the STIM study (Mahon et al. Lancet Oncol 11: 1029‐1035, 2010) and the TWISTER study (Ross et al. Blood 122: 515‐522, 2013). Table 1 summarizes the data of TCR clonality and tetramer analyses in CP‐CML patients having HLA‐A∗02:01:01/02:06:01 or A∗24:02 treated with dasatinib. Patient‐4 has both HLA‐A∗02:01:01 and A∗24:02. Effector and/or memory CTL clonality was observed in all patients except for Patient‐5. TCR Vb2 and Vb14 genes were predominantly observed in patients having A∗02:01:01/02:06:01; while TCR Vb1, Vb2, and Vb9 genes were predominantly observed in patients having A∗24:02. Tetramer assays showed that tumor specific CTLs were positive in 2 patients (50%) having A∗02:01:01/02:06:01 and 4 patients (80%) having A∗24:02.Summary/Conclusion:Effector and memory CTL clonality was attained more rapidly and frequently in dasatinib‐treated CP‐CML patients than in patients treated with TKIs without dasatinib. The positive percentages of CTL clonality resembled the percentages of TFR in various TKI‐stop studies. These results suggest that the acquisition of CTL clonality may provide long‐term remission and TFR to CP‐CML patients and that cessation of TKIs should be considered in patients with clonal expansion of memory CTLs.image