Abstract 7158: Molecular residual disease detection via CAPP-Seq in PTCL patients undergoing stem cell transplantation

Abstract Introduction: Despite advances in therapy, improved biomarkers are needed to guide stem cell transplantation (SCT) in peripheral T-cell lymphoma (PTCL). We hypothesized that molecular residual disease (MRD) detection in pre-SCT apheresis T-cells via Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) could predict relapse post-SCT. Methods: Eligible patients had diagnostic FFPE tissue and underwent either autogenic or allogenic SCT from 2005-2024. Autologous stem cells (ASC) harvested at the end of induction chemotherapy were sorted into T-, myeloid, NK/B-cell populations. Whole exome sequencing (WES) was performed on DNA isolated from FFPE, with NK/B-cells as the germline control to identify patient-specific single nucleotide variants (SNVs) and design hybrid-capture panels. A PTCL focused canonical gene panel was designed to capture emerging pathogenic SNVs. The ASC fractions and cell-free DNA (cfDNA) samples were interrogated with both panels as a composite approach to quantify MRD. Results: 20 AITL and 2 PTCL-NOS cases were included. Median age at diagnosis was 61.3y (IQR 55.4-67.5). In the frontline setting, 6 (27.3%) patients received CHOP, 3 (13.6%) CHOP-azacitidine, 9 (40.9%) CHOEP, 3 (13.6%) BV-CHP, and 1 (4.5%) azacitidine-romidepsin. A median of 25 (IQR 17-37.5) SNVs were recovered per patient. Across all cases RHOA was most frequently mutated (86.5%), followed by IDH2 (54.5%) and PLCG1 (27.3%), consistent with the known mutation profile of PTCL. MRD+ was defined as the detection of tumor-specific SNVs in the ASC T-cell fraction (T-ASC) as previously described (Newman et al, Nat Biotechnol 2016). When limited to canonical PTCL genes, 6/22 patients were T-ASC MRD+. In contrast, when using all SNVs, 14/22 were T-ASC MRD+, demonstrating the benefit of tracking multiple patient-specific SNVs. Shared mutations between hematopoietic lineages, including variants associated with clonal hematopoiesis (CH), are frequently observed in PTCL. Similarly, we found multiple mutations were shared between cell compartments, which limited MRD specificity. To account for this and the effect of CH, SNVs detected in the myeloid and B-cell populations were removed. This significantly improved MRD detection, with 9/10 (90%) T-ASC MRD+ patients relapsing post-SCT, compared to 3/12 (25%) T-ASC MRD- patients (specificity 88.9%, sensitivity 75%, PPV 90%). T-ASC MRD- was associated with superior PFS (p=0.007, HR 5.1, 95% CI 1.4-19.2). Higher levels of T-ASC MRD tumor burden were also associated with inferior PFS (p=0.006, HR 1.4, 95% CI 1.1-1.7). MRD analysis in longitudinal cfDNA samples was performed in a subset of cases and correlated with clinical disease status. Conclusion: Our PTCL-CAPP-Seq approach enables highly sensitive MRD detection, with T-ASC MRD+ predicting high relapse risk post-SCT. In addition, MRD monitoring in cfDNA samples can help facilitate early treatment decisions. Citation Format: Chandan Sanghera, Josie Ford, Ruwan Gunaratne, Kusha Chopra, Anna B. Rider, Aliyah R. Sohani, Sean M. McCabe, Ronald A. Nemec, Yi-Bin Chen, Steven McAfee, Ephraim Hochberg, Jeffrey A. Barnes, Caroline MacVicar, Eric D. Jacobsen, Mwanasha H. Merrill, Michael S. Khodadoust, David Kurtz, Salvia Jain. Molecular residual disease detection via CAPP-Seq in PTCL patients undergoing stem cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7158.