Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. The clinical course of CLL is highly heterogeneous. During the last decade, the treatment options for CLL has developed from single and combination chemotherapy to immune-chemotherapy and targeted agents, thereby significantly improving the outcome for patients. A more comprehensive approach to immune complications, treatment outcome, and disease outcome among patients with CLL is warranted.
By capture of paraclinical, clinical and demographic data along with genetic and functional characterization of primary CLL cells in our laboratory, we assemble multidimensional data on patients with CLL through the PERSIMUNE platform. With this unique three-pronged setup (translational research, clinical trials and registry based “real world evidence”), we explore patterns predictive of treatment outcome, infectious complications and disease outcome upon specific treatment.
By development of machine learning based algorithms in collaboration with DTU Compute, we aim for individually tailored CLL specific treatment and supportive care in CLL. By developing investigator-initiated, inter-group studies in collaboration between the Nordic, Hovon and German CLL study groups, we assure assessment of novel combination treatments for CLL and form a basis for testing individually tailored treatment in future clinical trials
Key results
With the B-cell receptor pathway as the core, our group has been part of a paradigm shift for treatment of CLL with novel targeted therapies developed also for patients with the most dismal outcome due to TP53 aberrations. With the parallel development of translational and experimental studies based on our own unique CLL biobank, CLL epidemiology studies based on the comprehensive Danish National CLL database, and CLL clinical inter-group trials, we have created a unique position for development of not only prognostic algorithms but also tailored novel treatment regimens, which can be prospectively validated via investigator-initiated clinical trials.
People
Carsten Utoft Niemann, MD, PhD, Principal Investigator, Head of CLL Laboratory, Chair of Nordic CLL Study Group
Christian H. Geisler, Prof Emeritus, MD
Clinical scientists
Caspar da Cunha-Bang, MD, PhD
Fie Juhl Vojdeman, MD, PhD: currently Dept of Biochemistry, Bispebjerg Hospital
Rudi Agius Post. Doc.
Christian Brieghel, MD, PhD: Herlev Hospital
Ph.D. candidates
Michael Asger Andersen, MD
Rebecca XMS Valentin, MD
Rebecka Svanberg, MD
Emelie Hamotal Curovic Rotbain, MD
Per Ishøy Nielsen, MD
Mehdi Parvis, upcoming PhD student
Pregraduate students
Kathrine Aarup
Noomi Vainer
Laboratory staff
Lone Bredo Pedersen, Scientific laboratory technician
Trine Enevoldsen, laboratory technician, in collaboration with the clinical trial unit
Jane Hinrichsen, laboratory technician, in collaboration with the clinical trial unit
Betina Gall, laboratory technician, in collaboration with the clinical trial unit
Louise Le Dous, laboratory staff
Marianne Blirup Jensen, laboratory staff
Assistant
Mette Højmose Thrane
Collaborators
- Finn Cilius Nielsen, Prof, MD, PhD: Center for Genomic Medicine, Righospitalet.
- Jens Lundgren, Prof, MD, PhD, PERSIMUNE: Department of Infection Medicine, Rigshospitalet.
- Henrik Hjalgrim, MD, PhD, DMSc, SSI: Statens Serum Institut.
- Matthew S. Davids, MD, PhD: Dana-Farber Cancer Institute, MA, USA
- Adrian Wiestner, MD, PhD, NHLBI: National Institutes of Health, MD, USA
- Arnon P Kater, Prof, MD, PhD, AMC: HOVON study group, Amsterdam, the Netherlands.
- Michael Hallek, Prof, MD, PhD: University of Cologne, German CLL study group, Cologne, Germany
- Ole Winther, Prof, MSc: DTU, DTU Compute, Cognitive Science.
- Anders Österborg Prof, MD: Nordic CLL study group: http://www.nordic-cll.org/
- Richard Rosenquist Brandell Prof, MD: Nordic CLL study group: http://www.nordic-cll.org/
- Sigrid Skånland, PhD: Department of Cancer Immunology, Oslo University Hospital
Clinical Trials
Chronic lymphocytic leukemia:
- PreVent-ACaLL (recruiting), founding member, sponsor
- Assure (recruting)
- CLL17 (planned), founding member
- HOVON158, Next Step trial (planned)
- Vision HO141 trial (completed), founding member
- GAIA CLL13 trial (completed), founding member
- CLL3011 GLOW (completed), founding member
- CLL14 (completed)
- HOVON68 (completed), founding member
- MURANO (completed)
- PROLONG (completed), founding member
Mantle Cell Lymphoma:
- Triangle (recruiting), responsible for laboratory analyses
- Philemon (completed), responsible for laboratory analyses
- Valeria (recruiting), responsible for laboratory analyses
- Vision (recruiting), responsible for laboratory analyses
Videos
Selected publications
Niemann CU: Cost-effectiveness targeting CLL, Blood, in press
Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink A, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Du K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner C, Kreuzer K, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K: Fixed-duration venetoclax-obinutuzumab for patients with previously untreated chronic lymphocytic leukaemia: follow-up of efficacy and safety results from the multicentre, open-label, randomised, phase 3 CLL14 trial, Lancet Onc, in press
Aarup K, Rotbain EC, Enggaard L, Pedersen RS, Bergmann OJ, Thomsen RH, Frederiksen M, Frederiksen H, Nielsen T, Christiansen I, Andersen MA*, Niemann CU* (* co senior-authors): Real-World Outcomes for 205 Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib, Eur J Hem, in press
Scarfò L, Chatzikonstantinou T, Rigolin GM, Quaresmini G, Motta M, Vitale C, Garcia-Marco JA, Hernández-Rivas JÁ, Mirás F, Baile M, Marquet J, Niemann CU, Reda G, Munir T, Gimeno E, Marchetti M, Quaglia FM, Varettoni M, Delgado J, Iyengar S, Janssens A, Marasca R, Ferrari A, Cuéllar-García C, Itchaki G, Špaček M, De Paoli L, Laurenti L, Levin MD, Lista E, Mauro FR, Šimkovič M, Van Der Spek E, Vandenberghe E, Trentin L, Wasik-Szczepanek E, Ruchlemer R, Bron D, De Paolis MR, Del Poeta G, Farina L, Foglietta M, Gentile M, Herishanu Y, Herold T, Jaksic O, Kater AP, Kersting S, Malerba L, Orsucci L, Popov VM, Sportoletti P, Yassin M, Pocali B, Barna G, Chiarenza A, Dos Santos G, Nikitin E, Andres M, Dimou M, Doubek M, Enrico A, Hakobyan Y, Kalashnikova O, Ortiz Pareja M, Papaioannou M, Rossi D, Shah N, Shrestha A, Stanca O, Stavroyianni N, Strugov V, Tam C, Zdrenghea M, Coscia M, Stamatopoulos K, Rossi G, Rambaldi A, Montserrat E, Foà R, Cuneo A, Ghia P: COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus. Leukemia. 2020 doi: 10.1038/s41375-020-0959-x
Fürstenau M, Langerbeins P, De Silva N, Fink AM, Robrecht S, von Tresckow J, Simon F, Hohloch K, Droogendijk J, van der Klift M, van der Spek E, Illmer T, Schöttker B, Fischer K, Wendtner CM, Tausch E, Stilgenbauer S, Niemann CU, Gregor M, Kater AP, Hallek M and Eichhorst B: COVID-19 among fit patients with CLL treated with venetoclax-based combinations, Leukemia, 2020 doi: 10.1038/s41375-020-0941-7
Ben-Dali Y, Hleuhel MH, da Cunha-Bang C, Brieghel C, Poulsen CB, Clasen-Linde E, Bentzen HHN, Frederiksen H, Christiansen I, Nielsen LH, Enggaard L, Helleberg M, Clausen MR, Frederiksen M, Pedersen RS, Niemann CU*, Andersen MA* (* co senior-authors): Richter’s Transformation in Patients with Chronic Lymphatic Leukemia: A Nationwide Epidemiological Study; Leukemia & Lymphoma, doi: 10.1080/10428194.2020.1719092
Agius R, Brieghel B, Andersen MA, Pearson AT , Ledergerber B, Cozzi-Lepri A, Louzoun Y, Andersen CL, Bergstedt J, von Stemann JH, Jørgensen M, Tang ME, Fontes M, Bahlo J, Herling CD, Hallek M, Lundgren J, MacPherson CR, Larsen J, Niemann CU: Identification of Newly Diagnosed Patients with Chronic Lymphocytic Leukemia at High Risk of Infection or Treatment using an Ensemble Machine Learning Algorithm – Selection of Patients for Enrollment in a Clinical Trial to Improve Immune Dysfunction, Nature Communications, DOI: 10.1038/s41467-019-14225-8
Brieghel B, da Cunha-Bang C, Yde CW, Schmidt AY, Kinalis S, Nadeu F, Andersen MA, Jacobsen LO, Andersen MK, Pedersen LB, Delgado J, Baumann T, Mattsson M, Mansouri L, Rosenquist R, Campo E,. Nielsen FC, Niemann CU: Number of Signaling Pathways Altered by Driver Mutations as a Prognostic Biomarker in Chronic Lymphocytic Leukemia, Clin Cancer Res. 2020 Jan 9. pii: clincanres.4158.2018. doi: 10.1158/1078-0432.CCR-18-4158. [Epub ahead of print]
de Weerdt I, Hofland T, Boer R, Dobber J, Dubois J, Nieuwenhuize D, Mobasher M, de Boer F, Hoogendoorn M, Velders GA, van der Klift M, Remmerswaal EBM, Bemelman FJ, Niemann CU, Kersting S, Levin M-D, Eldering E, Tonino SH and Kater AP: Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment, Blood Advances 2010, DOI 10.1182/bloodadvances.2019000360
Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M: Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. doi: 10.1056/NEJMoa1815281. Epub 2019 Jun 4.
Hleuhel MH, Ben-Dali Y, Da Cunha-Bang C, Brieghel C, Clasen-Linde E, Niemann CU, Andersen MA: Risk factors associated with Richter's transformation in patients with chronic lymphocytic leukaemia: protocol for a retrospective population-based cohort study. BMJ Open. 2019 Mar 3;9(3):e023566. doi: 10.1136/bmjopen-2018-023566
Bidrag (CLL og lymfoproliferative sygdomme) til Kap. 34: Blodsygdomme i Medicinsk Kompendium (19. udgave) red. af Jesper Hastrup, Hendrik Vilstrup og Ove Schaffalitzky, 2019, ISBN 978-87-628-1752-4
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: Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase II study. Blood. 2018 Feb 26. pii: blood-2017-12-820910. doi: 10.1182/blood-2017-12-820910.
Niemann CU, Mora-Jensen HI, Dadashian EL, Krantz F, Covey T, Chen SS, Chiorazzi N, Izumi R, Ulrich R, Lannutti BJ, Wiestner A, Herman SEM: Combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model. Clin Cancer Res. 2017 doi: 10.1158/1078-0432.CCR-17-0650.
Jerkeman M, Eskelund CW, Hutchings M, Räty R, Wader KF, Laurell A, Toldbod H, Pedersen LB, Niemann CU, Dahl C, Kuitunen H, Geisler CH, Grønbæk K, Kolstad A: Ibrutinib-Lenalidomide-Rituximab in Relapsed/Refractory Mantle Cell Lymphoma. The Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial, Lancet Haem, 2018,doi: 10.1016/S2352-3026(18)30018-8.
Rawstron AC, Kreuzer KA, Soosapilla A, Spacek M, Stehlikova O, Gambell P, McIver-Brown N, Villamor N, Psarra K, Arroz M, Milani R, de la Serna J, Cedena MT, Jaksic O, Nomdedeu J, Moreno C, Rigolin GM, Cuneo A, Johansen P, Johnsen HE, Rosenquist R, Niemann CU, Kern W, Westerman D, Trneny M, Mulligan S, Doubek M, Pospisilova S, Hillmen P, Oscier D, Hallek M, Ghia P, Montserrat E.:Reproducible diagnosis of Chronic Lymphocytic Leukemia by flow cytometry: an European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) harmonisation project. Cytometry B Clin Cytom. 2017 Oct 10. doi: 10.1002/cyto.b.21595.
Malcikova J, Tausch E, Rossi D, Sutton LA, Soussi T, Zenz T, Kater AP, Niemann CU, Gonzalez D, Davi F, Gonzalez Diaz M, Moreno C, Gaidano G, Stamatopoulos K, Rosenquist R, Stilgenbauer S, Ghia P, Pospisilova S: ERIC Recommendations for TP53 Mutation Analysis in Chronic Lymphocytic Leukemia – Update on Methodological Approaches and Results Interpretation, Leukemia, 2018, , doi:10.1038/s41375-017-0007-7
Vojdeman FJ, Herman SEM, Kirkby N, Wiestner A, van t’Veer MB, Tjønnfjord GE, Itälä- Remes MA, Kimby E, Farooqui MZ, Polliack A, Wu KL, Doorduijn JK, Alemayehu WG, Wittebol S, Kozak T, Walewski J, Abrahamse-Testroote MCJ, van Oers MHJ, Geisler CH and Niemann CU: Soluble CD52 is an indicator of disease activity in chronic lymphocytic leukemia, Leuk Lymphoma. 2017 doi.org/10.1080/10428194.2017.1285027
Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A, Pedersen LB, Montano-Almendras CP, Husby S, Freiburghaus C, Ek S, Pedersen A, Niemann CU, Räty R, Brown P, Geisler CH, Andersen MK, Guldberg P, Jerkeman M, Grønbæk K: TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017 doi: 10.1182/blood-2017-04-779736.
Niemann CU and Christiansen I: Kronisk Lymfoproliferative Sygdomme, kapitel i Hæmatologi i klinisk praksis (Overgaard U and Birgens H ed.), Munksgaard januar 2017
Niemann CU and Christiansen I: Kronisk Lymfoproliferative Sygdomme, kapitel i Hæmatologi i klinisk praksis (Overgaard U and Birgens H ed.), Munksgaard januar 2017
von-Tresckow J, Bahlo J, Niemann CU, Kater AP, Fink AM, Fischer K, Ritgen M, Kreuzer KA, Stilgenbauer S, van Oers R, Geisler CG, Hellek M, Eichhorst B: The GAIA (CLL13) trial – an international, randomized, four-arm study for first line treatment of physically fit CLL patients without del17p or TP53 mutation, Integr Cancer Sci Therap, 2017 doi: 10.15761/ICST.1000252 Volume 4(5): 1-2
Niemann CU and Christiansen I: Kronisk Lymfoproliferative Sygdomme, kapitel i Hæmatologi i klinisk praksis (Overgaard U and Birgens H ed.), Munksgaard 2016.
Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, Mantel R, Smith LL, Harrington B, Colomer D, Covey T, Byrd JC, Izumi R, Kaptein A, Urlich R, Johnson AJ, Lannutti BJ, Wiestner A, and Woyach JA: The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia, Clin Cancer Res. 2016 nov, DOI: 10.1158/1078-0432.CCR-16-0463
da Cunha-Bang C, Geisler CH, Enggaard L, Poulsen CB, de Nully Brown P, Frederiksen H, Bergman O, Pulczynski E, Pedersen R, Nielsen L, Christiansen I, Niemann CU: The Danish National CLL Registry, Clinical Epidemiology, 2016 Oct 25;8:561-565
da Cunha-Bang C, Christiansen I, Niemann CU: The International prognostic Index for patients with chronic lymphocytic leukemia (CLL-IPI) applied in a population-based cohort. Blood. 2016 Oct 27;128(17):2181-2183
Sutton LA, Young E, Baliakas P, Hadzidimitriou A, Moysiadis T, Plevova K, Rossi D, Kminkova J, Stalika E, Pedersen LB, Malcikova J, Agathangelidis A, Davis Z, Mansouri L, Scarfò L, Boudjoghra M, Navarro A, Muggen AF, Yan XJ, Nguyen, 20Khac F, Larrayoz M, Panagiotidis P, Chiorazzi N, Niemann CU, Belessi C, Campo E, Strefford JC, Langerak AW, Oscier D, Gaidano G, Pospisilova S, Davi F, Ghia P, Stamatopoulos K, Rosenquist R: Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors. Haematologica. 2016 Aug;101(8):959-67. Doi: 10.3324/haematol.2016.141812
Niemann CU, Herman SEMH, Maric I, Gomez-Rodriguez J, Biancotto A, Chang BY, Martyr S, Stetler-Stevenson M, Yuan C, Calvo KR, Braylan RC, Valdez J, Lee YS, Wong DH, Jones J, Sun CCL, Marti GE, Farooqui MZ, Wiestner A: Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib – findings from an investigator initiated phase 2 study, Clin Cancer Res. 2016 Apr 1;22(7):1572-82. doi: 10.1158/1078-0432.CCR-15-1965
Skarzynski M, Niemann CU, Lee YS, Martyr S, Maric I, Salem D, Stetler-Stevenson M, Marti GE, Calvo KR, Yuan CM, Valdez J, Soto S, Farooqui MZH, Herman SEM, Wiestner A: Inter¬actions between ibrutinib and anti-CD20 antibodies; competing effects on the outcome of combi¬nation therapy, Clin Cancer Res. 2016 Jan 1;22(1):86-95. doi: 10.1158/1078-0432.CCR-15-1304.
Lipsky AH, Farooqui MZH, Tian X, Martyr S, Cullinane AM, Nghiem K, Sun C, Valdez J, Niemann CU, Herman SEM, Saba N, Soto S, Marti G, Uzel G, Holland SM, Lozier JN, Wiestner A: Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib, Haematologica. 2015 Dec;100(12):1571-8. doi: 10.3324/haematol.2015.126672
Farooqui MZH, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SEM, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A: Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial, Lancet Oncol. 2015 Feb;16(2):169-76. doi: 10.1016/S1470-2045(14)71182-9
Herman SEM*, Niemann CU*, Farooqui M*, Jones J, Mustafa RZ, Lipsky A, Saba N, Martyr S, Soto S, Valdez J, Gyamfi JA, Maric I, Calvo KR, Pedersen LB, Geisler CH, Liu D, Marti GE, Aue G, Wiestner A: Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014 Nov;28(11):2188-96. doi: 10.1038/leu.2014.122. *shared 1st authors
Niemann CU, Geisler CH: Målrettet behandling af lymfoproliferativ sygdom: Kinasehæmmere og Bcl-2 hæmmere, Ugeskr Læger 2014;176:V66229
Niemann CU: Målrettet behandling af kronisk lymfatisk leukæmi, Statusartikel, Ugeskrift for Læger, 2014, April, Ugeskr Læger 2014;176:V11130682
Niemann CU, Polliack A, Hutchings M: Suspected Richter transformation: positron emission tomography/computed tomography tells us who should have a biopsy and where. Leuk Lymphoma. 2014 Feb;55(2):233-4
Niemann CU, Wiestner A: B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013 Dec;23(6):410-21
Niemann CU, Jones J, Wiestner A: Towards targeted therapy of Chronic Lymphocytic Leukemia, book chapter in: Advances in Chronic Lymphocytic Leukemia, in the series: Advances in Experimental Medicine and Biology, 2013;792: 259-91