Utility of PET/CT Imaging in Predicting Outcomes of Patients with Lymphoid Malignancy-Associated Hemophagocytic Lymphohistiocytosis: A Retrospective Analysis from a Single Tertiary Center

Introduction: Hemophagocytic Lymphohistiocytosis (HLH) is an inflammatory syndrome that occurs across a spectrum of clinical situations, including infection, autoimmune disorders, and malignancy. Malignancy-associated HLH (MA-HLH) in patients with lymphoid malignancies poses a higher mortality risk due to overlapping clinical and laboratory features of both conditions. While interval FDG PET/CT imaging is an established tool for evaluating lymphoid malignancies, assessing MA-HLH with this technique is challenging due to similar pathophysiology. We investigated the outcomes of MA-HLH patients with lymphoid malignancies in association with PET/CT scan results to assess the role of imaging in the management of these overlapping diseases. Methods: We conducted a retrospective study involving patients at MD Anderson Cancer Center from January 2018 to May 2024. Patients with lymphoid malignancy and MA-HLH were identified, and demographics, clinical features, and biomarker profiles were collected at timepoints around the time of HLH presentation. PET/CT imaging data was gathered within a 60-day window of MA-HLH, focusing on spleen involvement, bone marrow involvement, and Deauville Lymphoma 5-Point Scores. Laboratory data included cytokine panels, complete blood counts, and relevant biomarkers. Both imaging and laboratory values were synchronized to reflect the closest temporal relationship to MA-HLH. Descriptive and correlative analysis was conducted on demographic and laboratory data, and Kaplan-Meier survival analysis was utilized to illustrate outcomes. Additionally, OHI and EASIX scores were calculated to evaluate potential relationships of HLH presentation with imaging results. Results: Out of103 patients with MA-HLH with lymphoma, 57 patients with baseline scans occurring within 60 days prior to HLH presentation were identified. The median age of this cohort was 62 years, predominantly presenting with Non-Hodgkin Lymphomas (87.7%), and the majority were White or Caucasian (70.2%) and Male (57.9%). Forty-nine (86%) patients were PET positive, and 8 (14%) patients were PET negative. Ferritin levels did not differ significantly between the groups, whereas PET positive patients exhibited significantly higher Interleukin 2 receptor (IL2sr) levels compared to PET negative patients (p = 0.00351). PET/CT indicated splenic involvement in 54.4% of patients and bone marrow involvement in 63.2% of patients. Kaplan-Meier analysis showed that there was no significant difference in survival probability between the two groups (p = 0.38). Utilizing the OHI index (Lorenz et al., Blood) as a measure of HLH severity, survival curves showed that OHI positive patients had a significantly lower probability of 1-year survival compared to OHI negative patients (p = 0.0315), and no difference in probability between PET positive and PET negative patients who were OHI negative (p = 0.583). Among 25 patients with synchronized cytokine panels and labs, a correlation matrix was used to cluster biomarkers and patients based on similarity. PET positive (n=4) and PET negative (n=21) patients did not exhibit distinct biomarker profiles. Univariate analysis did not reveal any significant differences between groups. 26 patients had baseline and post-therapy follow-up PET/CT imaging. Survival analysis showed significantly higher survival probability (p=0.0083) between patients who responded to therapy, than patients who progressed or were refractory to treatment. Comparative analysis of baseline and post-treatment Ferritin and IL2sr levels did not show significant differences between groups. Among PET response patients (n=10), 4 patients had resolution of HLH, and 6 patients responded to HLH treatment, with significant reduction in Ferritin and IL2sr levels. Conclusions: Baseline PET/CT imaging lacks clear prognostic value for HLH patients, particularly in the context of lymphoid malignancies. The absence of PET-avid malignancy does not guarantee better survival, highlighting potential diagnostic challenges in MA-HLH cases. While follow-up imaging response may indicate better outcomes, developing alternative diagnostic and monitoring methods for HLH, distinct from those used for lymphoid malignancies, is essential.