T Large Granular Lymphocytes Leukemia (T-LGLL) and Natural Killer Chronic Lymphoproliferative Disorder (NK-CLPD): Two Diseases With a Common Etiopathogenetic Mechanism?
Authors: Gattazzo Cristina , Teramo Antonella , Nardin Chiara , Passeri Francesca , Barilà Gregorio , Trimarco Valentina , Pavan Alberto , Carraro Samuela , De March Elena , Facco Monica , Trentin Livio , Semenzato Gianpietro , Zambello Renato 
Published: October 2019

Abstract

Introduction
The large granular lymphocytes (LGL) disorders are characterized by expansions of T or NK cells with cytotoxic activity. WHO classification considers these disorders as separate entities, referred to as T-LGL Leukemia (T-LGLL) or NK-Chronic Lymphoproliferative Disease (NK-CLPD). The marker of clonality is the rearrangement of TCR in T-LGLL and a restricted pattern of Killer Immunoglobulin-like Receptor (KIR) expression in NK-CLPD. Although these disorders are characterized by the expansion of different cells types, compelling evidence supports the hypothesis that a common pathogenetic mechanism would be involved in both these disorders. Accordingly, the transcription factor STAT3 has been found mutated in a consistent percentage in both T-LGLL and NK-CLPD, suggesting a similar molecular dysregulation. Here, we evaluated whether clonal T and KIR restricted NK cell populations were detectable in patients with LGL, to support the hypothesis that a common pathogenetic mechanism takes place in both T-LGLL and NK-CLPD disorders.

Methods
We enrolled 370 therapy-free patients with LGL, 133 of which were available for serial measurements over 2 to 15 years. Peripheral blood sample and data collection from patients were performed at clinically indicated testing after informed consent, according to the protocols approved by the Institutional Review Board of the Experimentation Ethic Committee of Padua and in accordance with the Declaration of Helsinki. Based on World Health Organization guidelines, the diagnosis of T-LGLL was made according to the presence of monoclonal TCRγ-chain rearrangement, flow cytometric evidence of an abnormal CTL population characterized by expression of CD2, CD3, TCRαβ (or γδ), CD4, CD5dim, CD8, CD16/56 and CD57, TCR Vβ expansions (when detectable) with negativity of CD28. The diagnosis of NK-CLPD was made according to flow cytometric evidence of a KIR restricted CD16+/CD3- NK population. For both disorders, a LGL count by peripheral blood smear of > 2,000 LGL/μL (this is not a critical criteria, since patients who met all other criteria but with an LGL count < 2,000 cells/μL were included) and persistence of these conditions for more than 6 months were confirmed.

Results
Based on World Health Organization guidelines for T-LGLL and NK-CLPD diagnosis, we classified our patients in 3 group: Group 1 (n=247), with a T clonal expansion characteristic of T-LGLL, Group 2 (n=79), with a KIR restricted NK expansion characteristic of NK-CLPD, and Group 3 (n=44), characterized by patients in whom the presence of both KIR restricted NK population and T clonal expansion were present. Moreover, during the follow-up, we observed that 15 patients underwent a clonal switch of pathologic clones as follows. Five patients switched from NK-CLPD to T-LGLL. Seven patients developed additional clone(s) during follow-up, leading to the coexistence of both NK and T clonal populations; 3 patients demonstrated either a gradual emergence of a dominant T or NK clone from an oligoclonal background observed at diagnosis.

Conclusions
These results support the hypothesis that an antigenic pressure present in LGL disorders sustains the proliferation of both NK and T clones, triggering in some circumstances the gradual switch from a disorder to the other one. This observation challenges the classification of these disorders as two separate entities, questioning the accuracy of T-LGLL and NK-CLPD classification made by WHO in 2008.

Disclosures:
No relevant conflicts of interest to declare.