Abstract

Imatinib mesylate has revolutionized the treatment of CML and, as an oral agent with few side effects, became the first-line therapy for patients with CML. However, patients who discontinue the drug invariably relapse. Currently, the only curative treatment for CML is allogeneic stem cell transplantation (ABMT). A major mechanism of ABMT is immunological as evidenced by the poor clinical outcome with T cell-depleted ABMT. To determine anti-leukemia immune responses in patients in remission on imatinib, blood and bone marrow samples before (12 samples) and serially after treatment (59 samples, range 10 months – 35 months) were collected and analyzed. The NK cell (CD56+CD3−) compartment in the 12 CML patients were significantly decreased before treatment (median 3,4 % vs 10 %, p<0.01) and remained low in patients in remission on imatinib (5 % vs 10 %, p< 0.01) compared to 32 age matched healthy donors. Within the CD8+ T cell compartment, naïve T cells (CD45+CD27+) were significantly higher before treatment (55.5 % vs 37.7 %, p=0.04) and decreased slowly to normal levels after successful treatment (41.5 % vs 37.7 %, p=0.28), whereas memory (CD45−CD27+) T cells presented the opposite way. They were significantly lower before treatment (21.7 % vs 31.1 %, p=0.03) and increased slowly to normal levels after successful treatment (27.5 % vs 31.1 %, p=0.39). However, the percentage of T cells (CD4+, CD8+, CD4+CD25+ regulatory T cells) and B cells were not significantly different. These results correlated (p<0.01) with T cell responses to autologous leukemia cells at the same time points, analyzed by IFN-g ELISPOT assay (median 36 SFCs vs 5 SFCs, p<0.01), and were confirmed by cytokine flow cytometry (IFN-g 3.6 % vs 0.29 % and TNF-a 6.6 vs 0.1 %). These results suggest that a significant portion of CML patients in remission with imatinib develop an anti-leukemia T cell response, whereas the NK cell compartment is disturbed. Mechanisms by which imatinib treatment leads to anti-leukemia immune responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge will be useful in the development of immunotherapy strategies against CML and may, in combination with imatinib, lead to eradication of residual leukemia cells for a durable cure.

Disclosures: No relevant conflicts of interest to declare.

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