AQUARIUS: A Longitudinal Multi-Center Molecular Biomarker Discovery Registry for Patients With Hematologic Malignancies

Background
Despite therapeutic innovations over the past decade in hematologic malignancies, there remains a significant unmet need in understanding disease progression, identifying progression and resistance biomarkers, and accurately predicting responses to various treatments. Identifying new therapeutic targets by moving deeper into the molecular and genetic architecture of the tumor is key to overcoming resistance and tailoring interventions to the unique biological profile of each individual. For example, follicular lymphoma (FL) demonstrates heterogeneous clinical behavior ranging from not requiring therapy (active observation), with not as yet well-defined high risk features for early progression, to patients who relapse early after initial therapy (POD24) and the ongoing risk of transformation to aggressive histology. Registry studies, in particular, provide insights into tumor heterogeneity, progression patterns, and clinical behaviors, which are essential for designing effective clinical trials and developing targeted therapies. The Tempus AQUARIUS hematologic biomarker discovery registry (NCT07154823) is a non- interventional, multi-center registry study aiming to create a robust dataset of molecular and clinical data from patients with hematologic malignancies to facilitate clinician-led research using whole genome sequencing (WGS) to generate hypotheses for predictive biomarkers, identify potential resistance mechanisms, and guide therapy selection.

Methods
AQUARIUS is designed as a master protocol with multiple real world (rw) cohorts continuously added as future research questions emerge. The first cohort is on patients with FL, followed by additional cohorts in 2026. The FL cohort will encompass the following populations: newly diagnosed active observation (n: 100), newly diagnosed high risk (n: 150), relapsed/refractory high risk POD24 (n: 125), and transformed FL (n: 125), aiming to enroll 500 patients in total. Lymph node tissue or bone marrow aspirate and blood samples are collected during routine standard of care visits, with blood samples collected at all follow-up timepoints. Clinical data is collected—including demographics, medical history, treatment, and outcomes—at all timepoints, along with standard of care images. The emerging DNA WGS assay (Tempus xH) and existing RNA whole transcriptome sequencing assay (Tempus xR) will be performed at screening and progression/primary refractory disease to capture specific molecular alterations and potential genomic variants. Multimodal molecular profiling data will be generated prospectively. The following endpoints will be assessed: rw Overall Survival (OS), rw Progression Free Survival (PFS), rw Time to Next Treatment (TTNT), rw Time to Discontinuation (TTD), and changes in biomarkers over time. The study is open and actively enrolling.