PF479 CLINICAL AND BIOLOGICAL PREDICTORS OF OUTCOME IN LARGE GRANULAR LYMPHOCYTE LEUKEMIA: A SINGLE CENTER EXPERIENCE OF 205 PATIENTS
Authors: Barila’ G. , Teramo A. , Calabretto G. , Vicenzetto C. , Gasparini V.R. , Pavan L. , Leoncin M. , Facco M. , Semenzato G. , Zambello R. 
Published: December 2023

Background:

Large Granular Lymphocyte Leukemia (LGLL) is a rare chronic lymphoproliferative disorder characterized by the expansion of LGLs. Among LGLL, WHO 2016 classification recognizes a CD3+ T‐LGLL and a CD3‐ Chronic Lymphoproliferative disorder of Natural Killer cells (CLPD‐NK), accounting for 85% and 15% of cases respectively. Moreover, according to the T cell receptor rearrangement, the Tαβ and Tγδ subsets can be identified. From a clinical point of view, LGLL is a heterogeneous disease with some patients being asymptomatic and other developing cytopenias, mostly neutropenia. The aetiology is still unknown but a constitutive activation of JAK/STAT pathway is involved in LGL proliferation, supported by the evidence of somatic STAT3 and STAT5b mutations in approximately 40% of patients. We previously demonstrated that in T‐LGLL STAT3 mutations are associated to symptomatic disease.

Aims:

The aim of this study is to analyse clinical and biological features of a large cohort of LGLL patients to identify prognostic markers affecting patients’ outcome.

Methods:

From 1992 to 2018, clinical and biological data of 205 patients affected by LGLL have been collected. STAT3 exon 21 mutation analysis and STAT5b exon 16–18 mutation analysis was performed by Sanger sequencing.

Results:

In our cohort, median age at diagnosis was 58 years. By phenotype, 129/205 (62.9%) patients were affected by Tαβ LGLL, 23/205 (11.2%) by Tγδ LGLL, and 36/205 (17.6%) by CLPD‐NK. Moreover, 17 patients (8.3%) were characterized by a bi‐phenotypical variant, identified by a concomitant T/NK or Tαβ/Tγδ clone. According to CD4 and CD8 expression, Tαβ LGLL was further classified in CD4‐/CD8+ LGLL (CD8+ T‐LGLL, 84/205, 41%) and CD4+/CD8dim/neg LGLL (CD4+ T‐LGLL, 45/205, 21.9%).

Neutropenia (Absolute Neutrophil's Count, ANC<1,500/mm3) was the most relevant feature (78/205, 38%), severe neutropenia (ANC<500/mm3) being present in 20.5% of patients. Anemia (Hb<120 g/L, 27/205, 13.2%), severe anemia (Hb<90 g/L, 20/205, 9.8%) and thrombocytopenia (PLTs <100.000/mm3, 12/205, 4.8%) were less recurring. 44 patients (21.5%) were affected by concomitant autoimmune/inflammatory disease, mostly autoimmune hemolytic anemia and rheumatoid arthritis.

DNA samples of 166 and 152 patients were available for STAT3 and STAT5b mutations analysis, respectively. STAT3 mutations were detected in 47 patients (28.3%), with higher frequency in CD8+ Tαβ LGLL towards Tγδ LGLL (60% vs 25%, p = 0.0232) and CLPD‐NK (60% vs 5.8%, p < 0.0001). At variance, STAT5b mutations were found in 15 patients (9.8%), mostly in CD4+ Tαβ LGLL (12/35 cases available, 34.3%) and in 3 cases were Tγδ LGLL. Interestingly, STAT3 and STAT5b mutations were mutually exclusive in CD8+ and CD4+ Tαβ LGLL.

With a median follow up of 8 years, median overall survival (OS) of our cohort was not reached. Major features associated to reduced OS were ANC<500/mm3 (267 months vs not reached, p = 0.0297), severe anemia (144 months vs not reached, p < 0.0001), treatment requirement (214 vs not reached, p = 0.0011) and presence of STAT3 mutations (267 months vs not reached, p = 0.0113) (Figure 1, Panel A to D). No significant survival differences were found between STAT5b mutated and wild‐type patients (not reached vs 267 months, p = 0.3514).

Summary/Conclusion:

Our results confirmed the remarkable biological and clinical heterogeneity of LGLL. We identified clinical and biological features associated to reduced OS in LGLL patients and, for the first time, we demonstrated the dismal impact of STAT3 mutations in patients’ survival, suggesting that this marker should be regarded as a potential target of therapy.

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