GATA-3 Expression in Peripheral T-Cell Lymphomas (PTCL): Identification of a Cut-Off and Prognostic Value in PTCL-NOS Versus Others Hystotypes

Background: Peripheral T-cell lymphomas (PTCL) have an aggressive clinical course with a poor 5-year overall survival with conventional therapy. Autologous stem cell transplantation (autoSCT) and allogeneic stem cell transplantation (alloSCT) can improve long-term disease control in first and second remission, respectively. Prognostic factors are not able to discriminate patients with chemorefractory disease. Preliminary evidence from gene expression profiling (GEP) and immunoistochemical study have suggested that the majority of PTCL-not otherwise specified (PTCL-NOS) can be subdivided in two different groups based on GATA3 and Tbet (transcription regulators of T-helper 2 and T-helper 1 lymphocytes) expression with a poorer prognosis in the former group. Because GEP studies are not feasible in routine clinical practice, we investigated whether expression changes of those proteins could be evaluated by immunohistochemistry (IHC) and used to predict prognosis. Material and Methods: We collected paraffin tissues from 63 consecutive patients (pts) with a diagnosis of PTCL [subtypes: PTCL-NOS (n=32), ALK-negative anaplastic large cell lymphomas (n=15, ALCL ALK-negative), angioimmunoblastic (n=16, AITL)] treated at different Italian Institutions. Sections were analyzed for Ki-67, GATA3, Tbet and CCR4 expression by IHC. Results were expressed as percentages of positive tumor cells. Histology was centrally reviewed. Median age was 58 years (range, 18-76 years); 20 of 63 (32%) pts were characterized by intermediate-high/high IPI; 47 of 63 (74%) pts were candidated to transplantation whereas 16 (25%) were not due to age ≥65 years (n=14) or limited stage/IPI 0 (n=2). Fifty-nine pts (93%) received anthracycline-based induction chemotherapy. Twenty of 47 (43%) pts underwent autoSCT in first (n=11) or subsequent remissions; 23 of 47 (49%) underwent alloSCT in first remission (n=3) or at relapse (n=20). The median follow-up of alive pts was 30 months (range, 8-250). Results: Expression of GATA3 was highly variable, but was significantly higher on average in PTCL-NOS [34% positive tumor cells (range, 1-99%)] than in other subtypes [11% (range,1-97%) in ALK-negative ALCL (p=0.027); 12% (range, 1-82) in AITL (p=0.0025)]; The mean value of Ki67 expression was higher in ALK-negative ALCL [87% (range, 70-95%)] as compared to other subtypes [46% (range,15-90%) in PTCL-NOS (p<0.0001)]; 42% (range, 15-70%) in AITL (p< 0.0001)]; Tbet and CCR4 expression was not significantly different among the subtypes. In PTCL-NOS (n=32), ROC curve analysis identified a cut-off of 27% for GATA3 with 16 pts showing a GATA3 expression higher than the cut-off value. While no significant difference in baseline clinical characteristics was observed among the two groups, pts with GATA3 ≥27% showed a significantly lower CR rate following induction [19% versus 62% (p=0.02)]. Cases with high GATA3 expression were significantly associated with a reduced 5-year PFS and OS as compared to those with low expression [PFS: 6% (95%CI:1%-24%) versus 49% (95%CI:22%-71%), (p=0,004); OS: 39% (95%CI:13%-65%) versus 72% (95%CI:35%-90%) (p=0,04) respectively]. In multivariate analysis including age, IPI score ≥2 and sex, high GATA3 expression retained a strong prognostic value in terms of PFS (p<0.01) and OS (p=0.04). In others hystotypes, high GATA3 expression did not predict the outcome. Conclusions: Our analysis identifies GATA3 ICH expression as a strong prognostic and predictive biomarker among PTCL-NOS. Pts with high GATA3 expression values were characterized by chemorefractory disease and poorer outcome even with transplantation strategies. Validation of this biomarker in a larger series of patients is ongoing.