Steven Wang

All Publications

• Roadmap for developing MRD as an early endpoint for drug approval in lymphoma. Seminars in hematology Goldstein, J. S., Wang, S. X., Chamuleau, M. E., Alizadeh, A. A. 2026

  Abstract

  Advances in lymphoma therapy have extended survival, but exposed limitations of traditional trial endpoints efficacy assessments. We propose two MRD-informed endpoints to accelerate drug development and improve regulatory decision-making: modified PFS (mPFS) and undetectable MRD (uMRD) rate. mPFS is a specific variant of event free survival (EFS) defined as the time from study enrollment until positive end-of-treatment MRD, clinical progression, or death and has potential as a validated surrogate endpoint for traditional approval. uMRD rate at a prespecified timepoint measures depth of response and can be useful in early phase and later-line studies for accelerated approval. Here, we outline the potential that can be slow, reliant on inconsistent imaging studies, and insensitive to molecular disease burden. Novel surrogate trial endpoints can expand and accelerate innovative therapies reaching patients. Advances in technology have led to ultrasensitive methods for detection of measurable residual disease (MRD) in peripheral blood, including circulating tumor DNA (ctDNA) and immunoglobulin clonotype sequencing. MRD methods have been studied with clear biologic rationale and prognostic ability across lymphomas including large B-cell, mantle cell, Hodgkin, and follicular lymphoma. Incorporating MRD into trial endpoints can lead to shorter trial times and perhaps more accurate treatment endpoints incorporating MRD, detail the current MRD data in lymphomas, and provide a practical roadmap towards regulatory use of MRD-based surrogate endpoints to speed drug development.

  View details for DOI 10.1053/j.seminhematol.2026.03.007

  View details for PubMedID 41982010

• Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wang, S., Nijland, M., Strobbe, L., Oosterveld, M., Boersma, R., Koene, H., Klerk, C., de Jongh, E., Koster, A., Pruijt, H., van der Poel, M., van Werkhoven, E., Zanders, H., Dinmohamed, A., Pegtel, M., Meek, S., Stowell, S. L., Warinske, H., Alizadeh, A. A., Kurtz, D. M., Chamuleau, M. E. 2025: JCO2501712

  Abstract

  End-of-treatment (EOT) response evaluation by positron emission tomography (PET) remains suboptimal in patients with large B-cell lymphoma (LBCL), because of its limited positive predictive value (PPV). Circulating tumor DNA (ctDNA)-based measurable residual disease (MRD) detection offers a minimally invasive approach and may improve prognostication. We prospectively evaluated EOT MRD using phased variant enrichment and detection sequencing (PhasED-Seq) in patients with first-line LBCL.Patients were enrolled in the HOVON-902 prospective cohort and received curative-intent first-line treatment. Phased variants (PVs) were identified and tracked using tumor biopsies or pretreatment plasma. The prognostic significance of EOT ctDNA-MRD status in progression-free survival (PFS) and overall survival (OS) was compared with that of the International Prognostic Index (IPI) and EOT PET-computed tomography (CT).PV identification was successful in 134 of 136 (99%) using either tissue or plasma. At EOT, 83% of patients were MRD-negative and 17% of patients were MRD-positive. MRD positivity was strongly associated with inferior outcomes: the 3-year PFS was 17% in MRD-positive versus 85% in MRD-negative patients (hazard ratio [HR], 9.8 [95% CI, 5.1 to 19]; P = 9.63 × 10-12), and the OS was 43% versus 92%, respectively (HR, 7.7 [95% CI, 3.4 to 17.4]; P = 1.27 × 10-6). In multivariate analysis, MRD was an independent prognostic factor when controlling for IPI and EOT PET-CT. MRD positivity had a higher PPV for 2-year PFS than positive PET (68% v 56%, P ≤ .001), whereas negative predictive value was similar between negative MRD and PET (89% v 88%, P = .71). MRD positivity was associated with a significantly higher relapse risk within both complete metabolic response (CMR) and non-CMR subgroups.This study validates ultrasensitive ctDNA-MRD detection using PhasED-Seq in a uniformly treated, prospective real-world LBCL cohort. These findings support further evaluation of MRD integration into clinical response assessment.

  View details for DOI 10.1200/JCO-25-01712

  View details for PubMedID 41385760

• Spatial anatomical genomic heterogeneity and aberrant somatic hypermutation define clonal evolution pathways that predict treatment resistance in aggressive B-cell lymphomas Goldstein, J., Wang, S., Tessoulin, B., Liu, C., Scherer, F., Le Gouill, S., Chamuleau, M., Nijland, M., Diehn, M., Kurtz, D., Alizadeh, A. ELSEVIER. 2025: 354-355

  View details for DOI 10.1182/blood-2025-354

  View details for Web of Science ID 001659571100005

• Longitudinal circulating tumor DNA dynamics during & after first-line therapy in a national cohort of large B-cell lymphomas Wang, S., Nijland, M., Bilgin, Y., Sandberg, Y., Bohmer, L., Visser, O., De Graauw, N., Ludwig, I., Van Zaanen, H., Tromp, Y., Mous, R., Koster, A., De Jongh, E., Van Werkhoven, E., Thuss, N., Dinmohamed, A., Pegtel, D., Garnett, A., Gregg, J., Alizadeh, A., Kurtz, D., Chamuleau, M. ELSEVIER. 2025: 474-475

  View details for DOI 10.1182/blood-2025-474

  View details for Web of Science ID 001659530100025

• Prospective validation of end of treatment ctDNA-MRD by PhasED-Seq in DLBCL patients from a national trial Wang, S., Nijland, M., Strobbe, L., Oosterveld, M., Boersma, R., Koene, H. R., Klerk, C., De Jongh, E., Koster, A., Pruijt, H., Van Der Poel, M., Van Werkhoven, E. D., Dinmohamed, A., Close, S., Brown, K., Meek, S., Alizadeh, A. A., Kurtz, D. M., Chamuleau, M. LIPPINCOTT WILLIAMS & WILKINS. 2025

  View details for DOI 10.1200/JCO.2025.43.16_suppl.7000

  View details for Web of Science ID 001707401700017

• Immunosuppressed Tumor Microenvironment in <i>MYC</i>-Rearranged High-Grade B-Cell Lymphomas Compared to Diffuse Large B-Cell Lymphomas, Not Otherwise Specified De Jonge, A., Noordenbos, T., De Groen, R. A. L., De Groot, F. A., De Haan-Treurniet, L. M., Jansen, P. M., Fu, L., de Heer, K., Klerk, C., Sandberg, Y., Fijnheer, R., Mutsaers, P., Beeker, A., Bohmer, L. H., Wang, S., Strobbe, L., Boersma, R., Oosterveld, M., Koene, H. R., De Miranda, N., van den Berg, A., Nijland, M., Roemer, M. G. M., Mutis, T., Chamuleau, M. E. D., Vermaat, J. S. P. ELSEVIER. 2024: 4380-4381

  View details for DOI 10.1182/blood-2024-205968

  View details for Web of Science ID 001409330600015