Morphologic findings and mutational profiles of myelodysplastic neoplasms with normal versus abnormal karyotype

Journal of Hematopathology · 2026-02-20

1168 Clinicopathologic and Molecular Characteristics of Merkel Cell Polyomavirus Positive T-cell Lymphoproliferative Disorders

Laboratory Investigation · 2026-03-01

Abstract 692: Novel single cell and bulk NGS assays for improved assessment of MRD (measurable residual disease) and clonal dynamics in acute myeloid leukemia (AML).

Cancer Research · 2026-04-03

Abstract Background: The genomic heterogeneity of AML and high rates of relapsed/refractory (R/R) disease necessitate improved tools for detecting MRD and studying clonal evolution. Standard-of-care (SOC) MRD methods, namely multiparametric flow cytometry (MFC) or single-variant molecular assays, are limited in sensitivity, applicability across diverse AML genomes, and ability to resolve clonal dynamics. We evaluated the Tapestri single-cell multiomics AML assay (Mission Bio) and HemeSTAMP-MRD, a novel high-sensitivity bulk NGS assay, as alternative platforms for MRD detection and clonal profiling. Methods: We analyzed 72 bone marrow or peripheral blood mononuclear cell samples from 24 AML patients at diagnosis (n=18), remission (n=35), or R/R disease (n=19). Tapestri single-cell genotypic and immunophenotypic analysis was performed after CD34+/CD117+ enrichment using a 41-gene panel and 17-cell surface marker panel. HemeSTAMP-MRD, a bioinformatically optimized version of an in-house 203-gene error-corrected clinical NGS panel (Kim et al. 2022), was performed on paired whole blood samples in the CLIA-certified Stanford Molecular Pathology Laboratory. Each patient had ≥ 1 trackable diagnostic variant(s). MRD results were compared with SOC MFC. Results: 87% (21/24) of patients achieved initial clinical remission (CR1), of whom 62.5% (15/21) relapsed. MFC detected MRD in only 33% (5/15) of patients with pre-relapse CR1 samples, while Tapestri and HemeSTAMP each identified MRD in 67% (10/15), including 8 patients with positive concordance. Among MFC-negative cases (n=10/15), 4 had detectable MRD by Tapestri and/or HemeSTAMP at variant allele frequencies < 1%, including one with actionable IDH2-mutant disease who relapsed and died before receiving targeted therapy. The 3 patients who relapsed despite negative MRD by all assays either had exclusively extramedullary relapse, loss of trackable variants, or inadequate sampling prior to relapse. Among patients yet to relapse, Tapestri and HemeSTAMP-MRD detected residual variants during CR1 in 5 of 6 patients, although 4 of whom later received allogenic transplant as a confounding factor. During active disease (diagnosis or R/R timepoints), Tapestri identified a median of 4 clones per sample (range 1-9). In paired samples, 8/9 (88%) patients showed clonal evolution between diagnosis and R/R disease: 3/8 (37.5%) gained at least one emergent clone and 5/8 (62.5%) lost at least one. The most dynamic genes were NRAS, NF1, PTPN11 and TET2, while TP53 and DNMT3A were most stable. Conclusion: Tapestri and HemeSTAMP-MRD both demonstrated improved MRD level detection, relapse prediction, and greater capacity to identify actionable mutations compared to MFC, with Tapestri uniquely enabling single-cell resolution of clonal dynamics to interrogate drivers of R/R disease. Larger cohort validation is ongoing. Citation Format: Crystal Zhou, Ruwan Gunaratne, Emily Yang, Rachel Agoglia, Diwash Jangam, Charu Tiwari, Kailee Tanaka, Tsoyu Chiang, Chandler Ho, Sydney Lu, James L. Zehnder, Bing Melody Zhang, Henning Stehr, Tian Yi Zhang. Novel single cell and bulk NGS assays for improved assessment of MRD (measurable residual disease) and clonal dynamics in acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 692.

Clinicopathologic and Molecular Characteristics of Merkel Cell Polyomavirus Positive T-Cell Lymphoproliferative Disorders

The American Journal of Surgical Pathology · 2026-03-31

Previous work described 3 cases of CD4+ T-cell lymphomas harboring Merkel cell polyomavirus (MCPyV), as demonstrated by in situ hybridization (ISH), next generation sequencing, and polymerase chain reaction. Two of these cases were cutaneous T-cell lymphomas compatible with mycosis fungoides in postcardiac transplant patients, while the third was a peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), in a patient without known immunosuppression. In this study, we assess an expanded cohort of T-cell neoplasms from 4 institutions for expression of MCPyV by ISH. This cohort includes 9 T-cell lymphomas occurring in the post solid organ transplant setting, of which 5 (60%) were positive for MCPyV by ISH. Four of these cases were classified as PTCL-NOS and the remaining case as nodal T follicular helper cell lymphoma, angioimmunoblastic type. In addition, we performed MCPyV ISH on a variety of neoplastic and non-neoplastic lymphoid tissues from both transplant and nontransplant patients. No evidence of MCPyV infection was found in lymphoid tissues in the absence of T-cell lymphoma, suggesting that the presence of MCPyV is specific to this rare subset of T cell lymphomas. Furthermore, all MCPyV-positive T-cell lymphomas (8 of 8) were CD4+ and the large majority were observed in the post-transplant setting (7 of 8). Multiplex single-molecule fluorescence ISH confirmed the presence of MCPyV in CD4+ T-cells. These findings support the hypothesis that MCPyV infection is specifically associated with rare CD4+ T-cell lymphomas, particularly in transplant recipients.

Deciphering response dynamics and treatment resistance from circulating tumor DNA after CAR T-cells in multiple myeloma

Nature Communications · 2025-02-20 · 13 citations

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 disease, we demonstrate the correlation between ctDNA and key clinical biomarkers, as well as patient outcomes. We further extend our approach to simultaneously track CAR-specific cell-free DNA (CAR-cfDNA) in patients undergoing anti-BCMA CAR T-cell (BCMA-CAR) therapy. We demonstrate that ctDNA levels following BCMA-CAR inversely correlate with relative time to progression (TTP), and that measurable residual disease (MRD) quantified by peripheral blood ctDNA (ctDNA-MRD) was concordant with clinical bone marrow MRD. Finally, we show that ctDNA-MRD can anticipate clinical relapse and identify the emergence of genomically-defined therapy-resistant clones. These findings suggest multiple clinical uses of ctDNA for MM in molecular characterization and disease surveillance.

Molecular taxonomy of MDS/CMML patients influences responses to hypomethylating agents and clinical outcomes

Leukemia Research · 2025-07-01 · 3 citations

We analyzed 268 patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) to determine the impact of their molecular taxonomic features on patient's clinical outcomes and responsiveness to therapy with hypomethylating agents (HMA). They were hierarchically classified via next-generation sequencing into molecular taxonomic groups based on previously described hierarchical mutational clusters (Bernard E et al, Blood 2024). The groups varied in size, molecular complexity and patient outcomes. With a median of 4 cycles of HMA-based regimens, 54 % patients were treated, with an overall response rate (ORR) of 35 % (IWG 2023 criteria). Focused evaluation of specific taxonomic subgroups demonstrated ORR in U2AF1 50 %, bi-TET2 44 %, SF3B1 40 %, TP53-multihit or CK 39 %, IDH-STAG2 36 %, SETBP1/-7 33 %, No molecular event 33 %, mNOS 28 %, CCUS-like 7 %. Notably, HMA response was not associated with International Prognostic Scoring System (IPSS-M) risk categories. The median follow-up time for the entire cohort was 4 years, with overall survival of 66 % and leukemia-free survival of 81 % at 3 years following initial diagnosis. Within the specific taxa these prognostic risk features were relatively higher for several taxonomic subgroups which were related to the patient's IPSS-M categorization. In contrast, our data demonstrated distinct differences of HMA responses within taxonomic subgroups, but without significant association between patients' HMA responses and their IPSS-M categorization. These findings indicate that molecular taxonomic classification could help refine therapeutic strategies for MDS and CMML, particularly in identifying subgroups more likely to benefit from HMA therapy.

An ultrasensitive method for detection of cell-free RNA

Nature · 2025-04-16 · 35 citations

Supplementary Tables S1-S15 from Tracing Founder Mutations in Circulating and Tissue-Resident Follicular Lymphoma Precursors

2025-12-11

<p>Supplementary Table S1. Patient and control clinical characteristics Supplementary Table S2. Sequencing metrics for FL cases & controls Supplementary Table S3. Identified mutations in EPIC FL pre-diagnostic samples Supplementary Table S4. Identified mutations in control samples Supplementary Table S5. Statistical significance for detection in prediagnostic samples with paired tumor biopsy Supplementary Table S6. Identified mutations in FL tumors with detection in paired prediagnostic samples Supplementary Table S7. Paired tumor cohort histology & sample characteristics Supplementary Table S8. Identified mutations in paired biopsy samples Supplementary Table S9. Clonal VDJ rearrangements in paired biopsies Supplementary Table S10. Concordance analysis of paired biopsy samples Supplementary Table S11. Patient characteristics, marrow and sorting studies Supplementary Table S12. DNA and sequencing metrics for marrow and sorting studies Supplementary Table S13. Monoclonal antibodies and manufacturers Supplementary Table S14. Mutations detected in marrow and sorting studies Supplementary Table S15. Genes fully or partially covered in lymphoma-focused CAPP-Seq selector</p>

MDM2 inhibition is associated with the emergence of TP53-altered clonal hematopoiesis

npj Precision Oncology · 2025-02-03 · 6 citations

Murine double minute 2 (MDM2) inhibitors have shown promising activity in TP53-wild type tumors and are under active investigation across a spectrum of malignancies. Herein, we report a 51-year-old female with MDM2-amplified, TP53-wild type adenoid cystic carcinoma who was treated with a MDM2 inhibitor and developed persistent pancytopenia despite drug discontinuation. Her pancytopenia was associated with 20 distinct pathogenic TP53 mutations in peripheral blood and bone marrow not present in drug-resistant tumor tissue. Plasma TP53 mutations were similarly detected among 4 other patients treated at our institution, with the number of mutations correlating strongly with duration of treatment. This case suggests that MDM2 inhibitors are associated with TP53 clonal hematopoiesis, which may confer a risk of subsequent myeloid malignancy. As multiple MDM2 inhibitor trials are ongoing, our findings underscore the need for further investigation into the potential long-term deleterious effects of these inhibitors in the hematopoietic stem and progenitor compartment.

Data from A Concordance Study among 26 NGS Laboratories Participating in the NCI Molecular Analysis for Therapy Choice Clinical Trial

2025-08-14

<div>AbstractPurpose:<p>NCI selected a network of Clinical Laboratory Improvement Amendments–certified laboratories performing routine next-generation sequencing (NGS) tumor testing to identify patients for the NCI Molecular Analysis for Therapy Choice (NCI-MATCH) trial. This large network provided a unique opportunity to compare variant detection and reporting between a wide range of testing platforms.</p>Experimental Design:<p>Twenty-eight NGS assays from 26 laboratories within the NCI-MATCH Network, including the NCI-MATCH central laboratory (CL) and 11 commercial and 14 academic designated laboratories (DL), were used for this study. DNA from eight cell lines and two clinical samples were sequenced. Pairwise comparisons in variant detection and reporting between each DL and CL were performed for single-nucleotide variant, insertion and deletion, and copy-number variant classes.</p>Results:<p>We observed high concordance in variant detection between CL and DL for single-nucleotide variants and insertions and deletions [average positive agreement (APA) > 95.4% for all pairwise comparisons] but lower concordance for variant reporting after analysis pipeline filtering. We observed much higher agreement between CL and assays using amplification as the target enrichment method (84.2% < APA ≤ 95.7%, average APA = 88.7%) than other assays using hybridization capture (69.7% < APA ≤ 93.8%, average APA = 77.4%) due to blacklisting of actionable variants in low complexity regions. For copy-number variant reporting, we observed high agreement (APA > 82%) except between CL and two assays (APA = 76.9% and 71.4%) due to differences in estimation of copy numbers. Notably, for all variants, differences in variant interpretation also contributed to reporting discrepancies.</p>Conclusions:<p>This study indicates that different NGS tumor profiling tests currently in widespread clinical use achieve high concordance between assays in variant detection. For variant reporting, observed discrepancies are mainly introduced during the bioinformatic analysis.</p></div>