Clinical Impact of Serum Ferritin Levels and EBV-Positivity in Nodal T-Cell Lymphomas
Authors: Nyalakonda Suraj , Williams Madeline , Fouladi Roxanna , Altieri Adrian , Dimino Michael , Gesiotto Quinto John , Masel Rebecca , Bhatti Safiyyah , Alpdogan Onder , Gong Jerald , Khoo Alan S , Porcu Pierluigi 
Published: December 2024

Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), Angioimmunoblastic T-cell Lymphoma (AITL) and Anaplastic Large Cell Lymphoma (ALCL), ALK-negative are common nodal T-cell lymphomas (TCL). Prognosis is dismal, with high rates (20-25%) of primary progression, 3-year progression-free survival (PFS) of &lt;30%, and median survival at first relapse &lt;6 months (Ellin et al. Blood 2014). The prognostic impact of a biomarker of hemophagocytic lymphohistiocytosis (HLH) in TCL, ferritin, is being explored (Yoh et al. CLML 2014). Moreover, EBV-positivity is associated with worse outcomes (Haverkos et al. Int J Cancer 2016). The goal of this study was to gain initial insight into the relationship between ferritin levels, EBV-positivity, and outcomes in patients with nodal TCL.
Methods
We performed a retrospective study of nodal TCL cases seen at Jefferson Health between 2017 and 2022. Inclusion criteria: (1) pathologically confirmed diagnosis of nodal TCL subtype between Jan 1, 2017 and Dec 31, 2022; (2) age &gt;18 years; (3) treated at Jefferson Health; 4) availability of clinical data to assess response and survival. Using EPIC's Slicer Dicer, we searched Jefferson Health's EMR to identify patients with ICD-10 codes corresponding to nodal TCL diagnoses entered into their records between Jan 1, 2017 and Dec 31, 2022. Inclusion criteria were verified manually. Data elements recorded: demographic and clinical characteristics; serum ferritin (sFe) levels closest to date of treatment initiation; and EBV status (positive = any EBER-ISH positive cell). HLH was defined as: 1) clinical documentation in EMR or sFe &gt;1000 ng/mL and soluble IL-2 receptor &gt;3900 U/ml (Zoref-Lorenz et al Blood. 2022). EFS and OS were defined as the time between date of treatment initiation and event or date of death/date of last contact, respectively. Event was defined as: (1) radiographic, histopathological, or clinical evidence of progression; (2) initiation of a new line of therapy; or (3) death. Kaplan Meier curves and median survival lengths were generated using the ggsurvfit package in R and compared using the log-rank test. Relationships between EBV status and sFe within the cohort were expressed by odds ratios and chi-squared analyses.
Results
We identified 76 patients who matched inclusion criteria. Of these, 10 were excluded due to inadequate data. 66 patients were included in the final cohort. Median age was 65. Of the 66 eligible patients, 69.7% (46) were &gt;60 years old, 62.1% (41) self-identified as White, 25.7% (17) as Black, 6.1% (4) as Hispanic, and 6.1% (4) were of unknown race; 47% (31) had PTCL-NOS; 27.2% (18) had AITL; 13.6% (9) had ALCL, ALK-positive; and 12.1% (8) had ALCL, ALK-negative. Eighty-six percent (57) of patients received curative therapy and 13.6% (9) received palliative therapy. Overall, EBV status was evaluable in 87.8% (58) of patients (EBER-ISH not done in 12). Of them, 27.6% (16) were EBV-positive and 72.4% (42) were EBV-negative. Of 18 AITL patients tested: 66.7% (12) were EBV-positive and 33.3% (6) were EBV-negative. Of 28 PTCL-NOS tested, 14.3% (4) were EBV-positive and 85.7% (24) were EBV-negative. None of the 17 ALCL tested were EBV-positive. EBV-positive status was associated with shorter EFS and OS in PTCL-NOS but not in AITL. Of the whole cohort (66), 69.7% (46) of patients had sFE levels tested either pre-treatment or during treatment. Of those, 65.2% (30) had an elevated sFE and 34.8% (16) did not. In the sFE-evaluable subset (46), sFe &gt;400, sFe &gt;1.5xULN, and sFe &gt;5000 ng/ml were associated with shorter EFS. When analyzed by TCL subtype, increased sFe levels were associated with lower EFS only in patients with PTCL-NOS. There was no association between EBV-positivity and ferritin levels. HLH was diagnosed in 5 cases (4 PTCL-NOS and 1 ALCL, ALK-negative). There was no association between diagnosis of HLH and EBV-positivity.
Conclusion
In this study we identified elevated sFe as a highly prevalent laboratory abnormality in nodal TCLs and a candidate predictive biomarker of EFS in PTCL-NOS. We confirm previous data (Haverkos et al. Int J Cancer. 2017) showing that ~ 30% of nodal TCL are EBV-positive and that EBV-positive status has a negative impact on EFS and OS in PTCL-NOS. The lack of association between ALCL and EBV-positivity suggests a distinct tumor immune environment in this subtype of nodal TCL. Our results need to be confirmed due to the inherent selection bias of this study.