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  • 1.
    Angenendt, Linus
    et al.
    Univ Hosp Munster, Munster, Germany.
    Röllig, Christoph
    Tech Univ Dresden, Univ Hosp, Dresden, Germany.
    Montesinos, Pau
    Hosp Univ & Politec La Fe, Valencia, Spain;Ctr Invest Biomed Red Canc, Madrid, Spain.
    Martinez-Cuadron, David
    Hosp Univ & Politec La Fe, Valencia, Spain;Ctr Invest Biomed Red Canc, Madrid, Spain.
    Barragan, Eva
    Hosp Univ & Politec La Fe, Valencia, Spain;Ctr Invest Biomed Red Canc, Madrid, Spain.
    Garcia, Raimundo
    Gen Hosp Castellon, Castellon de La Plana, Spain.
    Botella, Carmen
    Hosp Gen Alicante, Alicante, Spain.
    Martinez, Pilar
    Hosp 12 Octubre, Madrid, Spain.
    Ravandi, Farhad
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Kadia, Tapan
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Kantarjian, Hagop M.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Cortes, Jorge
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Juliusson, Gunnar
    Lund Univ, Lund, Sweden.
    Lazarevic, Vladimir
    Lund Univ, Lund, Sweden.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Recher, Christian
    CHU Toulouse, Toulouse, France.
    Pigneux, Arnaud
    CHU Bordeaux, Hop Haut Leveque, Bordeaux, France.
    Bertoli, Sarah
    CHU Toulouse, Toulouse, France.
    Dumas, Pierre-Yves
    CHU Bordeaux, Hop Haut Leveque, Bordeaux, France.
    Dombret, Herve
    Paris Diderot Univ, Paris, France.
    Preudhomme, Claude
    Inst Natl Sante & Rech Med Lille, Lille, France.
    Micol, Jean-Baptiste
    Paris Saclay Univ, Gustave Roussy, Villejuif, France.
    Terre, Christine
    Ctr Transfus Sanguine, Le Chesnay, France.
    Racil, Zdenek
    Masaryk Univ, Univ Hosp Brno, Brno, Czech Republic.
    Novak, Jan
    Charles Univ Prague, Univ Hosp Kralovske Vinohrady, Fac Med 3, Prague, Czech Republic.
    Zak, Pavel
    Charles Univ Prague, Univ Hosp Hradec Kralove, Hradec Kralove, Czech Republic.
    Wei, Andrew H.
    Monash Univ, Alfred Hosp, Melbourne, Vic, Australia.
    Tiong, Ing S.
    Monash Univ, Alfred Hosp, Melbourne, Vic, Australia.
    Wall, Meaghan
    St Vincents Hosp, Melbourne, Vic, Australia.
    Estey, Elihu
    Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA.
    Shaw, Carole
    Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA.
    Exeler, Rita
    Univ Munster, Munster, Germany.
    Wagenführ, Lisa
    Tech Univ Dresden, Univ Hosp, Dresden, Germany.
    Stölzel, Friedrich
    Tech Univ Dresden, Univ Hosp, Dresden, Germany.
    Thiede, Christian
    Tech Univ Dresden, Univ Hosp, Dresden, Germany.
    Stelljes, Matthias
    Univ Hosp Munster, Munster, Germany.
    Lenz, Georg
    Univ Hosp Munster, Munster, Germany.
    Mikesch, Jan-Henrik
    Univ Hosp Munster, Munster, Germany.
    Serve, Hubert
    Univ Hosp Frankfurt, Frankfurt, Germany.
    Ehninger, Gerhard
    Tech Univ Dresden, Univ Hosp, Dresden, Germany.
    Berdel, Wolfgang E.
    Univ Hosp Munster, Munster, Germany.
    Kramer, Michael
    Tech Univ Dresden, Univ Hosp, Dresden, Germany.
    Krug, Utz
    Klinikum Leverkusen, Leverkusen, Germany.
    Schliemann, Christoph
    Univ Hosp Munster, Munster, Germany.
    Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts2019In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 29, p. 2632-2642Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

    METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1(mut)/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

    RESULTS: Among 2,426 patients with NPM1(mut)/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1(mut)/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.

    CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1(mut)/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1(mut) share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1(mut)/FLT3-ITDneg/low AML.

  • 2. Armuand, Gabriela M.
    et al.
    Rodriguez-Wallberg, Kenny A.
    Wettergren, Lena
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lampic, Claudia
    Sex Differences in Fertility-Related Information Received by Young Adult Cancer Survivors2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 17, p. 2147-2153Article in journal (Refereed)
    Abstract [en]

    Purpose The aim was to investigate male and female cancer survivors' perception of fertility-related information and use of fertility preservation (FP) in connection with cancer treatment during reproductive age.

    Methods The study sample consisted of cancer survivors diagnosed from 2003 to 2007 identified in population-based registers in Sweden. Inclusion criteria included survivors who were age 18 to 45 years at diagnosis and had lymphoma, acute leukemia, testicular cancer, ovarian cancer, or female breast cancer treated with chemotherapy. Of 810 eligible participants, 484 survivors (60% response rate) completed a postal questionnaire.

    Results The majority of male participants reported having received information about treatment impact on fertility (80%) and FP (68%), and more than half of the men banked frozen sperm (54%). Among women, less than half (48%) reported that they received information about treatment impact on fertility, and 14% reported that they received information about FP. Only seven women (2%) underwent FP. Predictors for receiving information about treatment impact on fertility were a pretreatment desire to have children (odds ratio [OR], 3.5), male sex (OR, 3.2), and being <= 35 years of age at diagnosis (OR, 2.0). Predictors for receiving information about FP included male sex (OR, 14.4), age <= 35 at diagnosis (OR, 5.1), and having no children at diagnosis (OR, 2.5).

    Conclusion Our results show marked sex differences regarding the receipt of fertility-related information and use of FP. There is an urgent need to develop fertility-related information adapted to female patients with cancer to improve their opportunities to participate in informed decisions regarding their treatment and future reproductive ability.

  • 3.
    Björkholm, Magnus
    et al.
    Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Bower, Hannah
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Dickman, Paul W.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lambert, Paul C.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Andersson, Therese M-L
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Temporal Trends in Chronic Myeloid Leukemia Outcome Using the Loss in Expectation of Life: A Swedish Population-Based Study2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 4. Bower, Hannah
    et al.
    Björkholm, Magnus
    Dickman, Paul W
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lambert, Paul C
    Andersson, Therese M-L
    Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 24, p. 2851-2858Article in journal (Refereed)
    Abstract [en]

    PURPOSE: A dramatic improvement in the survival of patients with chronic myeloid leukemia (CML) occurred after the introduction of imatinib mesylate, the first tyrosine kinase inhibitor (TKI). We assessed how these changes affected the life expectancy of patients with CML and life-years lost as a result of CML between 1973 and 2013 in Sweden.

    MATERIALS AND METHODS: Patients recorded as having CML in the Swedish Cancer Registry from 1973 to 2013 were included in the study and followed until death, censorship, or end of follow-up. The life expectancy and loss in expectation of life were predicted from a flexible parametric relative survival model.

    RESULTS: A total of 2,662 patients with CML were diagnosed between 1973 and 2013. Vast improvements in the life expectancy of these patients were seen over the study period; larger improvements were seen in the youngest ages. The great improvements in life expectancy translated into great reductions in the loss in expectation of life. Patients of all ages diagnosed in 2013 will, on average, lose < 3 life-years as a result of CML.

    CONCLUSION: Imatinib mesylate and new TKIs along with allogeneic stem cell transplantation and other factors have contributed to the life expectancy in patients with CML approaching that of the general population today. This will be an important message to convey to patients to understand the impact of a CML diagnosis on their life. In addition, the increasing prevalence of patients with CML will have a great effect on future health care costs as long as continuous TKI treatment is required.

  • 5.
    Bower, Hannah
    et al.
    Karolinska Institutet.
    Björkholm, Magnus
    Karolinska Univ Hosp.
    Dickman, Paul W
    Karolinska Institutet.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lambert, Paul C
    Karolinska institutet; University of Leicester.
    Andersson, Therese M-L
    Karolinska institutet.
    Reply to D. Pulte et al.2017In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 35, no 6, p. 696-697Article in journal (Refereed)
  • 6.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Adjuvanted influenza a (H1N1) 2009 vaccine in patients with hematological diseases: good safety and immunogenicity even in chemotherapy-treated patients2013In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 90, no 5, p. 413-419Article in journal (Refereed)
    Abstract [en]

    Background Patients with hematological malignancies are more susceptible to viral infections including influenza. In 2009, the World Health Organization classified the novel influenza A (H1N1) virus as pandemic. The potential impact of this pandemic for patients with hematological disorders was unknown. Institutional guidelines recommended two doses of AS03-adjuvanted influenza A (H1N1) 2009 pandemic vaccine for these patients. Objectives We aimed to determine the safety, immunogenicity, and clinical efficacy of this vaccine in patients with hematological diseases. Furthermore, we compared the immunological responses to that obtained by the non-adjuvanted trivalent seasonal influenza vaccine (TIV). Methods All included patients received adjuvanted pandemic vaccine and the majority received TIV. Serum for antibody analyses was collected at five time points. Results Thirty-one patients with different hematological diseases were included. After the second vaccine dose, a total of 25 (81%) reached both protective levels of antibodies and seroconversion response. Antibody titers1:40 persisted for 50% of responding patients at 1yr. Seroconversion was observed in 69% of 14 patients who had undergone hematopoietic stem cell transplantation and in all (9/9) patients with myeloma (five with ongoing treatment including high-dose corticosteroids). After vaccination with TIV, seroconversions against the three included strains were detected in 28%, 40%, and 20%. Response to the adjuvanted pandemic vaccine was superior (P<0.009). Conclusions A substantial proportion of patients with hematological malignancies including patients undergoing chemotherapy mounted a good response to the adjuvanted pandemic vaccine. This vaccine had superior immunogenicity as compared to the non-adjuvanted TIV.

  • 7.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Influenza A H1N1 2009 Vaccine in Patients with Hematological Diseases: Good Safety and Immunogenicity Even in Heavily Chemotherapy-Treated Patients2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21, p. 1054-Article in journal (Refereed)
  • 8.
    Christiansson, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevarn, Berit
    Norrland Univ Hosp, Dept Hematol, Umea, Sweden..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Coagulat, Lund, Sweden..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Mustjoki, Satu
    Univ Helsinki, Dept Med, Div Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses2015In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed)
    Abstract [en]

    Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. 

  • 9. Dahlen, Torsten
    et al.
    Edgren, Gustaf
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lambe, Mats
    Bjorkholm, Magnus
    Sandin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sjalander, Anders
    Richter, Johan
    Ohm, Lotta
    Back, Magnus
    Stenke, Leif
    Increased Risk of Cardiovascular Events Associated with TKI Treatment in Chronic Phase Chronic Myeloid Leukemia. Data from Swedish Population-Based Registries2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 10.
    Deneberg, Stefan
    et al.
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden.;Karolinska Inst, Inst Med, Stockholm, Sweden..
    Lundin, Ebba
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden..
    Lazarevic, Vladimir
    Skane Univ Hosp, Dept Hematol, Lund, Sweden..
    Benson, Lina
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden..
    Uggla, Bertil
    Orebro Univ Hosp, Med, Orebro, Sweden..
    Antunovic, Petar
    Linkoping Univ Hosp, Hematol, S-58185 Linkoping, Sweden..
    Mollgard, Lars
    Sahlgrens Univ Hosp, Dept Hematol, Gothenbourg, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Skane Univ Hosp, Dept Hematol, Lund, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Derolf, Asa Rangert
    Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Reasons for Decreasing Early Mortality in Acute Myeloid Leukemia: An Epidemiological Study from the Swedish Acute Leukemia Registry2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 11.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gammelgård, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wikstrom, Kristina I.
    Karolinska Univ Hosp Huddinge, VECURA, Stockholm, Sweden.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia2018In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 24, p. 6185-6194Article in journal (Refereed)
    Abstract [en]

    Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.

    Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.

    Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.

    Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.

  • 12.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wikström, Kristina I.
    Karolinska Hosp, VECURA, Huddinge, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Clinical Trial Using Third Generation CD19 Targeting CAR T Cells for Relapsed Lymphoma and Leukemia2016In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 24, p. S295-S296Article in journal (Other academic)
  • 13.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wikström, Kristina
    Karolinska Univ Hosp, VECURA, Stockholm, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Collage Med, Ctr Cell & Gene Therapy, Houston, TX USA..
    Brenner, Malcolm K.
    Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.;Houston Methodist Hosp, Houston, TX USA..
    Dotti, Gianpietro
    Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.;Houston Methodist Hosp, Houston, TX USA..
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Third Generation CD19-CAR T Cells for Relapsed and Refractory Lymphoma and Leukemia Report from the Swedish Phase I/IIa Trial2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 14.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wikström, Kristina I.
    Karolinska Univ Hosp, VECURA, Huddinge, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    CD19-targeting third generation CAR T cells for relapsed and refractory lymphoma and leukemia: report from the Swedish phase Ulla trial2016In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 4, no 1Article in journal (Other academic)
  • 15.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Chantzi, Efthymia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 41-46Article in journal (Refereed)
    Abstract [en]

    We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.

  • 16.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 367-368Article in journal (Other academic)
  • 17.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Ekholm, C
    Jenmalm Jensen, A
    Löthgren, A
    Lehmann, F
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Parrow, V
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia2012In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 2, p. e81-Article in journal (Refereed)
    Abstract [en]

    Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

  • 18.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hassan, Sadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekholm, Carina
    Fhölenhag, Karin
    Jensen, Annika Jenmalm
    Löthgren, Agneta
    Scobie, Martin
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Parrow, Vendela
    Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia2010In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 80, no 10, p. 1507-1516Article in journal (Refereed)
    Abstract [en]

    Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low molecular weight kinase inhibitor, AKN-032, targeting the FMS-like tyrosine kinase 3 (FLT3) and discovered in a new type of screening funnel combining the target therapy approach with sequential cellular screens. AKN-032 was identified among 150 selected hits from three different high throughput kinase screens. Further characterization showed inhibitory activity on FLT3 enzyme with an IC50 of 70 nM. Western blot analysis revealed reduced autophosphorylation of the FLT3-receptor in AML cell line MV4-11 cells after exposure to AKN-032. Flow cytometry disclosed cytotoxic activity against MV4-11, but not against non-malignant 3T3-L1 fibroblast cells. Using a fluorometric microculture cytotoxicity assay, AKN-032 was tested against 15 cell lines and displayed a potent cytotoxic activity in AML cell lines MV4-11 (IC50 = 0.4 mu M) and Kasumi-1 (IC50 = 2.3 mu M). AKN-032 was also highly cytotoxic in tumor cells from AML patients in vitro. Furthermore, AKN-032 demonstrated significant antileukemic effect in a relatively resistant in vivo hollow fiber mouse model. No major toxicity was observed in the animals. In conclusion. AKN-032 is a promising new kinase inhibitor with significant in vivo and in vitro activity in AML Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML.

  • 19.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hilhorst, Riet
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson Kultima, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    de Wijn, Rik
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Parrow, Vendela
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia2014In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 87, no 2, p. 284-291Article in journal (Refereed)
    Abstract [en]

    AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

  • 20.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Osterros, Albin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hassan, Sadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Repositioning of Quinacrine for Treatment of Acute Myeloid Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 21.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Österroos, Albin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hassan, Sadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia2015In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 5, article id e307Article in journal (Refereed)
    Abstract [en]

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 mu M drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.

  • 22. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nahi, Hareth
    Palmqvist, Lars
    Paul, Christer
    Paul, Esbjorn
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Correlation between cytidine deaminase single nucleotide polymorphisms and in vitro drug sensitivity, DNA methylation and outcome in normal karyotype acute myelogenous leukemia2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 23. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5 '-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A> C rs2072671 and 2451C> T rs532545), 50-nucleotidase (cN-II 7A> G rs10883841), and deoxycytidine kinase (DCK 30UTR 948T> C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P< 0.001 and 5 vs. 23 months, P50.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P50.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML. Am. J. Hematol. 88: 1001-1006, 2013.

  • 24. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, no 5, p. 671-680Article in journal (Refereed)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 25.
    Geelen, Inge G. P.
    et al.
    Albert Schweitzer Hosp, Dept Internal Med Hematol, Dordrecht, Netherlands.
    Sandin, Fredrik
    Reg Canc Ctr, Uppsala, Sweden.
    Thielen, Noortje
    Diakonessen Hosp, Dept Internal Med, Utrecht, Netherlands;Vrije Univ Amsterdam, Dept Hematol, Med Ctr, Amsterdam, Netherlands.
    Janssen, Jeroen J. W. M.
    Vrije Univ Amsterdam, Dept Hematol, Med Ctr, Amsterdam, Netherlands.
    Hoogendoorn, Mels
    Med Ctr Leeuwarden, Dept Hematol, Leeuwarden, Netherlands.
    Visser, Otto
    Netherlands Comprehens Canc Org IKNL, Utrecht, Netherlands.
    Cornelissen, Jan J.
    Erasmus MC, Dept Hematol, Rotterdam, Netherlands.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Westerweel, Peter E.
    Albert Schweitzer Hosp, Dept Internal Med Hematol, Dordrecht, Netherlands.
    Validation of the EUTOS long-term survival score in a recent independent cohort of "real world" CML patients2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 10, p. 2299-2303Article in journal (Refereed)
  • 26. Genovese, Giulio
    et al.
    Kaehler, Anna K.
    Handsaker, Robert E.
    Lindberg, Johan
    Rose, Samuel A.
    Bakhoum, Samuel F.
    Chambert, Kimberly
    Mick, Eran
    Neale, Benjamin M.
    Fromer, Menachem
    Purcell, Shaun M.
    Svantesson, Oscar
    Landen, Mikael
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gabriel, Stacey B.
    Moran, Jennifer L.
    Lander, Eric S.
    Sullivan, Patrick F.
    Sklar, Pamela
    Groenberg, Henrik
    Hultman, Christina M.
    McCarroll, Steven A.
    Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 371, no 26, p. 2477-2487Article in journal (Refereed)
    Abstract [en]

    Background Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Methods We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Results Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Conclusions Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers.

  • 27.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 28.
    Gunnarsson, N.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Sandin, F.
    Reg Canc Ctr, Uppsala, Sweden..
    Bjorkholm, M.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Dreimane, A.
    Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Lambe, M.
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, B.
    Univ Hosp, Dept Hematol, Umea, Sweden..
    Olsson-Stromberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Hosp, Dept Med Sci, Uppsala, Sweden.;Univ Hosp, Div Hematol, Uppsala, Sweden..
    Wadenvik, H.
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Sjalander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    No increased prevalence of malignancies among first-degree relatives of 800 patients with chronic myeloid leukemia: a population-based study in Sweden2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 8, p. 1825-1827Article in journal (Other academic)
  • 29.
    Gunnarsson, N.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Wallberg-Jonsson, S.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Sandin, F.
    Reg Canc Ctr, Uppsala, Sweden..
    Björkholm, M.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Dreimane, A.
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Lambe, M.
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, B.
    Univ Umea Hosp, Dept Hematol, Umea, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wadenvik, H.
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Själander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 7, p. 1562-1567Article in journal (Refereed)
    Abstract [en]

    We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

  • 30.
    Gunnarsson, Niklas
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Gavle, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Jonsson, Solveig Wallberg
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Sandin, Fredrik
    Reg Canc Ctr, Uppsala, Sweden..
    Bjorkholm, Magnus
    Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Dreimane, Arta
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Lambe, Mats
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Sjalander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Increased Prevalence of Prior Malignancies and Autoimmune Diseases in Patients Diagnosed with Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 31. Gunnarsson, Niklas
    et al.
    Leif, Stenke
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bjorkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevarn, Berit
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Sjalander, Anders
    Second Malignancies Following Treatment of Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 32.
    Gunnarsson, Niklas
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Sandin, Fredrik
    Reg Canc Ctr, Uppsala, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Hosp, Dept Med Sci, Uppsala, Sweden.;Univ Hosp, Div Hematol, Uppsala, Sweden..
    Stenke, Leif
    Karolinska Inst, Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Björkholm, Magnus
    Karolinska Inst, Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Lambe, Mats
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Hosp, Dept Med Sci, Uppsala, Sweden.;Univ Hosp, Div Hematol, Uppsala, Sweden..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Själander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Population-based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence2016In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 97, no 4, p. 387-392Article in journal (Refereed)
    Abstract [en]

    The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5-year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5-year relative survival was close to normal for 40-year-old, but considerably lower for 80-year-old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.

  • 33. Gunnarsson, Niklas
    et al.
    Stenke, Leif
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandin, Fredrik
    Bjorkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevarn, Berit
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Sjalander, Anders
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 5, p. 683-688Article in journal (Refereed)
    Abstract [en]

    Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 37 (range 0-99)years, 65 (75%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 152 (95% CI 113-199). The SIR before and after the second year following diagnosis of CML was 158 and 147, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment.

  • 34.
    Haglund, Caroline
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues2012In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 69, no 3, p. 697-707Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to evaluate a phenotypic cell panel with tumor cells from various patients and normal cells for preclinical profiles of antitumor efficacy and toxicity of anticancer drugs.

    METHODS: The antitumor activity of fourteen anticancer drugs was tested in over one hundred tumor samples from patients with solid or hematological malignancies. Drug activity against four normal cell types was used for the assessment of normal tissue toxicity. In vitro activity of the drugs was compared with indications approved by the Food and Drug Administration and established adverse event profiles.

    RESULTS: In general, in vitro drug activity in tumor cells from patients reflected known clinical activity of the drugs investigated. For example, the clinical activity of imatinib in chronic myeloid leukemia was clearly detected in the tumor panel. Further, and in accordance with clinical use, cisplatin and bortezomib showed high activity in ovarian cancer and myeloma samples, respectively. The normal cell models roughly reflected known clinical toxicity profiles and were able to detect differences in therapeutic index, e.g., between targeted drugs and classical cytotoxic agents. For example, the high tolerability of imatinib and the well-known renal toxicity of cisplatin were demonstrated.

    CONCLUSIONS: In preclinical drug development, primary tumor cells from patients can be used for the prediction of cancer diagnosis-specific activity and may aid in the selection of diagnoses for clinical trials. By using tumor and toxicity panels together, information about therapeutic index may be derived, which may be useful when choosing among drug candidates with similar tumor effects.

  • 35.
    Hjorth-Hansen, Henrik
    et al.
    Norwegian Univ Sci & Technol NTNU, Dept Canc Researc & Mol Med IKM, Trondheim, Norway.;St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Stentoft, Jesper
    Richter, Johan
    Aarhus Univ Hosp, Dept Hematol, DK-8000 Aarhus, Denmark.;Lund Univ, Dept Mol Med & Gene Therapy, Lund, Sweden.;Lund Univ, Dept Hematol & Vasc Disorders, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden.;Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Koskenvesa, Perttu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Dreimane, Arta
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Cty Council Ostergotland, Dept Hematol, Linkoping, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Gedde-Dahl, Tobias
    Oslo Univ Hosp, N-0450 Oslo, Norway.;Oslo Univ Hosp, Dept Internal Medcine, N-0450 Oslo, Norway..
    Gjertsen, Bjorn
    Haukeland Hosp, Dept Internal Med, N-5021 Bergen, Norway..
    Gruber, Franz X.
    Univ Hosp North Norway, Dept Internal Med, Tromso, Norway..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lubking, Anna
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Myhr-Eriksson, Kristina
    Sunderby Hosp, Dept Internal Med, Lulea, Sweden..
    Markevarn, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Vestergaard, Hanne
    Odense Univ Hosp, Dept Hematol, DK-5000 Odense, Denmark..
    Bjerrurn, Ole Weis
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Dept Hematol, Ctr Comprehens Canc, Helsinki, Finland..
    Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Safety and Efficacy of Addition of Pegylated Interferon alpha2b to Standard Dose Dasatinib in Newly Diagnosed Chronic Phase CML Patients2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 36. Hoffmann, V S
    et al.
    Baccarani, M
    Hasford, J
    Castagnetti, F
    Di Raimondo, F
    Casado, L F
    Turkina, A
    Zackova, D
    Ossenkoppele, G
    Zaritskey, A
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Indrak, K
    Sninska, Z
    Sacha, T
    Clark, R
    Bogdanovic, A
    Hellmann, A
    Griskevicius, L
    Schubert-Fritschle, G
    Sertic, D
    Guilhot, J
    Lejniece, S
    Zupan, I
    Burgstaller, S
    Koskenvesa, P
    Everaus, H
    Costeas, P
    Lindoerfer, D
    Rosti, G
    Saussele, S
    Hochhaus, A
    Hehlmann, R
    Treatment and outcome of 2904 CML patients from the EUTOS population-based registry2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 3, p. 593-601Article in journal (Refereed)
    Abstract [en]

    The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.Leukemia advance online publication, 23 September 2016; doi:10.1038/leu.2016.246.

  • 37. Hoffmann, Verena S.
    et al.
    Lindoerfer, Doris
    Thaler, Josef
    Boris, Labar
    Melanthiou, Frederiki
    Mayer, Jiri
    Everaus, Hele
    Guilhot, Joelle
    Schubert-Fritschle, Gabriele
    Castagnetti, Fausto
    Lejniece, Sandra
    Griskevicius, Laimonas
    Thielen, Noortje
    Sacha, Tomasz
    Hellmann, Andrzej
    Turkina, Anna G.
    Zaritskey, Andrey
    Bogdanovic, Andrija
    Indrak, Karel
    Zupan, Irena
    Steegmann, Juan Luis
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clark, Richard
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hehlmann, Ruediger
    Hasford, Joerg
    Baccarani, Michele
    Incidence of CML in Europe -- a Comparison of 19 European Countries with US SEER Data2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 38. Hulegårdh, Erik
    et al.
    Nilsson, Christer
    Lazarevic, Vladimir
    Garelius, Hege
    Antunovic, Petar
    Derolf, Asa Rangert
    Möllgård, Lars
    Uggla, Bertil
    Wennström, Lovisa
    Wahlin, Anders
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Stockelberg, Dick
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Characterization and prognostic features of secondary acute myeloid leukemia (AML) in a population-based setting: A report from the Swedish Acute Leukemia Registry2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 3, p. 208-214Article in journal (Refereed)
    Abstract [en]

    Patients with secondary AML often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3363 adult patients of which 2474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients whereas it lacks prognostic value among the elderly patients.

  • 39.
    Höglund, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandin, Fredrik
    Hellstrom, Karin
    Bjoreman, Mats
    Bjorkholm, Magnus
    Brune, Mats
    Dreimane, Arta
    Ekblom, Marja
    Lehmann, Soren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Ljungman, Per
    Malm, Claes
    Markevarn, Berit
    Myhr-Eriksson, Kristina
    Ohm, Lotta
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sjalander, Anders
    Wadenvik, Hans
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Richter, Johan
    Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 7, p. 1284-1292Article in journal (Refereed)
    Abstract [en]

    Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100 000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (<70 years) and 79% for older (>80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.

  • 40.
    Höglund, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandin, Fredrik
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Epidemiology of chronic myeloid leukaemia: an update2015In: Annals of Hematology, ISSN 0939-5555, E-ISSN 1432-0584, Vol. 94, p. S241-S247Article, review/survey (Refereed)
    Abstract [en]

    National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7-1.0/100,000, a median age at diagnosis of 57-60 years and a male/female ratio of 1.2-1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10-12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research.

  • 41. Ilander, M
    et al.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Schlums, H
    Guilhot, J
    Brück, O
    Lähteenmäki, H
    Kasanen, T
    Koskenvesa, P
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevärn, B
    Själander, A
    Lotfi, K
    Dreimane, A
    Lübking, A
    Holm, E
    Björeman, M
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden.
    Stenke, L
    Ohm, L
    Gedde-Dahl, T
    Majeed, W
    Ehrencrona, H
    Koskela, S
    Saussele, S
    Mahon, F-X
    Porkka, K
    Hjorth-Hansen, H
    Bryceson, Y T
    Richter, J
    Mustjoki, S
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, p. 1108-1116Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.Leukemia advance online publication, 16 December 2016; doi:10.1038/leu.2016.360.

  • 42. Ilander, Mette Matilda
    et al.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lahteenmaki, Hanna
    Tiina, Kasanen
    Koskenvesa, Perttu
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevarn, Berit
    Sjalander, Anders
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Bjoreman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Pfirrmann, Markus
    Muller, Martin C.
    Guilhot, Joelle
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Richter, Johan
    Mustjoki, Satu
    Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 43. Ilander, Mette
    et al.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lahteenmaki, Hanna
    Kasanen, Tiina
    Koskenvesa, Perttu
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevarn, Berit
    Sjalander, Anders
    Lofti, Kouros
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Bjoreman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Richter, Johan
    Mustjoki, Satu
    Disease Relapse After Tyrosine Kinase Inhibitor Treatment Discontinuation in Chronic Myeloid Leukaemia is Related to Both Low Number and Impaired Function of NK Cells2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 467-468Article in journal (Other academic)
  • 44.
    Ilander, Mette
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Canc, Helsinki, Finland..
    Schlums, Heinrich
    Karolinska Univ, Huddinge Hosp, Karolinska Inst, Ctr Infect Med,Dept Med, S-14186 Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lahteenmaki, Hanna
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Canc, Helsinki, Finland..
    Kasanen, Tiina
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Canc, Helsinki, Finland..
    Koskenvesa, Perttu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Dept Hematol, Ctr Comprehens Canc, Helsinki, Finland..
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevarn, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Sjalander, Anders
    Umea Univ, Dept Publ Heath & Clin Med, Umea, Sweden..
    Lotfi, Kourosh
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Malm, Claes
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Lubking, Anna
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Ekblom, Marja
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Holm, Elena
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Bjoreman, Mats
    Univ Hosp, Orebro, Sweden..
    Lehmann, Soren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden..
    Stenke, Leif
    Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden..
    Ohm, Lotta
    Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden..
    Majeed, Waleed
    Stavanger Univ Hosp, Stavanger, Norway..
    Muller, Martin C.
    Heidelberg Univ, Univ Med Mannheim, Med Klin 3, Mannheim, Germany..
    Ehrencrona, Hans
    Skane Univ Hosp, Dept Clin Genet, Lund, Sweden..
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Saussele, Susanne
    Heidelberg Univ, Univ Med Mannheim, Med Klin 3, Mannheim, Germany..
    Mahon, Francois-Xavier
    Univ Bordeaux Segalen, Inserm U1035, Bordeaux, France..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Dept Hematol, Ctr Comprehens Canc, Helsinki, Finland..
    Guilhot, Joelle
    Univ Hosp, Inserm CIC 1402, Poitiers, France..
    Bryceson, Yenan
    Karolinska Univ, Huddinge Hosp, Karolinska Inst, Ctr Infect Med,Dept Med, S-14186 Stockholm, Sweden..
    Richter, Johan
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Dept Hematol, Ctr Comprehens Canc, Helsinki, Finland..
    Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 45.
    Jamalpour, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mostoslavsky, Gustavo
    Center for Regenerative Medicine (CReM), Department of Medicine, School of Medicine, Boston University..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 10Article in journal (Refereed)
    Abstract [en]

    Objective: The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Methods: Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Results: Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes (PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. Conclusions: It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.

  • 46.
    Juliusson, Gunnar
    et al.
    Skane Univ Hosp, Dept Hematol & Oncol, Lund, Sweden; Lund Univ, Dept Lab Med, Lund, Sweden.
    Abrahamsson, J
    Lazarevic, V
    Antunovic, P
    Derolf, Å
    Garelius, H
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Myhr-Eriksson, K
    Möllgård, L
    Uggla, B
    Wahlin, A
    Wennström, L
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Prevalence and characteristics of survivors from acute myeloid leukemia in Sweden2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 3, p. 728-731Article in journal (Refereed)
  • 47.
    Juliusson, Gunnar
    et al.
    Lund Univ, Dept Hematol, Lund Stem Cell Ctr, Lund, Sweden..
    Lazarevic, Vladimir
    Skane Univ Hosp, Dept Hematol, Lund, Sweden..
    Antunovic, Petar
    Univ Hosp Linlkoping, Hematol, Linkoping, Sweden..
    Derolf, Asa Rangert
    Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Garelius, Hege
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Med, Gothenburg, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Myhr-Eriksson, Kristina
    Sunderby Hosp, Dept Internal Med, Lulea, Sweden..
    Mollgard, Lars
    Sahlgrens Univ Hosp, Hematol, Gothenburg, Sweden..
    Uggla, Bertil
    Orebro Univ Hosp, Med, Orebro, Sweden..
    Wahlin, Anders
    Norrland Univ Hosp, Hematol, Umea, Sweden..
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Hematol, Gothenburg, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Prevalence and Characteristics of Survivors from Adult Acute Myeloid Leukemia (AML) in Sweden 20142015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 48. Juliusson, Gunnar
    et al.
    Lazarevic, Vladimir
    Hörstedt, Ann-Sofi
    Hagberg, Oskar
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Acute myeloid leukemia in the real world: why population-based registries are needed2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 119, no 17, p. 3890-3899Article in journal (Refereed)
    Abstract [en]

    Population-based registries may provide data complementary to that from basic science and clinical intervention studies, all of which are essential for establishing recommendations for the management of patients in the real world. The same quality criteria apply for the evidence-based label, and both high representation and good data quality are crucial in registry studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations. Thus, data useful for clinical decision in situations not well covered by clinical studies can be provided. The potential clinical impact of data from population-based studies is exemplified with analyses from the Swedish Acute Leukemia Registry containing more than 3300 acute myeloid leukemia (AML) patients diagnosed between 1997 and 2006 with a median follow-up of 6.2 years on (1) the role of intensive combination chemotherapy for older patients with AML, (2) the impact of allogeneic stem cell transplantation on survival of younger patients with AML, and (3) the continuing problem with early deaths in acute promyelocytic leukemia. We also present the first Web-based dynamic graph showing the complex interaction between age, performance status, the proportion of patients given intensive treatment, early death rate, complete remission rate, use of allogeneic transplants, and overall survival in AML (non-AML). 

  • 49. Juliusson, Gunnar
    et al.
    Lazarevic, Vladimir
    Lehmann, Soren
    Derolf, Asa Rangert
    Mollgard, Lars
    Garelius, Hege
    Wennstrom, Lovisa
    Uggla, Bertil
    Antunovic, Petar
    Myhr-Eriksson, Kristina
    Wahlin, Anders
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Improved Survival of Patients with Acute Myeloid Leukemia Following Implementation of Swedish National Guidelines: Results from the AML Registry 1997-20132014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 50.
    Knight, Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hjorton, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Smedby, Karin E
    Askling, Johan
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 4, p. 690-694Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more detail.

    METHODS: From the Swedish population-based patient register, all individuals with a diagnosis of GPA from 1964-2012 were identified (n = 3224). Through linkage with the Swedish Cancer Register, we searched for all cases of leukemia [International Classification of Diseases (ICD) 7: 204-207 and corresponding codes ICD 8-10] registered after the first discharge listing GPA. The GPA diagnosis was evaluated using the European Medical Association classification algorithm. To confirm the hematological malignancy, all diagnostic bone marrow samples were reclassified. Clinical data of both the GPA and hematological malignancy were collected from medical files.

    RESULTS: Twenty-one cases were identified, all of myeloid origin, including 9 with myelodysplastic syndrome developing to acute myeloid leukemia (MDS-AML), 7 AML, 3 MDS, and 2 chronic myeloid leukemia. The median time from GPA diagnosis to hematological malignancy was 8 years (range 5-21). All patients had severe generalized GPA and had received high doses of cyclophosphamide (CYC; median cumulative dose 96.5 g). Cytopenia occurred in 76% of the patients prior to the hematological malignancy.

    CONCLUSION: The findings emphasize the longterm risk of leukemia and MDS in CYC-treated, severely ill patients with GPA. Cytopenia during the course of GPA may be a warning sign and warrants a liberal attitude toward bone marrow examination.

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