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Review: Progress Made Toward More Precise Diagnosing of NK-LGL Leukemia


About 15% of cases of large granular lymphocytic leukemia involve natural killer cells.

New research may make it easier for clinicians to confirm clonality of natural killer (NK) cells, ultimately allowing for a more precise diagnosis of natural killer large granular lymphocytic (NK-LGL) leukemia, according to a new review article.

LGL leukemia is a chronic lymphoproliferative disorder that is considered rare — affecting between 2 and 5% of patients with chronic lymphoproliferative disorders.

The disease tends to take an indolent course, sometimes without any symptoms for long periods of time. Yet, Tony Marchand, MD, PhD, of the University of Rennes, in France explained that two-thirds of patients will eventually need some kind of treatment. Diagnosing LGL leukemia can be a challenge, he said.

“LGL leukemia needs to be distinguished from reactive LGL proliferation, which is frequent, particularly in the context of viral infections, autoimmune diseases, after splenectomy, or in post-transplant patients,” Marchand and colleagues wrote.

There are 2 types of LGL leukemia, one involving T-lineage lymphocytes and one with an NK phenotype; the latter accounts for just 15% of cases. Two criteria are used to diagnose LGL leukemia: cytological identification of lymphocytes with granules greater than 0.5 G/L observed for at least 6 months, and proof of clonality. In the case of T-LGL leukemia, diagnosing clonality is relatively easy and entails looking at a patient’s T-cell antigen receptor arrangement, Marchand and colleagues said.

“On the other hand, NK-LGL clonality is far more complex to identify, as NK cells do not express CD3 on their surface and lack the T cell antigen receptor,” they wrote.

Yet, the task of diagnosing NK-LGL may be getting easier.

In a new review article in Frontiers in Oncology, Marchand and colleagues outlined some of the latest developments and progress toward an improved classification system for NK-LGL.

Currently, one of the best clues of NK clonality relates to cytotoxic profiles. In most cases, NK leukemic cells have a uniform CD16-high profile, while normal NK cells have heterogeneous CD16 expression, they said.

“High CD16 expression is not sufficient to affirm NK clonality but provides an invaluable clue in the diagnostic procedure,” the authors noted.

Bone marrow analysis can also help identify the correct diagnosis, they added, particularly in cases with atypical presentation.

The strongest tool, Marchand and colleagues suggested, is genomic analysis. The authors proposed creating an NK-cell clonality score, based on mutational screening. They then laid out a number of mutations which, in combination with killer immunoglobulin-like receptor (KIR) profiles, could be used to pinpoint NK-LGL leukemia.

“The identification of a phenotypic restriction in KIRs combined with identification of a STAT3, STAT5B, TET2, TNFAIP3, and CCL2 mutations constitute strong arguments to confirm NK clonality in most cases,” the investigators wrote.

Marchand and colleagues also reviewed the therapeutic implications of the latest research. They noted that there have not been any major studies looking specifically at the NK-LGL subtype, as studies of treatment outcomes have generally not distinguished between the 2 subtypes.

Marchand and colleagues said immunosuppressive drugs are generally the first-line therapy, though complete response rates are low and relapse is frequent.

A number of other potential therapies have also been investigated, however most of those studies are in the early phases, the investigators said.

“Targeted JAK/STAT pathway therapies and demethylating agents in the case of TET2 mutation, represent promising therapies that warrant assessment in prospective studies in order to reduce the relapses frequently reported after immunosuppressive therapy.

The authors concluded that advances in understanding NK-LGL leukemia, along with emerging technology, should pave the way to replace vague diagnostic categories like “chronic NK lymphocytosis” with more precise diagnoses.

“Proof of clonality of NK-LGL leukemia is crucial given the frequency of reactive NK-LGL proliferations,” they wrote.


Drillet G, Pastoret C, Moignet A, Lamy T, and Marchand T. Toward a better classification system for NK-LGL disorders. Front Oncol. Published online February 1, 2022. doi:10.3389/fonc.2022.821382

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