T-Cell Lymphoma Associated Hemophagocytic Lymphohistiocytosis Has Worse Survival When Compared to T-Cell Lymphoma: A Retrospective Analysis from a Single Tertiary Center
Authors: Gonugunta Amrit S. , Prakash Rishab , Nair Ranjit , Al Zaki Ajlan , Ahmed Sairah , Nze Chijioke , Chihara Dai , Hagemeister Frederick , Lee Hun Ju , Westin Jason R. , Patel Krina K. , Fayad Luis E. , Malpica Luis , Rodriguez Maria Alma , Wang Michael , Jain Preetesh , Strati Paolo , Neelapu Sattva S. , Flowers Christopher R. , Iyer Swaminathan P 
Published: December 2024

Background: T- Cell Lymphoma (TCL) is a rare malignancy that may present with a hyperinflammatory state that resembles hemophagocytic lymphohistiocytosis (HLH), a disease characterized by hyperactive macrophages and T-cells. Patients (Pts) with TCL are known to develop lymphoma-associated HLH (LA-HLH), making distinguishing the two challenging. Pts with LA-HLH also tend to have worse prognoses, making identification crucial. While both diseases are characterized by hyperinflammation, differences between cytokines and other laboratory data may exist. Differences may be implemented into scoring systems, such as the endothelial activation and stress index (EASIX) or the optimized HLH inflammatory (OHI) index to further distinguish the two groups.
Methodology: This single-center retrospective study included pts with TCL or LA-HLH treated at MD Anderson Cancer Center. Cytokine data was collected at various time points throughout treatment. Patients in the TCL cohort did not develop LA-HLH at any point; patients with LA-HLH had cytokine data collected following their diagnosis of LA-HLH. Analyses for these laboratory values of interest along with EASIX and OHI scoring systems were conducted. The EASIX score was calculated by (LDH × creatinine/thrombocytes), and patients were determined to be OHI positive if they had CD25 &gt;3900 U/mL and ferritin &gt;1000 ng/mL. Kaplan-Meier curves were used to compare median survival times between the patient cohorts with a significance threshold p-value of 0.05.
Results: We evaluated61 pts with TCL and 103 pts with LA-HLH. Pts with TCL were predominantly white (74%) and male (66%); pts with LA-HLH were also predominantly white (66%) and male (55%). At the time of diagnosis, 29% of pts with TCL had marrow involvement and 61% had extranodal disease; of the pts with HLH, 33% had marrow involvement and 73% had extranodal disease. Forty nine percent of pts with LA-HLH had the T-Cell Subtype. Of these pts, 29% were classified as PTCL, 16% were MF or Cutaneous, 14% were anaplastic large cell lymphoma (ALCL), 14% were cytotoxic NK/TCL (NKTCL), and 8% were AITL. Of pts with TCL 36% were classified as PTCL, 21% had AITL, 11% had MF or cutaneous, 8% had ALCL, and 5% had NKTCL.
Pts with LA-HLH, when compared to TCL, had lower WBC, lower ANC, lower ALC, higher ALT, lower Hb, and lower PLT (P &lt;0.005). Pts with LA-HLH, when compared to TCL had higher LDH, and Beta-2 Microglobulin, and Ferritin (P = 0.000). Cytokine values for Pts with LA-HLH demonstrated significantly elevated IL-10 (P &lt;0.002), IL2R CD25 (P =0.000), IL-13 (P &lt;0.049), Interferon-Y (P &lt; 0.028), Tumor Necrosis Factor (P = 0.005) and IL-6 (P = 0.005) when compared to TCL. Principle component analysis demonstrated distinct clustering in Pts with TCL when compared to LA-HLH despite an overlap. Correlation Scatter plots in Pts with TCL correlate IL6 and IL2 Soluble Receptor, IL-6 and IL-10, and IL6 and Tumor Necrosis Factor, whereas Pts with LA-HLH correlate TNF and IL-10. Aggregated heatmap showed prominently elevated IL2 in both LA-HLH and TCL, with IL2 soluble receptor much higher in LA-HLH than in TCL. Pts with HLH also demonstrated prominently elevated LDH and decreased platelet; whereas Pts with TCL had normal LDH and normal/increased platelets. Pts with LA-HLH had elevated EASIX scores when compared to Pts with TCL (P = 0.001); Pts with LA-HLH had a greater proportion of Pts with OHI + (P = 0.000). Pts with positive OHI status also had higher quartiles of EASIX scores. Pts with LA-HLH had worse median survival when compared to TCL (5.98 months vs. 149.93, P&lt; 0.000). Pts with TCL LA-HLH had lower median survival compared to TCL (4.27 months vs. 149.93, P &lt; 0.000). 60-day mortality was significantly higher in pts with T-Cell LA-HLH when compared to TCL (31.31% vs. 1.85%, P =0.00)
Conclusions: LA-HLH and T-Cell LA-HLH harbor worse outcomes when compared to TCL. Significant cytokine differences exist between LA-HLH and TCL, which may help distinguish the two. Furthermore, scoring differences, such as OHI and EASIX, are pertinent and should be considered when managing these pts. Additional analyses, including treatment-related outcomes, are ongoing and will be presented at ASH 2024.