Sustained upregulation of effector natural killer cells in chronic myeloid leukemia after discontinuation of imatinib

Abstract

A number of CML patients who achieve a sustained complete molecular response (CMR) for at least 2 years during imatinib (IM) therapy can discontinue IM without relapse. With the longterm goal of developing immunological criteria for managing IM therapy in CML patients, we compared the immunophenotypic profiles of three groups of CML patients: those who received IM and had a CMR for more than two consecutive years (CMR group); patients who received IM and did not have a sustained CMR but maintained a major molecular response for more than 2 years (fluctuating CMR group); and patients with a sustained CMR for more than 6 months after IM discontinuation (STOP-IM group), together with healthy controls. The percentages of effector populations of natural killer (NK) cells, such as interferon (IFN)-c + CD3À CD56 + cells, were significantly higher in the STOP-IM and CMR groups than in the fluctuating CMR and control groups. The elevated levels of these effector NK cells were sustained for more than 3 years after IM discontinuation. In contrast, the percentages of effector memory CD8 + T cells, such as IFN-c + CCR7 À CD45RO + CD8 + cells, were significantly higher in the STOP-IM and control groups than in the CMR and fluctuating CMR groups, possibly owing to IM intake. These results suggest that the immunological activation status of NK cells contributes to CMR maintenance. Higher activation levels of effector NK cells in CML patients being treated with IM might reflect minimization of BCR-ABL1 transcript levels and therefore could be additive information for determining whether to stop IM. (Cancer Sci 2013;

Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib

“…A substantial proportion of such patients maintains the response for more than 12 months after discontinuation of imatinib 39 or dasatinib. 40 Notably, increases in NK cells 40,41 but not T cells 40 In conclusion, this study using PCA suggests that the distinctive NK cell subset, that is, CMV-associated adaptive NK cells, is responsible for the dasatinibinduced NK cell expansion, which likely occurs through subclinical CMV reactivation.…”

Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

“…Briefly, we observed that ESR and CRP were increased in some patients with IMWS (data not shown) but CPK were not noted in association with the musculoskeletal symptoms. The importance of immunologic status for successful TFR is illustrated by the beneficial effect of natural killer (NK) cell activity 17,18 and interferon treatment on a higher TFR rate, 4,7 indicating that the re-activation of autologous immunity may contribute to the elimination of MRD after IM discontinuation via the emergence of NK cells or cytotoxic T lymphocytes (CTLs) against CML-associated antigens. [19][20][21] Although we analyzed the frequency and function of NK cells after IM discontinuation in some patients, no significant association was found.…”

Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients

“…Despite the well-known antitumor effect of the innate immune system, few data exist on the role of natural killer (NK) cells and their killer-cell immunoglobulin-like receptors (KIRs) in CML [6][7][8]. According to some recent reports, early disease relapse after TKI discontinuation was associated with both low numbers and impaired function of NK cells [9][10][11]. NK cells can express both inhibitory and activating KIR receptors, which recognize four exclusive epitopes carried by human leukocyte antigen (HLA)-A, -B, and -C class I molecules expressed on target cells: C1, C2, Bw4, and A3/A11 [12].…”