Low-Count T-/NK-Large Granular Lymphocytic Leukemia: A Nosologically Distinct Disease Subtype at the Crossroads between Lymphoproliferation, Autoimmunity and Immunodeficiency

Classical diagnosis of large granular lymphocytic leukemia (LGLL) relies on increased blood LGLs ≥2x10⁹/L in analogy to other low grade leukemias/lymphomas. However, despite fulfilling standard criteria, the disease does not often present with hyperleukocytosis but is associated with normal/low lymphocyte counts. A new threshold of LGLs ≥ .5x10⁹/L has been proposed and updated criteria allow diagnosis with lower counts in the context of cytopenias.

Using an analytic cohort of 416 consecutive patients (pts), we queried whether LGLL cases with low LGL counts constitute a nosologically distinct subtype, and whether peculiar patterns corresponding likely to a different pathophysiology can be discerned from cases with increased LGL counts. Mutational spectra of 50 lymphoid/myeloid genes (targeted n=271) and 465 genes linked to errors of immunity (WES n=90) were assessed.

388/416 pts had persistent T/NK cell proliferations. While 134 (35%) pts had high LGL counts (HC ≥2x10⁹/L), a significant fraction of cases had lower counts: 144 (37%) had intermediate (IC .5-2x10⁹/L) and 110 (28%) had low counts (LC <.5x10⁹/L). Cross check validation of these latter cases resulted in the exclusion of 5 pts due to other diagnoses. In the remaining 105, 84 (80%) had signs of neoplastic/active disease, including BM, spleen or liver involvement (n=80), complications requiring therapy (n=66) or lymphoid mutations (n=23). These pts were considered LC-LGLL in further analysis. The other 21 cases with TCUS were excluded.

We then focused on the characteristics of LC-LGLL. 81 (96%) and 3 (4%) cases were T and NK cell subtypes. As opposed to increased counts, LC-LGLL was enriched in the γδ T variant (6 vs 2% P=.05), also in atypical cases with double CD4/CD8 (15 vs 7% P=.02), retention of CD5/CD7 (60 vs 40% P=.03), or negativity of CD16/56 or CD57 (65 vs 80% P=.02). Low LGL count correlated with lymphocytopenia (P<.01) and reduced CD4 (P<.01), NK (P<.01) and B cells (P<.01); as well as with bi/pancytopenia (P<.001), and severe cytopenia (P=.01). Genetics of LC-LGLL, vs IC vs HC-LGLL, showed a lower STAT3 mutation rate (24 vs 37 vs 49% P<.01) and a lower median VAF (7 vs 11 vs 22% P<.01). Mutations in STAT5B, TNFAIP3 or other non-STAT genes were present in 12% of LC-LGLL with no differences across groups.

Random forest importance and trend models accounting for interactions across multiple variables revealed that LC-LGLL, vs IC/HC-LGLL, was enriched in autoimmune diseases (49 vs 48 vs 37% P=.03), mainly Felty Sd (14 vs 4 vs 4% P=.02) and BMF/immune cytopenia (33 vs 24 vs 18% P=.04). Clinical and laboratory signs of immunodeficiency were also more frequent in LC-LGLL (85 vs 78 vs 69% P=.01). We further tested the theory that the clonal LGL expansion in these cases could be counteracting a cryptic immunodeficiency trait. Genetic screening for errors of immunity showed overall 19/90 (17%) carriers. The genetic immunodeficiency burden significantly increased with lower counts (36 vs 23 vs 3% P<.01). Concurrent myeloid neoplasms (MN) were also enriched in LC-LGLL (13 vs 9 vs 5% P=.04). In 275 pts with BM exam, low LGL count correlated with reduced hematopoietic cellularity (P=.02) and dysplasia (P<.01). Molecular profiling also pointed an enrichment in myeloid mutations (P=.10).

Clinical outcome analysis showed that the proportion of cases requiring therapy did not differ based on LGL count. However, there was a trend to lower response rates in LC-LGLL. In multivariable analysis, adjusting by age, sex and STAT3/5B, LC-LGLL implied a shorter time-to-next-treatment (HR=2.15 P<.01) and a lower overall survival (HR=1.97 P<.01).

In conclusion, a significant fraction of LGLL presents with low counts. LC-LGLL has distinct features, including atypical immunophenotypes, severe/multilineage cytopenia, and lower STAT3 burden. Associations with long-standing autoimmunity, immunodeficiency, BMF, or CCUS/MN, which might result in an impairment of the LGL proliferative potential, could explain such characteristics. Altogether, the clonal LGL expansion in these cases might be sort of maladaptive compensation as an attempt to counterbalance an inefficient/impaired immune system. Unlike TCUS, the need for therapy and the worse prognosis of these pts should prompt referral to centers of excellence for thorough examination, follow up, and inclusion in trials. We propose this nosological subtype of the disease to be included into the newest classifications.