Integrating Circulating Tumor DNA Features and Plasma Protein Markers to Detected Early Lymphoid Neoplasm

Introduction The disease burden of lymphoid neoplasm has been rising in China over the last decade. But most patients manifest with advanced stage disease at initial diagnosis, and the prognosis is poor with a 5-year survival rate of 38.3%. Here we reported a novel multivariate cancer risk score (CRS) model which is used to detect early lymphoid neoplasm from the peripheral blood. It incorporates three cancer hallmarks, copy number aberrations (CNA) and fragment size (FS) via shallow whole genome sequencing (sWGS) from cell-free DNA (cfDNA), and a panel of seven tumor protein markers in a single blood draw (10ml). Methods 44 newly diagnosed and untreated stage I-IV lymphoid neoplasm patients and 247 healthy individuals with no cancer diagnosis were enrolled in this study. 10ml peripheral blood was collected from each participant after enrollment. cfDNA was extracted and subjected to sWGS whereas plasma was subjected to measure the levels of 7 PTMs. The cancer risk score (CRS) of a subject was calculated via an established CRS model [1]. Results Firstly, genomic and epigenetic features were explored from cfDNA sWGS results. CNA is a ubiquitous genomic hallmark in a wide spectrum of cancers. In this study, 26 of the 44 (59.1%) lymphoid neoplasm patients had CNA in at least one genomic segment (>5Mb). FS feature of cfDNA bears the correspondence of the epigenetic landscapes of cells that give rise to those cfDNA fragments. When CNA was combined with FS, 29 (65.9%) patients were able to be detected by the CNA+FS classifier. On the other hand, 13 (29.5%) patients were tested positive by PTMs alone, indicating non-DNA molecular surrogates can also serve as cancer biomarkers with acceptable performance. When CNA, FS and PTM were incorporated into a multidimensional and multivariate CRS model, it achieved the best performance allowing 31 (70.0%) lymphoid neoplasm cases to be identified with a positive predictive value (PPV) of 86.1% at 98.0% specificity. The sensitivity of CRS model increases with the advances of disease with a sensitivity of 50.0% in early stage (stage I -Ⅱ) and 90.0% in late stage (stage Ⅲ-Ⅳ). Conclusion In summary, this study provides an efficient and non-invasive method to detect lymphoid neoplasm. Instead of relying only on one dimension of cancer markers, the multidimensional approach which incorporating CNA, fragment size and protein markers is plausible in early detection of lymphoid neoplasm with sufficient accuracy and robustness. Disclosures Zhu: Clinical Laboratories, Shenyou Bio: Current Employment. Li: SeekIn Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Geng: Clinical Laboratories, Shenyou Bio: Current Employment. Chang: Clinical Laboratories, Shenyou Bio: Current Employment. Chen: SeekIn Inc: Current Employment, Current holder of individual stocks in a privately-held company. Mao: SeekIn Inc: Current Employment, Current holder of individual stocks in a privately-held company.

ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML

Myeloid/lymphoid neoplasm with eosinophilia (MLN-Eo) is a World Health Organization (WHO) established category of hematologic malignancies primarily arising in adults. We discuss an 8-month-old infant who presented with clinical features similar to those of juvenile myelomonocytic leukemia (JMML) but who was diagnosed with MLN-Eo driven by an ETV6-FLT3 fusion. Results of patient-derived leukemia ex vivo studies demonstrated increased sensitivity to type I FLT3 inhibitors as compared with type II inhibitors. Treatment with the type I inhibitor gilteritinib resulted in complete immunophenotypic and cytogenetic remission. This patient subsequently underwent a hematopoietic stem cell transplant and remains in complete remission 1 year later. This is the youngest patient reported with an ETV6-FLT3 fusion and adds to the mounting reports of FLT3-rearranged MLN-Eo, supporting its addition to the WHO classification. Furthermore, this case highlights the clinical utility of ex vivo drug testing of targeted therapies.

Early induction and increased risk of precursor B-cell neoplasms after exposure of infant or young-adult mice to ionizing radiation

Epidemiological studies of atomic-bomb survivors have revealed an increased risk of lymphoid neoplasm (i.e. acute lymphoblastic leukemia) associated with radiation exposure. In particular, children are more susceptible to radiation-induced precursor lymphoid neoplasm than adults. Although ~75% of human lymphoid tumors are B-cell neoplasms, the carcinogenic risk associated with each stage of differentiation of B-cells after radiation exposure is poorly understood. Therefore, we irradiated mice at infancy or in young adulthood to investigate the effect of age at exposure on the risk of developing B-cell neoplasms. Histopathology was used to confirm the presence of lymphoid neoplasms, and the population of B-cell neoplasms was classified into the precursor B-cell (pro-B and pre-B cell) type and mature B-cell type, according to immunophenotype. The data revealed that precursor B-cell neoplasms were induced soon after radiation exposure in infancy or young adulthood, resulting in a greater risk of developing the neoplasms. This was particularly the case for the pro-B cell type after young adult exposure. Our findings suggest that exposure to radiation at young age increases the risk of developing precursor B-cell neoplasms in humans.