David M Kurtz

• Professor
• Professor (Assistant) at Stanford University

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed...

Introduction Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by serial acquisition of somatic mutations in hematopoietic stem and progenitor cells which lead to their clonal expansion and differentiation arrest. Current methods for genomically profiling AML are limited by (1) the need for serial invasive bone marrow biopsie...

Introduction Current MRD detection methods for AML (multiparameter flow cytometry and single-gene assays) are limited by suboptimal sensitivity, narrow coverage for molecular monitoring and clonal resolution, and/or reliance on invasive bone marrow biopsies. To address these issues, we developed AML-CAPP-Seq, a ctDNA-based assay leveraging a custom...

Background Accurate detection of copy number alterations (CNAs) and reliable estimation of tumor fraction from liquid biopsies are crucial for effectively triaging patient samples in large clinical trials. This is particularly vital in scenarios where variant allele frequency (VAF) data is unavailable, yet an estimation of tumor fraction remains ne...

Introduction Localized cancers are increasingly treated with neoadjuvant therapies prior to resection. For operable breast cancers, this approach can aid in breast-conservation, therapeutic response assessment, and prognostication. For patients with residual disease, addition of adjuvant therapy can reduce recurrence risk and improve outcomes. Path...

Despite advances in treatments, multiple myeloma (MM) remains an incurable cancer where relapse is common. We developed a circulating tumor DNA (ctDNA) approach in order to characterize tumor genomics, monitor treatment response, and detect early relapse in MM. By sequencing 412 specimens from 64 patients with newly diagnosed or relapsed/refractory...

Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCL). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). Targeted DNA sequencing including coverage of HLA loci re...

Various clinical scenarios preclude or delay invasive stereotactic biopsies and subsequent histopathological assessment for the diagnosis of central nervous system lymphoma (CNSL), necessitating innovative minimal-invasive strategies. We designed a digital droplet PCR (ddPCR) assay for minimal-invasive identification of CNSL in clinical practice by...

Background: Circulating tumor DNA (ctDNA) is a non-invasive biomarker that can be used as a tool to detect minimal residual disease (MRD). MRD can provide important prognostic information in diffuse large B-cell lymphomas (DLBCL). Here, we present an MRD assay with an improved detection method for ctDNA, Phased Variant Enrichment and Detection Sequ...

Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disea...

Background: Neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can down-stage disease prior to surgery, monitor chemo-sensitivity, and provide key prognostic information via pathologic response that guides adjuvant treatment. Greater residual disease as assessed by the residual cancer burden (RCB) index is associated with inferior ou...

Background: ctDNA assay use for minimal residual disease (MRD) detection in early stage NSCLC has been limited by suboptimal sensitivity of first generation assays. It is unclear how improving assay limit of detection (LOD) would translate to improvements in clinical sensitivity. Here, we performed mathematical modeling of ctDNA dynamics after cura...

Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexu...

The scarcity of malignant Hodgkin and Reed–Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1–4. Here we show that the plasma representation of mutations exceeds...

Introduction: Despite advances in therapeutic options, the majority of AML patients experience relapsed or refractory disease. Standard-of-care (SOC) methods for MRD detection (multiparametric flow cytometry and single gene or structural variant molecular assays) are hampered by (1) inadequate lower limits of detection (LOD), (2) paucity of recurre...

Introduction While cell-free DNA (cfDNA) plays an increasingly defined role in aggressive lymphomas, its characteristics in indolent lymphomas are less established. Many follicular lymphoma (FL) patients experience durable remissions and late relapses ( Fig A). We therefore explored circulating tumor DNA (ctDNA) kinetics during long-term blood-base...

Introduction: The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells has hampered comprehensive genomic profiling of classic Hodgkin lymphoma (cHL) from tumor tissue. Multiple recent studies have demonstrated that plasma cfDNA profiling facilitates molecular characterization of cHL. Leveraging noninvasive genotypes and Latent Dirichlet Al...

Background : Lymphoma response criteria rely on PET/CT scans at end of therapy (EOT) to determine complete response (CR), which is necessary for cure. ~25% of patients achieve <CR by response criteria, but PET/CT scans have imperfect specificity and the positive predictive value of a single PET/CT scan at EOT is only ~50% (Kostakoglu 2021). To over...

Background: The prognostic value of MRD using ultra-sensitive ctDNA assays after 1L DLBCL immunochemotherapy was recently reported (Roschewski, ASH 2022). However, real-world evidence (RWE) for the utility of ctDNA MRD assays to predict survival outcomes after standard-of-care (SOC) 1L treatment for DLBCL remains less clear. Here, we report longitu...

Background: For patients with relapsed/refractory large B-cell lymphomas (rrLBCL), CD19-directed chimeric antigen receptor T cells (CAR19) improve survival compared to autologous hematopoietic cell transplantation (HCT). However, major toxicities of CAR19 therapy include prolonged cytopenias and associated infections. To better understand the impac...

Introduction: Circulating tumor DNA (ctDNA) has emerged as a tool to characterize tumors and track minimal residual disease (MRD) in many malignancies, including diffuse large B-cell lymphoma (DLBCL). ctDNA levels have been shown as prognostic after first-line treatment and CD19-targeted chimeric antigen receptor (CAR19) T cell therapy in DLBCL. Lo...

Background: While the prognostic value of MRD using ultrasensitive circulating tumor DNA (ctDNA) assays after first-line immunochemotherapy for DLBCL has been shown (Roschewski M, et al. Blood 2022;140[suppl 1]:785), its relevance to outcomes after second-line (2L) treatment with CD19-directed CAR T cell therapy remains unclear. The phase 3 TRANSFO...

Introduction: Despite significant progress in curing younger patients with classical Hodgkin lymphoma (cHL), older patients continue to have substantially inferior outcomes. The bimodal distribution of age at cHL diagnosis has suggested distinct underlying pathogenesis in older adults. For example, among older patients where EBV+ disease is more pr...

Background: In the absence of tumor tissue, several studies have shown the utility of plasma cell-free DNA (cfDNA) for blood based noninvasive genotyping of diverse human tumors, including aggressive lymphomas. However, it remains unclear whether these same cfDNA advantages also apply to follicular lymphoma (FL), and if they could inform noninvasiv...

Background : Current diagnostic criteria for mature B-cell tumors require a combination of histopathological, immunophenotypic, cytogenetic, and genetic evaluations on tissue biopsy specimens (Campo, Blood 2022; Alaggio, Leuk 2022). Despite this battery of techniques, substantial heterogeneity remains in specific subgroups that can be further resol...

Background: Circulating tumor DNA (ctDNA) assessment is effective in diffuse large B-cell lymphoma (DLBCL) monitoring and risk stratification, with prognostic utility throughout first-line (1L) therapy. DLBCL ctDNA assays vary in analytical sensitivity, or limit of detection (LOD), which range from parts per thousand to below 1 part per million (1...

Background Measurable residual disease (MRD) is an important predictor of survival outcomes in both newly diagnosed and relapsed/refractory multiple myeloma (MM). Currently, it is assessed by bone marrow aspirate, either using next-generation sequencing or multi-color flow cytometry. However, not only does it require an invasive procedure, it may n...

Large B-cell lymphomas (LBCLs) are a strikingly diverse set of diseases, including clinical, biological, and molecular heterogeneity. Despite a wealth of information resolving this heterogeneity in the research setting, applying molecular features routinely in the clinic remains challenging. The advent of circulating tumor DNA (ctDNA) liquid biopsi...

Background: Circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection is a promising approach for personalization of adjuvant therapy in non-small cell lung cancer (NSCLC). First generation ctDNA MRD assays that employ tumor-informed approaches to track single nucleotide variants (SNVs) have limits of detection (LOD95) of ~1E-4 and hav...

Background: Multiple myeloma (MM) is an incurable disease with a heterogenous clinical course and genomic landscape. Autologous anti-BCMA chimeric antigen receptor (CAR) T-cells are a promising new therapy, but determinants of response and resistance are not well known. Cell-free DNA (cfDNA) is a useful tool to study MM as it allows for repeated, n...

Background: Comparison of a blood or tissue sample with a matched germline control is a key step for accurate detection of somatic mutations. This is particularly important for tracking minimal residual disease (MRD), since alterations erroneously considered to be tumor derived may lead to false detection. Use of blood leukocytes as a germline cont...

Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals, suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultradeep sequencing of prediagnostic blood and tissue speci...

PURPOSE Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better st...

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the R-CHOP regimen for large B-cell lymphomas, but it is unknown if Pola can be safely incorporated into intensified regimens (eg. DA-EPOCH-R) typically utilized for the highest risk histologies. This was a single-center, open label, prospective clinica...

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simul...

Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy (R-CHOP), but a third of patients experience refractory or relapsed disease after frontline R-CHOP. Randomized studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding le...

Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. H...

To obtain a deeper understanding of poor responses to COVID-19 vaccination in patients with lymphoma, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of pati...

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragm...

Background Diffuse large B-cell lymphoma (DLBCL) is a genetically and clinically heterogeneous disease. The cell-of-origin (COO) classification subdivides DLBCL into the transcriptionally defined activated B-cell (ABC) and germinal center B-cell (GCB) subtypes. While RNA based methods are considered the gold standard to determine COO, they are rare...

Background: Patients with B-cell lymphoma have poor clinical outcomes to SARS-CoV-2 infection (COVID-19) and are also more likely to have suboptimal responses to immunization. An understanding of which lymphoma patients are at greatest risk of poor COVID-19 vaccine response and what aspects of immunity are most impaired is critical for developing s...

Background: Diffuse large B-cell lymphoma (DLBCL) subtypes have differential response to BTK inhibitors (BTKi). Ibrutinib with R-CHOP improves survival in DLBCL subsets, but toxicity is limiting. Precise characterization of BTKi-responsive tumors enhances pt selection. Acalabrutinib (acala) is a BTKi with activity in DLBCL, but the molecular correl...

Background: Mutations in chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 have been inferred as early events in follicular lymphoma (FL) by truncal status in mature tumors and persistence between diagnosis and relapse. We previously reported frequent detection of CREBBP lysine acetyltransferase (KAT) domain mutations in pre...

Introduction: Clinical outcomes for patients with central nervous system lymphoma (CNSL) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure remains challenging with existing methods. In addition, diagnosis of CNSL requires invasive neurosurgical biopsies that carry procedural risks and often cannot be pe...

Lymphomas are heterogeneous tumors with striking genetic diversity and variable outcomes even within pathologic diagnoses. Treatment response assessment relies on radiologic and nuclear scans, which cannot detect disease at the molecular level. Molecular tumor analyses require invasive tissue biopsies that cannot accurately capture spatial tumor he...

Biological heterogeneity in diffuse large B cell lymphoma (DLBCL) is partly driven by cell-of-origin subtypes and associated genomic lesions, but also by diverse cell types and cell states in the tumor microenvironment (TME). However, dissecting these cell states and their clinical relevance at scale remains challenging. Here, we implemented EcoTyp...

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarco...

7565 Background: Detection of circulating tumor DNA (ctDNA) has prognostic value in diverse tumors, including DLBCL. Despite uses for assessing molecular response to therapy, current methods using immunoglobulin or hybrid-capture sequencing have suboptimal sensitivity, particularly when disease-burden is low. This contributes to a high false negati...

8518 Background: Detection of circulating tumor DNA (ctDNA) has prognostic value in lung cancer and could facilitate minimal residual disease (MRD) driven approaches. However, the sensitivity of ctDNA detection is suboptimal due to the background error rates of existing assays. We developed a novel method leveraging multiple mutations on a single c...

Purpose: Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here,...

Background: We previously reported that approximately half of local recurrences (LR) after radiotherapy for localized NSCLC harbor mutations in KEAP1 or NFE2L2. Here we sought to explore factors associated with LR after radiotherapy in KEAP1/NFE2L2 wildtype NSCLC. Methods: We identified consecutive patients with stage IA1-IIIC NSCLC treated at our...

Early cancer detection aims to find tumors before they progress to an incurable stage. To determine the potential of circulating tumor DNA (ctDNA) for cancer detection, we developed a mathematical model of tumor evolution and ctDNA shedding to predict the size at which tumors become detectable. From 176 patients with stage I to III lung cancer, we...

In this article, we broadly review the application of cfDNA analysis to the diagnosis and management of lymphoma. We introduce the advantages of cfDNA measurement over conventional tissue biopsy and describe how cfDNA may be utilized for both genotyping and detection of minimal residual disease. First, we discuss genotyping, beginning with differen...

Tumor genotyping is not routinely performed in localized non–small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Ha...

Background: Characterization of T-cell receptor (TCR) diversity and dynamics is increasingly critical to understanding therapeutic immune responses targeting tumors. Current TCR profiling methods generally require invasive tissue biopsies that capture a single snapshot of immune activity or are limited by the sheer diversity of the circulating TCR...

Background: Follicular lymphoma (FL) is genetically characterized by translocations involving the BCL2 locus on chromosome 18q21. However, up to 70% of healthy individuals also carry detectable t(14;18)-positive cells, suggesting BCL2 translocation is critical but not sufficient for FL development. Chromatin modifying genes (CMGs) including KMT2D,...

CD19 CAR T cells have revolutionized the treatment of relapsed and refractory (R/R) large B cell lymphomas (LBCL), mediating durable complete responses in approximately 40-50% of patients. Besides a loss or decrease in CD19 expression, no studies have identified tumor specific factors driving inherent or acquired resistance to CAR T cells in LBCL....

Over the last decade, circulating tumor DNA (ctDNA) has emerged as an important biomarker across a range of cancers, including lymphomas. The potential clinical applications of ctDNA technologies are broad, including tumor mutational genotyping, detection of molecular responses and minimal residual disease, as well as early detection of relapsing d...

The tumor microenvironment (TME) plays critical roles in cancer development, tumor progression, and susceptibility to therapy. However, the phenotypic states and interaction patterns of its underlying cell types remain poorly understood. To address this challenge, we developed a new computational framework, EcoTyper, for large-scale dissection of c...

Introduction: Cell-free DNA (cfDNA) is a robust analyte for non-invasively genotyping cancer patients and useful for both detection and disease monitoring. ecent studies have revealed signals in cfDNA fragmentation patterns useful for inferring epigenetic information by analyzing chromatin accessibility patterns (Snyder et al. 2016; Ulz et al. 2017...