Natural Killer Cells Play Role in Ability of CML Patients to Discontinue TKIs

Patients with chronic myeloid leukemia (CML) who have higher proportions of natural killer (NK) immune cells, and more mature NK cells, fare better when discontinuing therapy with imatinib, according to a new study.

“Recent reports suggest that approximately 40% of CML patients who have achieved optimal therapy responses (deep molecular remission) can discontinue imatinib treatment without recurrence of detectable BRC-ABL1 transcripts,” wrote study authors led by Satu Mustjoki, MD, PhD, of Helsinki University Hospital Comprehensive Cancer Center in Finland. Residual leukemic cells can still be detected in blood samples, however, and a complete cure would “either need to eradicate or alternatively regain the immune control of the remaining leukemic cells.”

The new study aimed to elucidate the role of the immune system in successful discontinuation of tyrosine kinase inhibitor (TKI) therapy in CML patients. It was a prospective analysis, including 132 chronic-phase CML patients treated with imatinib (107 patients), dasatinib (15 patients), or nilotinib (9 patients) for at least 3 years prior to the study; only the imatinib-treated patients were included in this analysis. All patients had sustained deep molecular response for at least 1 year; these were compared with 48 healthy volunteer control patients. The results of the trial were published online ahead of print in Leukemia.

Among patients who had a relative proportion of NK cells that was higher than the median, the 6-month relapse-free survival rate was 73%; among those lower than the median, that rate was 51%, for a hazard ratio (HR) of 2.17 (P = .02). The researchers determined an optimal cutoff for the NK cell proportion; the difference between “high” and “low” NK groups was even more pronounced at 6 months, at 70% vs 43% for an HR of 2.35 (P = .009).

This association was not seen with regard to relative or absolute numbers of T and B cells, or with total monocyte, lymphocyte, or leucocyte counts.

Patients who relapsed within the first 6 months after imatinib discontinuation had a lower relative proportion of NK cells, compared with non-relapsing patients (12.8% vs 17.1%), but this was not the case among late-relapsing patients.

The researchers used detailed immunophenotyping to better understand the NK cells’ role. CD56^bright NK cells are considered immature; as they mature, they lose some CD56 receptors and become CD56^dim NK cells. Patients with a higher than median number of the immature version had a trend toward poorer relapse-free survival; this became significant when an optimal cutoff was determined, with decrease relapse-free survival seen in patients with a lower proportion of mature NK cells.

“We hypothesize that an increased amount of mature NK cells may be capable of both directly killing the tumor cells and potentiating adaptive immune responses against leukemia, thereby maintaining remission after imatinib discontinuation,” the authors wrote. “As NK modulating agents … 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.”