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		Search Text: Home/< Back ToThe Science/Lymphoid Malignancies
  Lymphoid Malignancies
    The Laboratory of Lymphoid Malignancies, led by Dr. Adrian Wiestner, aims to improve the treatment of patients with chronic lymphocytic leukemia (CLL).
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          Adrian Wiestner, M.D., Ph.D.
  Adrian Wiestner, M.D., Ph.D.
          Senior Investigator
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      Meet the Team
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  Senior Investigator Research Interests
            
  Research Interests
              I lead the lymphoid malignancies section of the Hematology Branch, supported by the intramural research program of the NHLBI, NIH. As senior investigator on clinical trials and principal investigator of the laboratory program, I combine clinical and laboratory investigation that aim to improve treatment for patients with B-cell malignancies, in particular Chronic Lymphocytic Leukemia (CLL). I am pursuing three major goals: First, identify pathogenic mechanisms to assist the development of targeted therapy. Second, evaluate novel agents and treatment concepts in clinical trials and investigate resistance mechanisms through pharmacodynamic and genetic studies in patients enrolled on our clinical trials. Third, study the impact of treatment on immune function, response to vaccines, the interplay between the immune system and the progression of CLL, and how we can harness immune mechanisms to improve treatment.
  Pathogenesis of Chronic Lymphocytic Leukemia (CLL)

            Past research indicated a possible role for antigen in the pathogenesis of CLL and identified numerous interactions between tumor cells and the tissue microenvironment. I lead work in my group that identified the lymph node microenvironment as a key site of CLL cell activation through B-cell receptor and NF-ĸB signaling. These studies provide a framework for targeted therapy in CLL. Extending these observations we have employed single cell sequencing to identify a distinct minor subpopulation of activated and proliferating CLL cells in the lymph node microenvironment that interface with the immune milieu, and promote disease progression. Using exome sequencing of matched samples from blood and lymph nodes, we found that clonal evolution primarily occurred in the lymph node and associated with a suppressed T-cell inflammatory response. In turn, CLL cells actively modulate their surroundings giving rise to a complex, bidirectional crosstalk between tumor and host cells.Beyond these microenvironmental dependencies, a diverse set of putative pathogenic mutations have been identified through large-scale sequencing efforts. Heterogeneity in the genetic architecture of CLL has been closely linked to disease aggressiveness and its capacity to evolve under the selective pressures of treatment. Over the last decade an increasing number of driver mutations have been identified revealing marked heterogeneity in the genetic composition of CLL. Together with many colleagues we contributed to an aggregate “CLL map” build on genomic, transcriptomic, and epigenomic data from over 1,000 patients.

          
Inhibitors of B-cell receptor signaling to treat CLL

            Among the first forays into targeted therapy of CLL, we conducted a single center study with ibrutinib in CLL patients. We focused the study on patients with deletion of chromosomal arm 17p (del17p) and/or mutations in *TP53*. These patients generally had poor outcomes with chemotherapy. Virtually all patients responded to ibrutinib and achieved long-lasting benefit.Kaplan Meier graph showing durable benefit for 34 patients with CLL and TP53 aberration (del17p and/or TP53) treated with ibrutinib. Follow up extends to 8 years; 61% progression-free survival and 79% overall survival at 6 years.**Figure 1.** Durable benefit of treatment with ibrutinib for patients with CLL and TP53 aberration (del17p and/or *TP53* mutation). From Ahn, Tian, Wiestner. NEJM 2020.We also reported on safety, especially regarding cardiac events and demonstrated on-target effects of ibrutinib on BCR and NF-ĸB signaling in blood and lymph node, and identified improvements in both humoral and cellular immunity on treatment. Investigating mechanisms of resistance to ibrutinib, we identified mutations in BTK and PLCG2 in most patients with CLL progressing on ibrutinib, showed that these mutations are often detectable long before the diagnosis of clinical relapse, and identified emergence of multiple subclones carrying different mutations. Based on our study results, we developed and validated a 4-factor prognostic model for patients being treated with BTK inhibitors. We also identified expression of CD49d on CLL cells as a predictor of outcome with BTKi therapy, and showed that CD49d could independently add to the prognostic information of the 4-factor model.In our phase 2 study of acalabrutinib, a more BTK selective inhibitor than ibrutinib, we found that twice daily dosing maintained near complete occupancy of BTK in blood and tissues and more profoundly inhibited oncogenic signaling than once daily dosing.Visual depiction of increased BTK occupancy downstream of the B-cell receptor for 100 mg twice daily dosing of acalabrutinib vs 200 mg once daily resulting in stronger downregulation of NF-kB signaling in the twice daily dosing regimen.  Graph showing % BTK occupancy in lymph node decreases as time from last dose increases from 4 hours to 36 hours from last dose. Bar graph of overall response rate by iwCLL criteria (complete responses and partial responses) for once daily dosing (79.2%) vs twice daily dosing (95%) of acalabrutinib.**Figure 2.** Visual abstract summarizing key aspects of our phase 2 investigator-initiated study of acalabrutinib in patients with relapsed/refractory or high-risk treatment-naïve CLL. From Sun et al, Blood 2020Novel therapies are needed for high-risk patients previously treated with BTKi and venetoclax. In the laboratory, NRX-0492, a targeted protein degrader, induced rapid and sustained degradation of wild type and C481 mutant BTK at sub-nanomolar concentrations in primary CLL samples and demonstrated in vivo anti-CLL activity in patient-derived xenografts and the CLL-PDX model. This led us to join a multi-center first in human study further investigating BTK degradation with the clinical compound, NX-2127, with the same pharmacological mechanism as NRX-0492.Refer to paragraph below for description of this figure.**Figure 3.**NRX-0492 effectively degrades wildtype and mutant BTK in vitro and in vivo. (A) NRX-0492 consists of noncovalent BTK-binding “hook” linked to a “harness” that recruits cereblon to target BTK for ubiquitination and proteasomal degradation. (B) NRX-492 degrades BTK in U-CLL and M-CLL samples at low nanomolar concentrations. (C) CLL cell transcriptome assessed by RNA sequencing of CLL cells from 4 patients treated with DMSO, hook, 1 μM ibrutinib or 2 nM NRX-0492 for 18 hours followed by 20 μg/ml anti-IgM stimulation for 6 hours. Median centered heatmap depicts expression of BCR target genes. (D) In vivo activity in the CLL PDX model. BTK degradation and inhibition of cell proliferation assessed by flow cytometry.

          
Immunotherapy and monoclonal antibodies for treatment of CLL

            In our clinical and laboratory efforts we investigate strategies to strengthen the immune system in patients with CLL. Response to vaccines in CLL patients are often inadequate and can be further reduced in patients undergoing treatment. Vaccines for herpes zoster (RZV, Shingrix) and hepatitis B (HepB-CpG, Heplisav) were approved in 2017 but were untested in CLL patients. These vaccines uniquely trigger a recall immune response, and de novo immune response, respectively. The antibody and cellular response rates to Shingrix, respectively, were 76.8% and 70.0% in treatment-naïve patients and 40% and 41.3% in patients receiving a BTKi (*P* =.0002). Response to HepB-CpG was nearly absent in CLL patients on BTKi and severely impaired in treatment-naïve patients. During the Covid pandemic, we found that interrupting BTKi therapy can improve response to SARS-CoV2 boosters. We now expand on these observations in a comprehensive vaccine study which provides a mechanism to investigate response to many vaccines in different treatment settings. In these studies, we strive to identify strategies that can improve vaccine responses.T-cell engaging bispecific antibodies targeting CD3 (on T cells) and CD19 (CD3×CD19) or CD20 (Epcoritamab) on tumor cells. The bispecific antibody recruits autologous (the patient’s own) T-cell cells to kill the CLL cells. In the laboratory, using CLL cells from patients for in vitro experiments, we found that this strategy works well against CLL cells from all patients but was most effective when patients were being treated with a BTKi. We are working on incorporating bispecific antibodies into clinical studies in our program.please refer to description below**Figure 4.** Humoral and cellular response to recombinant zoster vaccine (RZV) in treatment-naïve and patients treated with a Bruton Tyrosine Kinase inhibitor.

          
Patient Information

            A New Oral BTK Protein Degrader with Dr. Adrian Wiestner - CLL SocietyASH 2020: Dr. Adrian Wiestner on Early Detection of BTK Mutations Preceding Ibrutinib Relapse in Chronic Lymphocytic Leukemia (CLL) - CLL SocietyASH 2020: Dr. Adrian Wiestner Discusses the Importance of Test Before TreatTM Predictive and Prognostic Biomarker Testing in Patients with Chronic Lymphocytic Leukemia (CLL) - CLL SocietyASH 2018: Dr. Wiestner on the Immune System in CLL (chronic lymphocytic leukemia) - CLL SocietyImprove the Response to COVID-19 Vaccination - CLL SocietyASH 2022: Dr. Clare Sun Explains Her Research on Sudden Death Among a Small Number of Chronic Lymphocytic Leukemia (CLL) Patients Using Ibrutinib - CLL SocietyClonal Evolution While on Acalabrutinib for CLL - CLL SocietyObservational Study of Cardiac Arrhythmia in Subjects Treated With BTK Inhibitors - CLL SocietyVaccinations in CLL - CLL SocietyASH 2020: Dr. Christopher Pleyer Discusses the Effect of Bruton Tyrosine Kinase Inhibitors on the Efficacy of Adjuvanted Recombinant Hepatitis B and Zoster Vaccines in Patients with Chronic Lymphocytic Leukemia (CLL) - CLL SocietyASH 2021: Effect of Bruton Tyrosine Kinase Inhibitor on Serologic and Cellular Immune Responses to Recombinant Herpes Zoster Vaccine - CLL Society
Clinical Trials and Studies
Early Clonal Dynamics During Venetoclax Treatment for Chronic Lymphocytic Leukemia (CLL)
				Recruiting
											
											Adult, Older Adult
					
											All Genders
					
																		Not Accepting Healthy Volunteers

				Are you an adult with chronic lymphocytic leukemia (CLL) who has relapsed despite treatment? This study is testing a medicine called venetoclax that treats CLL. Participants will give blood and bone marrow while taking the medicine to help researchers study genetic changes that may happen during treatment. To participate in this study, you must be an adult with active CLL. This study is located at the NIH Clinical Center in Bethesda, Maryland.Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)
				Recruiting
											
											Adult, Older Adult
					
											All Genders
					
																		Not Accepting Healthy Volunteers

				Are you an adult with MBL, CLL/SLL, LPL, WM, or SMZL? This study will follow people with these conditions before and after treatment to look at how their conditions progress or improve, with the goal of discovering new treatments. To participate in this study, you must be at least 18 years old. This study is located at the NIH Clinical Center in Bethesda, Maryland.Observational Study of Cardiac Arrhythmias in Subjects Treated With BTK Inhibitors
				Recruiting
											
											Adult, Older Adult
					
											All Genders
					
																		Not Accepting Healthy Volunteers

				Do you have cancer that is treated with something called Bruton's tyrosine kinase inhibitors or BKTi?
												In this study, researchers want to learn more about Bruton's tyrosine kinase inhibitors, which are often used to treat cancer, affect the heart. You can participate in this study if you are currently receiving or will be receiving Bruton's tyrosine kinase inhibitors. This study is taking place at the National Institutes of Health Clinical Center in Bethesda, Maryland.
Featured Publications
                NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts
            Authors:Zhang D, Harris HM, Chen J, Judy J, James G, Kelly A, McIntosh J, Tenn-McClellan A, Ambing E, Tan YS, Lu H, Gajewski S, Clifton MC, Yung S, Robbins DW, Pirooznia M, Skånland SS, Gaglione E, Mhibik M, Underbayev C, Ahn IE, Sun C, Herman SEM, Noviski M, Wie
                                                                                                                        
            Blood
      
                2023 Mar 30;141(13):1584-1596
        Read Publication
                      BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL
            Authors:Pleyer C, Laing KJ, Ali MA, McClurkan CL, Soto S, Ahn IE, Nierman P, Maddux E, Lotter J, Superata J, Tian X, Wiestner A, Cohen JI, Koelle DM, Sun C.
                                                                                                                        
            Blood Adv
      
                2022 Mar 22;6(6):1732-1740
        Read Publication
                      BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL
            Authors:Mhibik M, Gaglione EM, Eik D, Kendall EK, Blackburn A, Keyvanfar K, Baptista MJ, Ahn IE, Sun C, Qi J, Rader C, Wiestner A.
                                                                                                                        
            Blood
      
                2021 Nov 11;138(19):1843-1854
        Read Publication
                      Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib
            Authors:Sun C, Nierman P, Kendall EK, Cheung J, Gulrajani M, Herman SEM, Pleyer C, Ahn IE, Stetler-Stevenson M, Yuan CM, Maric I, Gaglione EM, Harris HM, Pittaluga S, Wang MH, Patel P, Farooqui MZH, Izumi R, Hamdy A, Covey T, Wiestner A.
                                                                                                                        
            Blood
      
                2020 Apr 02;136(1):93-105
        Read Publication
                      Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study
            Authors:Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, Lotter J, Housel S, Stetler-Stevenson M, Yuan CM, Maric I, Calvo KR, Nierman P, Hughes TE, Saba NS, Marti GE, Pittaluga S, Herman SEM, Niemann CU, Pedersen LB, Geisler CH, Childs R, Aue G, Wiestner A.
                                                                                                                        
            Blood
      
                2018 May 04;131(21):2357-2366
        Read Publication
                                View More Publications
  Meet the Team

    Adrian Wiestner, M.D., Ph.D.

            Adrian Wiestner, M.D., Ph.D.
                Senior Investigator
                Dr. Adrian Wiestner leads the Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, NIH.  Dr. Wiestner earned his M.D. from the University of Basel Medical School in Switzerland in 1992, and a Ph.D. in genetics in 1998.  He joined the NIH with the NHLBI Hematology Fellowship Program in 2000.  In September 2004, Dr. Wiestner was appointed as a Tenure Track Investigator with the NHLBI Hematology Branch and was promoted to Senior Investigator in December 2013.  As senior investigator on clinical trials and principal investigator of the laboratory program, he combines clinical and laboratory investigation that aim to improve treatment for patients with B-cell malignancies, in particular Chronic Lymphocytic Leukemia (CLL). He is pursuing three major goals: First, identify pathogenic mechanisms to assist the development of targeted therapy. Second, evaluate novel agents and treatment concepts in clinical trials. Third, investigate resistance mechanisms through pharmacodynamic and genetic studies in patients enrolled on our clinical trials.
    
          Contact the lab
    10 Center DrBethesda, MD 20892United States
        Phone:
                    301-594-6855
                Fax:
            301-480-0041 and 301-480-5303
  Clare Sun, M.D.
    
            Clare Sun, M.D.
        

    Associate Research Physician

        clare.sun@nih.gov
        
                    View
                    Clare's Profile
            Isabelle Abreo
    
            Isabelle Abreo
        

    Program Specialist

        isabelle.abreo@nih.gov
            Rachel Adams, BSN, MSN
    
            Rachel Adams, BSN, MSN
        

    Research Nurse Specialist

        rachel.adams@nih.gov
            Sivasubramanian Baskar, Ph.D.
    
            Sivasubramanian Baskar, Ph.D.
        

    Staff Scientist

        baskars@mail.nih.gov
            Lita Freeman
    
            Lita Freeman, Ph.D.
        

    Research Biologist

        litaf@nhlbi.nih.gov
            Christine Gruessner, M.D., MPH
    
            Christine Gruessner, M.D., MPH
        

    Clinical Fellow

        christine.gruessner@nih.gov
            Rohan Herur, BS
    
            Rohan Herur, B.S.
        

    Post-Baccalaureate Fellow

        rohan.herur@nih.gov
            Shellin Jose, BSN
    
            Shellin Jose, BSN
        

    Research Specialist

        shellin.jose@nih.gov
            Jennifer Lotter
    
            Jennifer  Lotter, P.A.
        

    Physician Assistant

        jennifer.lotter@nih.gov
            Gerald Marti M.D., Ph.D.
    
            Gerald Marti, M.D., Ph.D.
        

    Special Volunteer

        gerald.marti2@nih.gov
            Rui Mu Ph.D.
    
            Rui Mu, Ph.D.
        

    Research Fellow

        rui.mu@nih.gov
            Pia Nierman
    
            Pia Nierman
        

    Clinical Operations Program Manager

        pia.nierman@nih.gov
            Heribert Playa Albinyana
    
            Heribert Playa Albinyana
        

    Special Volunteer

        heribert.playaalbinyana@nih.gov
            Chris Pleyer M.D.
    
            Christopher Pleyer, M.D.
        

    Staff Clinician

        christopher.pleyer@nih.gov
        
                    View
                    Christopher's Profile
            Layla Saleh Ph.D.
    
            Layla Saleh, Ph.D.
        

    Postdoctoral Fellow

        layla.saleh@nih.gov
            Susan Soto
    
            Susan Soto
        

    Research Nurse Specialist

        sotos@nhlbi.nih.gov
            Jeanine Superata
    
            Jeanine Superata, CRFNP
        

    Nurse Practitioner

        superatj@nhlbi.nih.gov
            Chingiz Underbayev M.D., Ph.D.
    
            Chingiz  Underbayev, M.D., Ph.D.
        

    Staff Scientist

        chingiz.underbayev@nih.gov
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Inhye Ahn, M.D.
        

    Fellow
        Inhye Ahn, M.D. is currently at Dana Farber Cancer Institute.
      Anfal Alsadhan, Ph.D.
        

    Fellow
        Anfal Alsadhan, Ph.D. is currently at King Saud bin Abdulaziz University.
      George Aue, M.D.
        

    Acting Clinical Director
                                        2006

      -
            2009
        George Aue, M.D. is currently a Acting Clinical Director at NHLBI, NIH, Bethesda, MD.
      Maria Joao Baptista, Ph.D.
        

    Fellow
        Maria Joao Baptista, Ph.D. is currently at Astra Zeneca, Portugal.
      Amy Blackburn, B.A.
        

    Post Baccalaureate Fellow
      Emily Bryer, D.O.
        

    Staff Clinician
        Emily Bryer, D.O. is currently at Penn Medicine.
      Jonathan Chen, B.S.
        

    Post Baccalaureate Fellow
        Jonathan Chen, B.S. is currently at University of Vermont Larner College of Medicine.
      Eman Dadashian, M.D.
        

    Fellow
        Eman Dadashian, M.D. is currently at Cedars Sinai Medical Center.
      Sanjal Desai, M.D.
        

    Fellow
        Sanjal Desai, M.D. is currently at University of Minnesota.
      David Eik, B.S.
        

    Post Baccalaureate Fellow
        David Eik, B.S. is currently at UCSF.
      Mohammed Farooqui, D.O.
        

    Fellow
        Mohammed Farooqui, D.O. is currently at Merck & Co.
      Amro Fulfulan
        

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        Amro Fulfulan  is currently at King Saud bin Abdulaziz University.
      Erica Gaglione, B.S.
        

    Post Baccalaureate Fellow
        Erica Gaglione, B.S. is currently at REGENXBIO.
      Federica Gibellini, Ph.D.
        

    Fellow
        Federica Gibellini, Ph.D. is currently at AccessDx, Houston, TX.
      Hailey Harris, M.D.
        

    Fellow
        Hailey Harris, M.D. is currently at Massachusetts General Hospital.
      Yair Herishanu, M.D.
        

    Fellow
        Yair Herishanu, M.D. is currently at Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Sourasky Medical Center.
      Sarah Herman, Ph.D.
        

    Fellow
        Sarah Herman, Ph.D. is currently at The Johns Hopkins University Applied Physics Laboratory.
      Andy Itsara, M.D., Ph.D.
        

    Fellow
        Andy Itsara, M.D., Ph.D. is currently at Amgen.
      Gabby James, B.A.
        

    Post Baccalaureate Fellow
        Gabby James, B.A. is currently at University of Wisconsin.
      Jade Jones, M.D.
        

    Fellow
        Jade Jones, M.D. is currently at Vanderbilt University.
      Ellen Kendall, M.D.
        

    Fellow
        Ellen Kendall, M.D. is currently at Massachusetts General Hospital.
      Janet Le, B.S.
        

    Post Baccalaureate Fellow
        Janet Le, B.S. is currently at Medical College of Wisconsin.
      Elinor Lee, M.D., Ph.D.
        

    Fellow
        Elinor Lee, M.D., Ph.D. is currently at UCLA, Los Angeles, CA.
      Yuh-Shan Lee, M.D.
        

    Fellow
        Yuh-Shan Lee, M.D. is currently at Singapore General Hospital.
      Andrew Lipsky, M.D.
        

    Fellow
        Andrew Lipsky, M.D. is currently at Columbia University Medical Center.
      Delon Liu, Ph.D.
        

    Fellow
        Delon Liu, Ph.D. is currently at National Heart, Lung, and Blood Institute.
      Sabrina Martyr, M.D.
        

    Fellow
        Sabrina Martyr, M.D. is currently at UPMC Hillman Cancer Center Hanover.
      Maissa Mhibik, Ph.D.
        

    Fellow
        Maissa Mhibik, Ph.D. is currently at Genmab.
      Helena Mora-Jensen, Ph.D.
        

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        Helena Mora-Jensen, Ph.D. is currently at Bavarian Nordic, Copenhagen, Denmark.
      Cydney Nichols, M.D.
        

    Fellow
        Cydney Nichols, M.D. is currently at Indiana University.
      Ndegwa Njuguna, M.D.
        

    Fellow
        Ndegwa Njuguna, M.D. is currently at Tacoma, WA.
      Carsten Niemann, M.D., Ph.D.
        

    Fellow
        Carsten Niemann, M.D., Ph.D. is currently at Rigshospitalet Copenhagen University Hospital, Denmark.
      Patricia Perez-Galan, Ph.D.
        

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        Patricia Perez-Galan, Ph.D. is currently at Fundació de Recerca Clínic Barcelona (FCRB)-IDIBAPS, Barcelona, Spain.
      Edgar G. Rizzatti, M.D., Ph.D.
        

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      Hannah Robinson, M.D.
        

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      Mark Roschewski, M.D.
        

    Fellow
        Mark Roschewski, M.D. is currently at National Cancer Institute.
      Nakhle Saba, M.D.
        

    Fellow
        Nakhle Saba, M.D. is currently at Tulane Cancer Center.
      Alankrita Taneja, M.D.
        

    Fellow
        Alankrita Taneja, M.D. is currently at Roswell Park Comprehensive Cancer Center.
      Lauren Vaughn, B.S.
        

    Post Baccalaureate Fellow
        Lauren Vaughn, B.S. is currently at Georgetown University.
      Berengere Vire, Ph.D.
        

    Fellow
        Berengere Vire, Ph.D. is currently at Biodena Care, France.
      Mark Weniger, Ph.D.
        

    Fellow
        Mark Weniger, Ph.D. is currently at University of Duisburg-Essen, Essen, Germany.
      Deanna Wong, M.D.
        

    Fellow
        Deanna Wong, M.D. is currently at Los Angeles, CA.
      Deyi Zhang, Ph.D.
        

    Fellow
        Deyi Zhang, Ph.D. is currently at Hansoh Bio, MD.

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