Ken Young

Overview:

I am a clinically-oriented diagnostic physician with clinical expertise in the pathologic diagnosis of hematologic cancers including tumors of the bone marrow, lymphoid tissue, spleen and pre-malignant hematologic conditions. Another area of interest is blood cancer classification with molecular and genetic profiling. In my research program, we focus on molecular mechanisms of tumor progression, cell-of-origin, biomarkers, and novel therapeutic strategies in lymphoma, myeloma and leukemia. In addition to patient care and translational research, medical education and scientific communication are also part of interest. Many residents, fellows, graduates and postdocs have worked and been trained in our program.

Positions:

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

Zhejiang University (China)

Grants:

Genetic and Epigenetic Biomarkers for B-cell Lymphoma

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma. METHODS: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens' immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry. RESULTS: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHMhigh) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell-like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHMhigh groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8+ T cells was significantly lower in IGHV SHMhigh than in SHMlow patients with activated B-cell-like DLBCL, whereas PD-1 expression in CD4+ T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHMhigh than in SHMlow patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM. CONCLUSIONS: These results show for the first time that IGV SHMhigh and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies.
Authors
Xu-Monette, ZY; Li, J; Xia, Y; Crossley, B; Bremel, RD; Miao, Y; Xiao, M; Snyder, T; Manyam, GC; Tan, X; Zhang, H; Visco, C; Tzankov, A; Dybkaer, K; Bhagat, G; Tam, W; You, H; Hsi, ED; van Krieken, JH; Huh, J; Ponzoni, M; Ferreri, AJM; Møller, MB; Piris, MA; Winter, JN; Medeiros, JT; Xu, B; Li, Y; Kirsch, I; Young, KH
MLA Citation
Xu-Monette, Zijun Y., et al. “Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies..” J Immunother Cancer, vol. 7, no. 1, Oct. 2019. Pubmed, doi:10.1186/s40425-019-0730-x.
URI
https://scholars.duke.edu/individual/pub1416613
PMID
31640780
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date
Start Page
272
DOI
10.1186/s40425-019-0730-x

MYC Mutation Profiling In 708 De Novo Diffuse Large B-Cell Lymphoma Demonstrates That Genetic Abnormalities In The Coding Sequence and Untranslated Regions Have Different Prognostic and Clinical Significance: A Report From The International DLBCL Rituxima

Authors
Xu-Monette, ZY; Tzankov, A; Li, Y; Visco, C; Montes-Moreno, S; Dybkaer, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; Van Krieken, JHJM; Huh, J; Ai, WZ; Ponzoni, M; Ferreri, AJM; Farnen, JP; Moller, MB; Winter, JN; Piris, MA; Medeiros, LJ; Young, KH
URI
https://scholars.duke.edu/individual/pub1405137
Source
wos
Published In
Blood
Volume
122
Published Date

Hematopoietic stem cell transplantation for adults with T-cell lymphoblastic lymphoma: can we successfully step into the era of precision medicine?

Authors
URI
https://scholars.duke.edu/individual/pub1417087
PMID
31641192
Source
pubmed
Published In
Leukemia
Published Date
DOI
10.1038/s41375-019-0608-4

Radiation Therapy Significantly Improves Survival Of Patients With Diffuse Large B-Cell Lymphoma Associated With MYC Translocation: A Report From The International DLBCL Rituximab-CHOP Consortium Program

<jats:title>Abstract</jats:title> <jats:p /> <jats:sec> <jats:title>Context and objective</jats:title> <jats:p>Approximately 5-10% of diffuse large B-cell lymphoma (DLBCL) patients carry MYC gene translocations (MYC-translocation+) with a poor prognosis after standard chemotherapy. MYC-translocation+ DLBCL patients carrying BCL2 translocations (MYC+/BCL2+ double-hit lymphoma) have a worse survival. The efficacy of adjuvant radiotherapy in this setting is unknown. The purpose of this study is to evaluate the efficacy of radiotherapy as a part of the therapeutic regimen for patients with MYC-translocation+ DLBCL.</jats:p> </jats:sec> <jats:sec> <jats:title>Patients and methods</jats:title> <jats:p>From the International DLBCL R-CHOP consortium program, we selected 581 patients with de novo DLBCL treated with standard R-CHOP immunochemotherapy (diagnosed and treated from 2000 to 2010). We excluded patients with transformed DLBCL, primary mediastinal, cutaneous, testicular or central nervous system large B-cell lymphomas, patients with HIV infection, and patients not treated with R-CHOP. The median follow-up was 54.9 months. Fluorescence in situ hybridization assessing MYC was performed for all the patients (n=581) and results were correlated with available clinical data to identify clinicopathologic features associated with MYC translocation, and to evaluate the prognostic significance of MYC translocations regarding overall survival (OS, from the time of diagnosis to death from any cause) and progression-free survival (PFS, from the time of diagnosis to relapse or death from any cause). In the MYC-translocation+ DLBCL group, 38 patients received chemotherapy alone and 21 patients received chemotherapy with adjuvant radiation therapy. The clinicopathologic features and survival of MYC-translocation+ DLBCL patients treated with (n=21) and without radiotherapy (n=38) after immunochemotherapy were compared to in order to evaluate the radiotherapy efficacy and other confounding factors.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>MYC translocations were detected in 59 DLBCL patients (10.2%). Patients with MYC-translocation+ DLBCL more often had bulky tumors, involvement of multiple extranodal sites, and poorer OS (hazard ratio [HR]: 2.0, 95% confidence interval [CI]: 1.20 - 3.35, P= .0083) and PFS (HR: 1.96, 95% CI: 1.22 - 3.13, P= .0005) independent of the International Prognostic Index score. Poor survival was primarily attributable to patients with MYC+/BCL2+ double-hit DLBCL who were predominantly of germinal center B-cell subtype. Among MYC-translocation+ DLBCL patients, a better survival was achieved in patients who received radiotherapy (for OS, HR: .32, 95% CI: .15 - .71, P= .0049; for PFS, HR: .35, 95% CI: .17 - .73, P= .0043). Conversely, radiotherapy abolished the adverse impact of MYC translocations. In addition, radiotherapy was associated with better survival in the subset of patients with MYC+/BCL2+ double-hit lymphoma (P = .017 for OS, and P = .05 for PFS). However, owing to the common use of radiotherapy as consolidation therapy, the favorable prognoses in the group of patients who received radiotherapy could also be attributed to limited-stage disease and more frequent complete remission (CR) after first-line treatment and therefore these factors confound interpretation of the data. To address these issues, we evaluated radiotherapy efficacy in separate patient groups: patients who achieved CR, non-CR (PR/SD/PD) patients, and patient with stage I/II, or stage III/IV disease. The efficacy of radiotherapy appeared more apparent in patients with advanced disease who did not achieve CR after first-line chemotherapy. Multivariate analysis after adjustment for stage and IPI score validated that radiotherapy significantly improved OS (HR: .28, 95% CI: .10 - .81, P= .018) and PFS (HR: .32, 95% CI: .13 - .80, P= .015) of MYC-translocation+ DLBCL patients.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The presence of MYC translocations in DLBCL is an important biomarker that facilitates prognostic prediction and treatment stratification independent of the IPI score. For chemoresistant MYC-translocation+ DLBCL patients, radiotherapy seems to be an effective adjuvant regimen likely due to the higher frequency of extranodal involvement and bulky disease in MYC-translocation+ DLBCL patients. Our results provide a rationale for larger scale studies to assess the potential role of radiotherapy in the management of MYC-translocation+ DLBCL patients, particularly patients with MYC+/BCL2+double-hit DLBCL.</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>Winter: Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents &amp; Royalties.</jats:p> </jats:sec>
Authors
Xu-Monette, ZY; Dabaja, BS; Tzankov, A; Visco, C; Miranda, RN; Dybkaer, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WL; Van Krieken, JHJM; Huh, J; Ai, WZ; Ponzoni, M; Ferreri, A; Moller, MB; Zhao, X; Go, RS; Winter, JN; Piris, MAA; McDonnell, TJ; Li, Y; Medeiros, LJ; Young, KH
MLA Citation
Xu-Monette, Zijun Y., et al. “Radiation Therapy Significantly Improves Survival Of Patients With Diffuse Large B-Cell Lymphoma Associated With MYC Translocation: A Report From The International DLBCL Rituximab-CHOP Consortium Program.” Blood, vol. 122, no. 21, American Society of Hematology, 2013, pp. 213–213. Crossref, doi:10.1182/blood.v122.21.213.213.
URI
https://scholars.duke.edu/individual/pub1405138
Source
crossref
Published In
Blood
Volume
122
Published Date
Start Page
213
End Page
213
DOI
10.1182/blood.v122.21.213.213

Genetic alterations and their clinical implications in DLBCL

Authors
Miao, Y; Medeiros, LJ; Li, Y; Li, J; Young, KH
MLA Citation
Miao, Yi, et al. “Genetic alterations and their clinical implications in DLBCL.” Nature Reviews Clinical Oncology, vol. 16, no. 10, Springer Science and Business Media LLC, Oct. 2019, pp. 634–52. Crossref, doi:10.1038/s41571-019-0225-1.
URI
https://scholars.duke.edu/individual/pub1411473
Source
crossref
Published In
Nature Reviews. Clinical Oncology
Volume
16
Published Date
Start Page
634
End Page
652
DOI
10.1038/s41571-019-0225-1

Research Areas:

Lymphoma