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Mature NK cells play key role in continued CML remission


Leukemia, November 2016; advance online publication

Patients with chronic myeloid leukemia (CML) who successfully discontinue imatinib treatment have a higher proportion of mature natural killer (NK) cells than those who experience early relapse, a substudy of the EURO-SKI data shows.

These findings “highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents,” say Satu Mustjoki (University of Helsinki, Finland) and co-authors of the study.

The researchers investigated the role of the immune system in sustained remission in 100 patients with CML who had been treated with imatinib for at least 3 years and had sustained deep molecular response for at least 1 year prior to treatment cessation.

They report in Leukemia that significantly more patients with NK cells above the median proportion of 16% were relapse-free at 6 months relative to those with a lower proportion, at 73% versus 51% and a hazard ratio of 2.17.

Furthermore, patients who experienced early relapse (before 6 months) had a lower relative proportion of NK cells compared with nonrelapsing patients (in remission for at least 12 months), at medians of 12.8% and 17.1%, respectively.

Further analysis showed that nonrelapsing patients had a higher proportion of more mature CD56dim NK cells at treatment cessation than those who relapsed early. And there was a trend for decreased molecular relapse-free survival among patients who had higher than the median number of more naïve CD56bright NK cells.

The researchers also found that nonrelapsing patients had significantly higher frequencies of adaptive NK cells with downregulated EAT-2 than early relapsing patients, at 2.1% versus 0.6%.

Moreover, above median secretion of tumor necrosis factor-α/interferon-γ by CD56dim NK cells was associated with significantly increased molecular relapse-free survival both at 6 (85 vs 40%) and 12 months (69 vs 40%) compared with lower TNF-α/IFN-γ secretion, and the level of secretion correlated with the relative number of NK cells.

Specifically, there was a trend toward positive correlation in the nonrelapsing group and a negative correlation in both the early- and late-relapsing groups “suggesting that in relapsing patients NK cells may not suffice to activate CD4+ T cells to mount Th1 type responses,” Mustjoki et al remark.

The researchers conclude that “the functional state of the immune system is associated with the molecular relapse free survival in CML patients discontinuing imatinib therapy.”

They add: “As NK modulating agents, such as antibodies blocking inhibitory [killer cell immunoglobulin like receptor], have already entered in the early clinical trials in other hematological malignancies, their testing in CML is warranted for increasing the proportion of patients who can discontinue imatinib treatment.”

By Laura Cowen

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