Abstract
Introduction: Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasms caused by a reciprocal translocation of chromosomes 9 and 22 [t(9;22)], producing the BCR-ABL fusion gene. Imatinib (Ima), the 1st generation tyrosine kinase inhibitor (TKI), has drastically improved the prognosis of CML compared to previous therapies. Imatinib and the 2nd-generation TKIs dasatinib (Dasa) and nilotinib (Nilo) are generally used for chronic phase CML (CP-CML) as induction chemotherapy. Lymphocyte proliferation and increased large granular lymphocytes (LGLs) are sometimes observed in patients treated with Dasa. These LGLs have been reported to be mainly natural killer (NK) cells. However, there is insufficient data about T-lymphocytes, including CD8 T cells, in CML patients treated with TKIs. We analyzed lymphocyte counts and percentages in CP-CML patients treated with Dasa and other TKIs. We also examined T cell receptor (TCR) V beta gene repertoire in some patients.
Methods: The patients in this study were CP-CML patients diagnosed at our hospital from August 2006 to June 2016 and treated with TKIs. The main aims were to examine (1) lymphocyte rates and (2) cytotoxic T lymphocytes (CTLs) and TCR V beta gene repertoire. These analyses were conducted using flow cytometry. All statistical analyses were performed using GraphPad Prism 6 software.
Results: Table 1 summarizes data comparing patients treated with Dasa and those treated with other TKIs. Six patients were treated with Dasa only. Seven and 2 patients, respectively, were treated with Ima or Nilo only. Eleven patients were treated with multiple TKIs including Dasa, and 2 patients were treated with multiple TKIs not including Dasa. The median age at first TKI administration was 60 years in patients treated with Dasa and 72 years in patients treated with other TKIs. No significant statistical difference was observed in age at first TKI administration. The median follow-up period of patients treated with TKIs without Dasa was significantly longer than that of patients treated with TKIs including Dasa. This was due to the difference in the timing of approval of Ima (1st generation TKI) and Dasa (2nd generation TKI). There was no significant difference in the best response between the Dasa and non-Dasa groups. There was also no significant difference in overall survival between the 2 groups (Log-rank, P = 0.7283). Pleural effusion was observed in 5 patients in the Dasa group and 1 in the non-Dasa group, without statistical significance. Figure 1 shows lymphocyte elevation in the Dasa group compared to the non-Dasa group with regard to both lymphocyte counts and percentages. Figure 2 shows the time courses of lymphocyte percentages. Counts from 1, 3, 6 and 12 months from the initiation of Dasa (A) and non-Dasa TKIs (B) are indicated. The lymphocyte rates in the non-Dasa group showed no significant change (Figure 2B). However, gradual lymphocyte elevation was clearly seen with the passage of time in Dasa group patients, with statistical significance (Figure 2A). The time courses of lymphocyte counts in 2 cases are shown in Figure 3. Lymphocyte elevations were clearly observed after changing to Dasa from Nilo (Figure 3A) and Ima (Figure 3B). We also analyzed the detailed lymphocyte fraction in some patients. Representative data of a patient treated with Dasa only are shown in Table 2 and Figure 4. NK cells were found in the peripheral blood, as have been seen in previous reports, and, interestingly, CTLs were also detected at all time points (Table 2). It is notable that about 20% of the peripheral blood consisted of CTLs 35 months after the first administration, which was the same percentage as that of NK cells. TCR V beta gene repertoire in the same patient is shown in Figure 4. Oligoclonal CD8 T cell expansion was observed using V beta 13.1, V beta 7.1, and V beta 2 expression. These results suggest that not only NK cells but also CTLs may play an important role in attacking CML blasts in patients treated with Dasa.
Conclusions: In CP-CML patients treated with TKIs, lymphocyte elevation was obviously observed only in patients treated with Dasa. CTL analyses and TCR V beta gene analyses suggest that CTLs can be induced along with NK cells in patients treated with Dasa. These results show that Dasa can work in a different way than other TKIs. Clarifying the tumor antigens recognized by these CTLs may bring new insights and connect to new cellular therapies for refractory CML cases.
No relevant conflicts of interest to declare.
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