Analysis of different biological factors in patients affected by peripheral T-cell lymphomas not otherwise specified: GATA-3 expression is associated to refractory disease and poor outcome

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 studies 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. Aims: Because GEP studies are not feasible in routine clinical practice, we investigated whether expression changes of those proteins could be evaluated by immunohistochemistry (ICH) and used to predict prognosis Methods: We collected paraffin tissues from 47 consecutive patients (pts) with a diagnosis of PTCL-NOS treated at different Italian Institutions, and 38 were available for analysis. Histology was centrally reviewed. Sections were analyzed for Ki-67, GATA3, T-bet expression by IHC. Results were expressed as mean percentages of positive tumor cells. Cases were regarded as immunoreactive for GATA-3 and T-bet if at least 27% and 25% of neoplastic cells exhibited positive staining, respectively. In case of GATA-3, we performed a quantitative analysis [from score 0 (<1%) to score 4 (>80%)] combined with staining intensity [score 1 (weak) to score 3 (strong)] and we defined high score for a summary value of 6-7. Median age was 57 years (range,18-79 years); 13 (38%) pts were charac- terized by IPI>2; 29 pts (76%) were candidated to transplantation whereas 9 (24%) were not due to age >65 years (n=8) or limited stage/IPI (n=1). All the pts received an anthracycline-based induction chemotherapy followed by autoSCT in 9 patients (7 in first remission); 16 pts (42%) underwent alloSCT in first remis- sion (n=3) or at relapse (n=13). The median follow-up of alive pts was 33 months. Results: The mean value of Ki67 expression was 60% (range, 10%>95%). Only 5 of 38 (13%) pts were immuno-reactive for T-bet whereas 17 of 38 (45%) were positive for GATA-3. Only two (5%) pts were characterized by double expression of GATA-3 and T-bet. 5 pts (31%) had a high GATA3 score that was associated with a median PFS of only 6 months. We did not observe dif- ferences baseline clinical characteristics between pts with positive (n=17) and negative (n=21) immunostaining for GATA-3. Pts immunoreactive for GATA3 were characterized by poor response to anthracycline therapy: 10 of 17 PD (58%) as compared to 4 of 21 (19%) in the negative cohort (p=0.01). Cases with positive GATA3 expression were significantly associated with a reduced 5-year PFS as compared to those with no expression [PFS: 6% (95%CI:0%>22%) versus 39% (95%CI:18%>59%), (p=0,03); OS: 38% (95%CI:13%>63%) versus 58% (95%CI:30%>78%),(p=ns), respectively]. By multivariable analysis, GATA-3 and Ki67 retained prognostic value on PFS whereas both GATA-3 and IPI influenced significantly the OS. Summary/Conclusions: Our analysis identifies GATA3 ICH expression as a strong prognostic and predictive biomarker among PTCL-NOS. Pts with positive GATA3 expression values were characterized by chemorefractory disease and poorer outcome even with transplantation strategies. Validation of this biomark- er in a larger series of patients is ongoing.