GATA-3 identifies a distinct subset of T-cell prolymphocytic leukemia (T-PLL) and is associated with CCR4 expression

Abstract Background: T-PLL is a rare mature T-cell malignancy. Despite improved understanding of disease pathogenesis, outcomes remain poor. The transcription factor GATA-3 is a proto-oncogene in other mature, and chemorefractory, T-cell lymphomas. Therefore, we explored its involvement in T-PLL. Methods: We retrospectively evaluated T-PLL patients diagnosed at the University of Michigan, Henry Ford Hospital and the University of Illinois between 2007 and 2023 using TPLL-ISG criteria. Tissue was stained for GATA-3 and CCR4, based on the distribution of the positive tumor cells for each marker in all the cases; the positive cases were those in which 30% or more of the tumor cells were positive. Survival was estimated using the Kaplan-Meier method. Relationships were examined by G-test or Mann-Whitney U test where appropriate. Statistical analyses were performed with JMP 17 software (SAS, Cary, NC). Results: 25 patients were evaluated with a median follow-up of 29 months (range: 4-270). GATA-3 was intensely and uniformly expressed in 44% of patients. GATA-3 positive patients were older than GATA-3 negative patients at time of diagnosis (65.6 years vs. 54.0 years, p=0.002). On presentation, GATA-3 positive patients were more likely to present with a moderate or severe anemia, as defined by Hgb <10 g/dL (45% vs. 9%, p=0.037). They were also more likely to present with elevated LDH (91% vs. 50%, p=0.026) and with Eastern Cooperative Oncology Group performance status greater than 0 (86% vs. 21%, p=0.004). As CCR4 is a GATA-3 target gene in other mature T-cell lymphomas and therapeutically targetable, we examined its expression by immunohistochemistry. Forty percent of patients expressed CCR4 and this was associated with GATA-3 expression (64% of GATA-3+ cases expressed CCR4 vs. 21% of GATA-3- cases expressed CCR4, p=0.031). While 47% of GATA-3 positive patients had a complex karyotype (as defined by greater than 3 chromosomal abnormalities), none of the GATA-3 negative patients had a complex karyotype (p=0.02). None of the GATA-3 positive patients were CD4- CD8+, whereas 46% of GATA-3 negative patients were CD4-CD8+ (p = 0.017). The frequencies of CD4+ CD8+ and CD4+ CD8- expression did not differ significantly between the two groups (p = 0.9 and p = 0.059, respectively). Overall response rates to frontline treatment did not differ by GATA-3 status (63% vs. 64%, p=0.973). GATA-3 positive patients were less likely to undergo allogeneic transplant (20% vs. 69%, p=0.016). Median progression free survival after initiation of frontline therapy (20 months vs. 19 months, p=0.985 from log-rank test) was similar. Median overall survival was 27 months in the GATA-3 positive group and 35 months in the GATA-3 negative group but this was not significantly different (p=0.313 from log-rank test). Discussion: GATA-3 expression is associated with distinct clinicopathologic features in T-PLL. Almost half of the patients within our T-PLL cohort expressed GATA-3 and this group presented with older age at diagnosis, increased frequency of anemia, elevated LDH levels and worse performance status. These features suggest a more aggressive disease phenotype in GATA-3 positive patients and is consistent with GATA-3's role as a proto-oncogene in other mature T-cell lymphomas that are similarly refractory to cytotoxic chemotherapies. The correlation between GATA-3 and CCR4 expression in our cohort is notable, as the CCR4 specific monoclonal antibody mogamulizumab is approved for other CCR4-expressing T-cell lymphomas, including those with peripheral blood involvement. The cytogenetic landscape differed markedly by GATA-3 status: GATA-3 positive patients exhibited more frequent complex karyotypes and had universal aberration of chromosomes 11 and 14. Immunophenotypically, GATA-3 positive cases were uniformly CD4+ and CD8-. Despite differences in both baseline features and cytogenetics, GATA-3 expression was not associated with significantly worse response to treatment or survival, despite the lower rate of allogeneic stem cell transplantation. While our findings are limited by the small sample size, they underscore the importance of biologic stratification in T-PLL. Further studies will be required to determine the extent to which GATA-3 is an oncogenic driver and relevant biomarker in T-PLL. Nonetheless, future studies investigating mogamulizumab in T-PLL are seemingly warranted.