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  • 1.
    Cavelier, Lucia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Höijer, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olsson-Strömberg, Ulla
    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, Medicinsk genetik och genomik.
    Clonal distribution of BCR-ABL1 mutations and splice isoforms by single-molecule long-read RNA sequencing2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 45Article in journal (Refereed)
    Abstract [en]

    Background: The evolution of mutations in the BCR-ABL1 fusion gene transcript renders CML patients resistant to tyrosine kinase inhibitor (TKI) based therapy. Thus screening for BCR-ABL1 mutations is recommended particularly in patients experiencing poor response to treatment. Herein we describe a novel approach for the detection and surveillance of BCR-ABL1 mutations in CML patients. Methods: To detect mutations in the BCR-ABL1 transcript we developed an assay based on the Pacific Biosciences (PacBio) sequencing technology, which allows for single-molecule long-read sequencing of BCR-ABL1 fusion transcript molecules. Samples from six patients with poor response to therapy were analyzed both at diagnosis and follow-up. cDNA was generated from total RNA and a 1,6 kb fragment encompassing the BCR-ABL1 transcript was amplified using long range PCR. To estimate the sensitivity of the assay, a serial dilution experiment was performed. Results: Over 10,000 full-length BCR-ABL1 sequences were obtained for all samples studied. Through the serial dilution analysis, mutations in CML patient samples could be detected down to a level of at least 1%. Notably, the assay was determined to be sufficiently sensitive even in patients harboring a low abundance of BCR-ABL1 levels. The PacBio sequencing successfully identified all mutations seen by standard methods. Importantly, we identified several mutations that escaped detection by the clinical routine analysis. Resistance mutations were found in all but one of the patients. Due to the long reads afforded by PacBio sequencing, compound mutations present in the same molecule were readily distinguished from independent alterations arising in different molecules. Moreover, several transcript isoforms of the BCR-ABL1 transcript were identified in two of the CML patients. Finally, our assay allowed for a quick turn around time allowing samples to be reported upon within 2 days. Conclusions: In summary the PacBio sequencing assay can be applied to detect BCR-ABL1 resistance mutations in both diagnostic and follow-up CML patient samples using a simple protocol applicable to routine diagnosis. The method besides its sensitivity, gives a complete view of the clonal distribution of mutations, which is of importance when making therapy decisions.

  • 2.
    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.
    Mustjoki, Satu
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Loskog, Angelica S.I.
    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.
    Mangsbo, Sara
    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.
    The use of multiplex platforms for absolute and relative protein quantification of clinical material2014In: EuPA Open Proteomics, ISSN 2212-9685, Vol. 3, p. 37-47Article in journal (Refereed)
    Abstract [en]

    When introducing multiplex platforms to measure protein content in precious clinical material there is an increased risk of cross reactivity, loss of sensitivity as well as accuracy. In this paper, four multiplex platforms and one singleplex platform were compared by running pre- and post-treatment plasma samples from CML patients. We found a variation of absolute protein concentrations between platforms. For some of the analytes and platforms, relative differences between pre- and post-treatment samples correlated. We conclude that absolute concentrations measured by different platforms should be compared with caution and comparing relative differences could be more accurate.

  • 3.
    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. 

  • 4.
    Dahlin, Joakim S.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekoff, Maria
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Grootens, Jennine
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    KIT signaling is dispensable for human mast cell progenitor development2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 130, no 16, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    Human hematopoietic progenitors are generally assumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation of mast cells. Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo. Furthermore, the absence of SCF or imatinib treatment prevents progenitors from developing into mast cells in vitro. However, these observations do not mean that mast cell progenitors require SCF and KIT signaling throughout differentiation. Here, we demonstrate that circulating mast cell progenitors are present in patients undergoing imatinib treatment. In addition, we show that mast cell progenitors from peripheral blood survive, mature, and proliferate without SCF and KIT signaling in vitro. Contrary to the prevailing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell development.

  • 5.
    Dolinska, Monika
    et al.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Klang, Johannis
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Xiao, Pingnan
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Durgaryan, Andranik
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Sandhow, Lakshmi
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Johansson, Anne-Sofie
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Kondo, Makoto
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Deneberg, Stefan
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden..
    Ungerstedt, Johanna
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Le Blanc, Katarina
    Karolinska Inst, Lab Med Clin Immunol, Stockholm, Sweden..
    Stenke, Leif
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Ekblom, Marja
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Lehmann, Soren
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Qian, Hong
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Phenotypic and Functional Alterations of Bone Marrow Mesenchymal Stem and Progenitor Cells in Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 6.
    Dolinska, Monika
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Piccini, Alexandre
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Wong, Wan Man
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Gelali, Eleni
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Johansson, Anne-Sofie
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Klang, Johannis
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Xiao, Pingnan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Yektaei-Karin, Elham
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Clin Chem & Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekblom, Marja
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Qian, Hong
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 (+)CD38(-) stem and progenitor cells in chronic myeloid leukemia2017In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 490, no 2, p. 378-384Article in journal (Refereed)
    Abstract [en]

    Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABL(+)CD34(+)CD38(-) cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long-term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34(+)CD38(-) cells from 7 CML patients. The majority of the single leukemic BCR-ABL(+)CD34(+)CD38(-) cells expressed cysteinyl leukotriene receptors CYSLTI and CYSLT2. However, montelukast, an inhibitor of CYSLTI, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLTI signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients. (C) 2017 The Author(s). Published by Elsevier Inc.

  • 7.
    El Missiry, M.
    et al.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Hjorth-Hansen, H.
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Olsson-Strömberg, Ulla
    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, Stockholm, Sweden..
    Porkka, K.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Kreutzmann, A.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Mustjoki, S.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Assessment Of Therapy Response In Chronic Myeloid Leukemia Via 1 Month Bcr-Abl1 Transcript Decline2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 63-63Article in journal (Other academic)
  • 8.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit, Helsinki, Finland..
    Adnan, Shady
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Rajala, Hanna
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, HRUH, Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Akademiska sjukhuset, Uppsala..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 9.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit, Helsinki, Finland..
    Adnan, Shady
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Rajala, Hanna
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, HRUH, Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Univ Uppsala Hosp, Dept Pathol, S-75185 Uppsala, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 10.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland..
    Awad, Shady Adnan
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland..
    Rajala, Hanna L.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Svedahl, Ellen Rabben
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Porkka, Kimmo
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Hjorth-Hansen, Henrik
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Haartmaninkatu 8,POB 700, FIN-00290 Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Assessment of bone marrow lymphocytic status during tyrosine kinase inhibitor therapy and its relation to therapy response in chronic myeloid leukaemia2016In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 142, no 5, p. 1041-1050Article in journal (Refereed)
    Abstract [en]

    Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p < 0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR-ABL1 < 10 % showed higher lymphocyte counts than patients with BCR-ABL1 > 10 % (23 vs. 17 %, p < 0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients. Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.

  • 11.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Kreutzman, Anna
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0171041Article in journal (Refereed)
    Abstract [en]

    In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083). Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p< 0.01) and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p< 0.05). The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p< 0.01; 18m 27% vs. 75%, p< 0.01; 24m 55% vs. 87%, p< 0.01). In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.

  • 12.
    Geelen, I.
    et al.
    Albert Schweitzer Hosp, Dordrecht, Netherlands.
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, S.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden.
    Blijlevens, N.
    Radboud UMC, Dept Hematol, Nijmegen, Netherlands.
    Smit, W.
    Med Spectrum Twente, Dept Hematol, Enschede, Netherlands.
    Gjertsen, B.
    Haukeland Hosp, Hematol Sect, Dept Internal Med, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Gedde-Dahl, T.
    Oslo Univ Hosp, Rikshosp, Dept Hematol, Oslo, Norway.
    Markevärn, B.
    Umea Univ Hosp, Dept Hematol, Umea, Sweden.
    Koppes, M.
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Westerweel, P.
    Albert Schweitzer Hosp, Dordrecht, Netherlands.
    Janssen, J.
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Hjorth-Hansen, H.
    St Olavs Hosp, Dept Hematol, Trondheim, Norway;Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.
    CLINICAL AND IMMUNOLOGICAL EFFECTS OF NILOTINIB IN COMBINATION WITH PEGYLATED INTERFERON-A2B IN PATIENTS WITH SUBOPTIMAL MOLECULAR RESPONSE ON IMATINIB (NORDDUTCHCML009)2017In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 435-435, article id E1057Article in journal (Other academic)
  • 13.
    Giustacchini, Alice
    et al.
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Thongjuea, Supat
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Barkas, Nikolaos
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Woll, Petter S.
    Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Povinelli, Benjamin J.
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Booth, Christopher A. G.
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Sopp, Paul
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Norfo, Ruggiero
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Rodriguez-Meira, Alba
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Ashley, Neil
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Jamieson, Lauren
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England..
    Vyas, Paresh
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England..
    Anderson, Kristina
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Cellular Therapy, Oslo, Norway..
    Segerstolpe, Åsa
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.;Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Qian, Hong
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Clin Chem & Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland..
    Sandberg, Rickard
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.;Ludwig Inst Canc Res, Stockholm, Sweden..
    Jacobsen, Sten Eirik W.
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England.;Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.;Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Mead, Adam J.
    Univ Oxford, Weatherall Inst Mol Med, MRC Mol Hematol Unit, Oxford, England.;Univ Oxford, Weatherall Inst Mol Med, Haemopoiet Stem Cell Biol Lab, Oxford, England.;Churchill Hosp, NIHR Biomed Res Ctr, Oxford, England..
    Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia2017In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 23, no 6, p. 692-+Article in journal (Refereed)
    Abstract [en]

    Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

  • 14.
    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.

  • 15.
    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)
  • 16. 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)
  • 17.
    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.

  • 18. 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.

  • 19. Hjorth-Hansen, Henrik
    et al.
    Stenke, Leif
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dreimane, Arta
    Ehrencrona, Hans
    Gedde-Dahl, Tobias
    Gjertsen, Bjørn Tore
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Koskenvesa, Perttu
    Lotfi, Kourosh
    Majeed, Waleed
    Markevärn, Berit
    Ohm, Lotta
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Remes, Kari
    Suominen, Merja
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Porkka, Kimmo
    Mustjoki, Satu
    Richter, Johan
    Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006)2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 64, no 3, p. 243-250Article in journal (Refereed)
    Abstract [en]

    We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR(3.0) was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR(4.5) was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.

  • 20.
    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)
  • 21. 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.

  • 22. 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)
  • 23. 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)
  • 24.
    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)
  • 25. Karlsson, H.
    et al.
    Svensson, E.
    Lindqvist, C.
    Hambardzumyan, K.
    Larsson, R.
    Jarvius, M.
    Stromberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, B.
    Dotti, G.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enhanced proliferation and tyrosine kinase pathway engagement in 4-1BB domain-containing CAR T cells2013In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 24, no 12, p. A163-A163Article in journal (Other academic)
  • 26.
    Karlsson, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gigg, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Antigen Signaling Enhances Proliferation and Cytotoxic Capacity of CD19-Targeting CD28/4-1BB CAR T Cells During Expansion Without Inducing Exhaustion2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S61-S61Article in journal (Other academic)
  • 27.
    Karlsson, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafsson, Wictor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    CAR T Cells Express CD40L and Activates Human Dendritic Cells2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S61-S61Article in journal (Other academic)
  • 28.
    Karlsson, Hannah
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gigg, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0144787Article in journal (Refereed)
    Abstract [en]

    CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G) CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G) CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

  • 29.
    Kreutzman, Anna
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Yadav, Bhagwan
    Univ Helsinki, Hematol Res Unit Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Brummendorf, Tim H.
    Univ Klinikum RWTH Aachen, Dept Hematol & Oncol, Aachen, Germany.
    Gjertsen, Bjorn Tore
    Univ Bergen, Haukeland Univ Hosp, Dept Internal Med, Hematol Sect, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Hee, Moon Lee
    Univ Helsinki, Hematol Res Unit Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Janssen, Jeroen
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Kasanen, Tiina
    Univ Helsinki, Hematol Res Unit Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
    Koskenvesa, Perttu
    Univ Helsinki, Hematol Res Unit Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
    Lofti, Kourosh
    Linkoping Univ, Cty Council Ostergotland, Dept Med & Hlth Sci, Dept Hematol, Linkoping, Sweden.
    Markevarn, Berit
    Umea Univ Hosp, Dept Hematol, Umea, Sweden.
    Stromberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stentoft, Jesper
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden;Karolinska Inst, Stockholm, Sweden.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Udby, Lene
    Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Richter, Johan
    Skane Univ Hosp, Dept Hematol, Lund, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway;Norwegian Univ Sci & Technol NTNU, Dept Clin & Mol Med IKOM, Trondheim, Norway.
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Haartmaninkatu 8, FIN-00290 Helsinki, Finland;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line2019In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 9Article in journal (Refereed)
    Abstract [en]

    Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

  • 30.
    Lauseker, Michael
    et al.
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Bachl, Katharina
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Turkina, Anna
    Natl Res Ctr Hematol, Moscow, Russia.
    Faber, Edgar
    Palacky Univ, Univ Hosp, Dept Hematol Oncol, Olomouc, Czech Republic.
    Prejzner, Witold
    Med Univ Gdansk, Dept Hematol, Gdansk, Poland.
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Baccarani, Michele
    Univ Bologna, Dept Hematol & Oncol L&A, Bologna, Italy.
    Lomaia, Elza
    Almazov Med Res Ctr, Clin Oncol Res Dept Oncol & Hematol, St Petersburg, Russia.
    Zackova, Daniela
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic;Masaryk Univ, Brno, Czech Republic.
    Ossenkoppele, Gert
    Vrije Univ Amsterdam Med Ctr, Amsterdam Univ Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Griskevicius, Laimonas
    Vilnius Univ, Vilnius Univ Hosp Santaros Klin, Vilnius, Lithuania;Vilnius Univ, Inst Clin Med, Vilnius, Lithuania.
    Schubert-Fritschle, Gabriele
    Ludwig Maximilians Univ Munchen, Munich Canc Registry, Munich, Germany.
    Sacha, Tomasz
    Jagiellonian Univ Hosp, Chair & Dept Hematol, Krakow, Poland.
    Heibl, Sonja
    Klinikum Wels Grieskirchen, Dept Internal Med 4, Wels, Austria.
    Koskenvesa, Perttu
    Helsinki Univ Hosp, Ctr Canc, Helsinki, Finland;Univ Helsinki, Hematol Res Unit, Helsinki, Finland.
    Bogdanovic, Andrija
    Univ Belgrade, Clin Hematol CCS, Belgrade, Serbia;Univ Belgrade, Fac Med, Belgrade, Serbia.
    Clark, Richard E.
    Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
    Guilhot, Joelle
    CHU Poitiers, Clin Invest Ctr, INSERM, CIC 1402, Poitiers, France.
    Hoffmann, Verena S.
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Hasford, Joerg
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Hochhaus, Andreas
    Univ Klinikum Jena, Klin Innere Med 2, Abt Hamatol Onkol, Jena, Germany.
    Pfirrmann, Markus
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin2019In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 94, no 11, p. 1236-1243Article in journal (Refereed)
    Abstract [en]

    Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.

  • 31.
    Lubking, Anna
    et al.
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Dreimane, Arta
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden.
    Sandin, Fredrik
    Uppsala Univ Hosp, Reg Canc Ctr, Uppsala, Sweden.
    Isaksson, Cecilia
    Umea Univ Hosp, Dept Hematol, Umea, Sweden.
    Markevarn, Berit
    Umea Univ Hosp, Dept Hematol, Umea, Sweden.
    Brune, Mats
    Sahlgrens Univ Hosp, Dept Hematol & Coagulat, Gothenburg, Sweden.
    Ljungman, Per
    Karolinska Univ Hosp, Dept Cellular Therapy & Allogene Stem Cell Transp, Stockholm, Sweden;Karolinska Inst, Dept Med Huddinge, Sect Hematol, Stockholm, Sweden.
    Lenhoff, Stig
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp Solna, Dept Med, Div Hematol, Stockholm, Sweden.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Richter, Johan
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Allogeneic stem cell transplantation for chronic myeloid leukemia in the TKI era: population-based data from the Swedish CML registry2019In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 54, no 11, p. 1764-1774Article in journal (Refereed)
    Abstract [en]

    Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in a population-based setting using the Swedish CML registry. Of 118 CML patients transplanted between 2002 and 2017, 56 (47.4%) received allo-HSCT in first CP, among whom TM resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at <65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Risk factors for relapse were EBMT score >2 and reduced intensity conditioning, and for death, CP > 2 at time point of allo-HSCT only. Non-relapse mortality for patients transplanted in CP was 11.6%. Our data indicate that allo-HSCT still constitutes a reasonable therapeutic option for patients with CML in first CP, especially those resistant to TKI treatment, providing high long-term survival and low non-relapse mortality.

  • 32.
    Löf, Liza
    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.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. 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.
    Siart, Benjamin
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlin, Joakim S
    Thörn, Ingrid
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Christiansson, Lisa
    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.
    Hermansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ahlstrand, Erik
    Wålinder, Göran
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Flow Cytometric Measurement of Blood Cells with BCR-ABL1 Fusion Protein in Chronic Myeloid Leukemia2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-9, article id 623Article in journal (Refereed)
    Abstract [en]

    Chronic myeloid leukemia (CML) is characterized in the majority of cases by a t(9;22)(q34;q11) translocation, also called the Philadelphia chromosome, giving rise to the BCR-ABL1 fusion protein. Current treatment with tyrosine kinase inhibitors is directed against the constitutively active ABL1 domain of the fusion protein, and minimal residual disease (MRD) after therapy is monitored by real-time quantitative PCR (RQ-PCR) of the fusion transcript. Here, we describe a novel approach to detect and enumerate cells positive for the BCR-ABL1 fusion protein by combining the in situ proximity ligation assay with flow cytometry as readout (PLA-flow). By targeting of the BCR and ABL1 parts of the fusion protein with one antibody each, and creating strong fluorescent signals through rolling circle amplification, PLA-flow allowed sensitive detection of cells positive for the BCR-ABL1 fusion at frequencies as low as one in 10,000. Importantly, the flow cytometric results correlated strongly to those of RQ-PCR, both in diagnostic testing and for MRD measurements over time. In summary, we believe this flow cytometry-based method can serve as an attractive approach for routine measurement of cells harboring BCR-ABL1 fusions, also allowing simultaneously assessment of other cell surface markers as well as sensitive longitudinal follow-up.

  • 33.
    Löf, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    FLOW CYTOMETRY-BASED ASSAY FOR DETECTION OF BCR-ABL FUSION PROTEIN IN BLOOD CELLS FROM CML PATIENTS2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 694-695Article in journal (Other academic)
  • 34.
    Löf, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pla Flow; A Flow Cytometry-Based Assay For Detection Of Bcr-Abl Fusion Protein In Blood Cells From Cml Patients2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 457-458Article in journal (Other academic)
  • 35. Mahon, Francois-Xavier
    et al.
    Richter, Johan
    Guilhot, Joelle
    Muller, Martin C.
    Dietz, Christian
    Porkka, Kimmo
    Hjorth-Hansen, Henrik
    Gruber, Franz
    Panagoitidis, Panos
    Ossenkoppele, Gert J.
    Mayer, Jiri
    Almeida, Antonio
    Polakova, Katerina Machova
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kairisto, Veli
    Berger, Marc G.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Hochhas, Andreas
    Pfirrmann, Markus
    Saussele, Susanne
    Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia: The EURO-SKI study2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 36.
    Pfirrmann, M.
    et al.
    LMU Munchen, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany.
    Mahon, F-X
    Univ Bordeaux, INSERM, Unit 916, Bergonie Canc Inst, Bordeaux, France.
    Guilhot, J.
    CHU Poitiers, INSERM, CIC 1402, Poitiers, France.
    Richter, J.
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Almeida, A.
    Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal.
    Janssen, J. J.
    Vrije Univ Amsterdam, Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Mayer, J.
    Masaryk Univ Hosp, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.
    Koskenvesa, P.
    Univ Helsinki, Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland;Univ Helsinki, Helsinki Univ Hosp, Ctr Comprehens Canc, Hematol Res Unit Helsinki, Helsinki, Finland.
    Panayiotidis, P.
    Univ Athens, Dept Propaedeut Med, Athens, Greece;Hellen Soc Hematol, Athens, Greece.
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Berger, M. G.
    CHU, Hematol Biol & CHELTER EA7453, Clermont Ferrand, France;CHU, Hematol Biol & CHELTER EA7453, Clermont Ferrand, France;Univ Clermont Auvergne, Clermont Ferrand, France.
    Diamond, J.
    Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal.
    Ehrencrona, H.
    Lund Univ, Off Med Serv, Dept Clin Genet, Lab Med, Lund, Sweden;Lund Univ, Dept Clin Genet, Lund, Sweden.
    Kairisto, V.
    Turku Univ, Cent Hosp, Dept Clin Chem, Turku, Finland;Turku Univ, Cent Hosp, TYKSLAB, Turku, Finland.
    Polakova, K. Machova
    Inst Hematol & Blood Transfus, Prague, Czech Republic.
    Mueller, M. C.
    IHO, Mannheim, Germany.
    Mustjoki, S.
    Univ Helsinki, Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland;Univ Helsinki, Helsinki Univ Hosp, Ctr Comprehens Canc, Hematol Res Unit Helsinki, Helsinki, Finland.
    Hochhaus, A.
    Univ Hosp Jena, Internal Med 2, Jena, Germany.
    Saussele, S.
    Heidelberg Univ, Med Fak Mannheim, Med Klin 3, Mannheim, Germany.
    Hjorth-Hansen, H.
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.
    CHRONIC MYELOID LEUKEMIA PATIENTS WERE NOT DIFFERENT IN MOLECULAR RELAPSE AFTER STOPPING IMATINIB IN MR4 WHETHER RESIDUAL DISEASE WAS DETECTED OR NOT - WHEN ADJUSTING FOR NUMBER OF CONTROL TRANSCRIPTS2017In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 153-153, article id S426Article in journal (Other academic)
  • 37.
    Rajala, Hanna L. M.
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Haartmaninkatu 8, Helsinki 00290, Finland..
    El Missiry, Mohamed
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Haartmaninkatu 8, Helsinki 00290, Finland..
    Ruusila, Anniina
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Haartmaninkatu 8, Helsinki 00290, Finland..
    Koskenvesa, Perttu
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Haartmaninkatu 8, Helsinki 00290, Finland..
    Bruemmendorf, Tim H.
    Univ Hosp Aachen RWTH, Internal Med Oncol Hematol & Stem Cell Transplant, Aachen, Germany..
    Gjertsen, Bjorn T.
    Univ Bergen, Inst Med, Hematol Sect, Bergen, Norway..
    Janssen, Jeroen
    Vrije Univ Amsterdam, Dept Hematol, Med Ctr, Amsterdam, Netherlands..
    Lotfi, Kourosh
    Linkoping Univ, Dept Hematol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Markevarn, Berit
    Univ Bergen, Inst Med, Hematol Sect, Bergen, Norway..
    Stromberg, Ulla Ohlsson
    Uppsala Univ Hosp, Dept Med Sci, Uppsala, Sweden..
    Stenke, Leif
    Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Stentoft, Jesper
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;NTNU, Dept Canc Res & Mol Med, Trondheim, Norway..
    Kreutzman, Anna
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Haartmaninkatu 8, Helsinki 00290, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Haartmaninkatu 8, Helsinki 00290, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia2017In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 143, no 8, p. 1543-1554Article in journal (Refereed)
    Abstract [en]

    Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.

  • 38.
    Richter, J.
    et al.
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Mahon, F. X.
    Univ Bordeaux, Bergonie Canc Inst INSERM Unit 916, Bordeaux, France..
    Guilhot, J.
    CHU Poitiers, Inserm CIC 1402, Poitiers, France..
    Hjorth-Hansen, H.
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Almeida, A.
    Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal..
    Janssen, J. J.
    Vrije Univ Amsterdam, Med Ctr, Dept Hematol, Amsterdam, Netherlands..
    Mayer, J.
    Masaryk Univ Hosp, Dept Internal Med, Hematooncol, Brno, Czech Republic..
    Porkka, K.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland..
    Panayiotidis, P.
    Univ Athens, Dept Propaedeut Med, Athens, Greece.;Hellen Soc Hematol, Athens, Greece..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Berger, M. G.
    CHU, Hematol Biol, Clermont Ferrand, France.;CHU, EA7823, Clermont Ferrand, France.;Univ Auvergne, Clermont Ferrand, France..
    Diamond, J.
    Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal..
    Ehrencrona, H.
    Skane Univ Hosp, Dept Clin Genet, Lund, Sweden..
    Kairisto, V.
    Turku Univ, Dept Clin Chem, Cent Hosp, Turku, Finland.;TYKSLAB, Turku, Finland..
    Polakova, K. Machova
    Inst Hematol & Blood Transfus, Prague, Czech Republic..
    Muller, M. C.
    IHO, Mannheim, Germany..
    Mustjoki, S.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland..
    Hochhaus, A.
    Univ Hosp Jena, Internal Med 2, Jena, Germany..
    Pfirrmann, M.
    Univ Munich, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany..
    Saussele, S.
    Heidelberg Univ, Med Fak Mannheim, Med Klin 3, Mannheim, Germany..
    Stopping Tyrosine Kinase Inhibitors In A Very Large Cohort Of European Chronic Myeloid Leukemia Patients: Results Of The Euro-Ski Trial2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 22-23Article in journal (Other academic)
  • 39. Richter, Johan
    et al.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lübking, Anna
    Dreimane, Arta
    Lotfi, Kourosh
    Markevärn, Berit
    Själander, Anders
    Saussele, Susanne
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 25, p. 2821-2823Article in journal (Refereed)
  • 40.
    Saussele, Susanne
    et al.
    Heidelberg Univ, Dept Haematol & Oncol, Univ Hosp Mannheim, Mannheim, Germany.
    Richter, Johan
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Guilhot, Joelle
    Ctr Hosp Univ CHU Poitiers, Ctr Invest Clin 1402, INSERM, Poitiers, France.
    Gruber, Franz X.
    Univ Hosp North Norway, Dept Haematol, Tromso, Norway.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Haematol, Trondheim, Norway.
    Almeida, Antonio
    Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal.
    Janssen, Jeroen J. W. M.
    Vrije Univ Amsterdam Med Ctr, Dept Haematol, Amsterdam, Netherlands.
    Mayer, Jiri
    Masaryk Univ, Dept Internal Med Haematol & Oncol, Brno, Czech Republic;Univ Hosp Brno, Brno, Czech Republic.
    Koskenvesa, Perttu
    Univ Helsinki, Haematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Ctr Comprehens Canc, Helsinki, Finland.
    Panayiotidis, Panayiotis
    Univ Athens, Dept Internal Med 1, Laikon Gen Hosp, Athens, Greece.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Martinez-Lopez, Joaquin
    Univ Complutense Madrid, Hosp Univ Octubre 12, Ctr Nacl Invest Oncol, Ctr Invest Biomed Red Canc, Madrid, Spain.
    Rousselot, Philippe
    Univ Paris Saclay, Dept Haematol & Oncol, Univ Versailles St Quentin En Yvelines, Ctr Hosp Versailles,Inserm,Unite Mixte Rech 1173, Le Chesnay, France.
    Vestergaard, Hanne
    Odense Univ Hosp, Dept Haematol, Odense, Denmark.
    Ehrencrona, Hans
    Off Med Serv, Dept Clin Genet & Pathol, Lab Med, Lund, Sweden;Lund Univ, Div Clin Genet, Lund, Sweden.
    Kairisto, Veli
    Turku Univ, Cent Hosp, Dept Clin Chem, Turku, Finland;Turku Univ, Cent Hosp, Dept Genet, Turku, Finland.
    Polakova, Katerina Machova
    Inst Hematol & Blood Transfus, Prague, Czech Republic.
    Mueller, Martin C.
    Inst Hematol & Oncol, Mannheim, Germany.
    Mustjoki, Satu
    Univ Helsinki, Haematol Res Unit Helsinki, Helsinki, Finland;Univ Helsinki, Dept Clin Chem & Haematol, Helsinki, Finland;Helsinki Univ Hosp, Ctr Comprehens Canc, Helsinki, Finland.
    Berger, Marc G.
    CHU Estaing, Hematol Biol & Equipe Accueil Hemopaties Chron He, Clermont Ferrand, France;Univ Clermont Auvergne, Clermont Ferrand, France.
    Fabarius, Alice
    Heidelberg Univ, Dept Haematol & Oncol, Univ Hosp Mannheim, Mannheim, Germany.
    Hofmann, Wolf-Karsten
    Heidelberg Univ, Dept Haematol & Oncol, Univ Hosp Mannheim, Mannheim, Germany.
    Hochhaus, Andreas
    Univ Klinikum Jena, Klin Innere Med 2, Jena, Germany.
    Pfirrmann, Markus
    Ludwig Maximilians Univ Munchen, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany.
    Mahon, Francois-Xavier
    Univ Bordeaux, Bergonie Canc Inst, INSERM, Unit 916, Bordeaux, France.
    Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial2018In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 19, no 6, p. 747-757Article in journal (Refereed)
    Abstract [en]

    Background Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. Methods In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0.1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Findings Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1.14 [95% CI 1.05-1.23]; p=0.0010) and longer deep molecular response durations (1.13 [1.04-1.23]; p=0.0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1.13 [0.98-1.29]; p=0.08). TKI discontinuation was associated with substantial cost savings (an estimated (sic)22 million). No serious adverse events were reported. Interpretation Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

  • 41. Skoglund, Karin
    et al.
    Richter, Johan
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Aluthgedara, Warunika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ubhayasekera, S J Kumari A
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Vikingsson, Svante
    Svedberg, Anna
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandstedt, Anna
    Johnsson, Anders
    Aagesen, Jesper
    Alsenhed, Jonas
    Hägg, Staffan
    Peterson, Curt
    Lotfi, Kourosh
    Gréen, Henrik
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients2016In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.

    METHODS: Forty-three CML patients were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.

    RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to non-optimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P=0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.

    CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

  • 42.
    Söderlund, Stina
    et al.
    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.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Hjorth-Hansen, H.
    Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, J.
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, S.
    Univ Helsinki, Dept Hematol, Hematol Res Unit, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Plasma Proteomics In Chronic Myeloid Leukemia Patients Before And After Initiation Of Tyrosine Kinase Inhibitor Therapy Reveals Induced Th1 Immunity And Loss Of Angiogenic Stimuli2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 730-730Article in journal (Other academic)
  • 43.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Uppsala Hosp, Sect Hematol, Entrance 50, S-75185 Uppsala, Sweden.
    Christiansson, Lisa
    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.
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway; Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.
    Richter, Johan
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland; Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland; Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    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.
    Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli2016In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 50, p. 95-103Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation.

    METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek.

    RESULTS: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX.

    CONCLUSIONS: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

  • 44.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dahlen, T.
    Karolinska Univ Hosp Solna, Div Hematol, Dept Med, Stockholm, Sweden..
    Creignou, M.
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Sandin, F.
    Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Olsson-Stromberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dreimane, A.
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Markevaem, B.
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Sjaelander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Wadenvik, H.
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Stenke, L.
    Karolinska Univ Hosp Solna, Div Hematol, Dept Med, Stockholm, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    PROGRESSION OF CHRONIC PHASE CHRONIC MYELOID LEUKEMIA TO ADVANCED PHASE ON TKI THERAPY: A POPULATION BASED ANALYSIS FROM THE SWEDISH CML REGISTER2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 233-233Article in journal (Other academic)
  • 45.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dahlén, Torsten
    Karolinska Univ Hosp, Dept Haematol, Stockholm, Sweden.; Karolinska Inst, Dept Med, Stockholm, Sweden.
    Sandin, Fredrik
    Reg Canc Ctr Uppsala-Örebro, Uppsala, Sweden.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Creignou, Maria
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden.
    Dreimane, Arta
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden.
    Lübking, Anna
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Markevärn, Berit
    Umea Univ Hosp, Dept Haematol, Umea, Sweden.
    Själander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat, Gothenburg, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Haematol, Stockholm, Sweden.; Karolinska Inst, Dept Med, Stockholm, Sweden.
    Richter, Johan
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 57-66Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.

    METHODS: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.

    RESULTS: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.

    CONCLUSION: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

  • 46.
    Warfvinge, Rebecca
    et al.
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Geironson, Linda
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Sommarin, Mikael N. E.
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Lang, Stefan
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Karlsson, Christine
    Lund Univ, Lund Stem Cell Ctr, Div Mol Med & Gene Therapy, Lund, Sweden..
    Roschupkina, Teona
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Stentoft, Jesper
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland..
    Soneji, Shamit
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Richter, Johan
    Lund Univ, Lund Stem Cell Ctr, Div Mol Med & Gene Therapy, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Karlsson, Göran
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 17, p. 2384-2394Article in journal (Refereed)
    Abstract [en]

    Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunopheno-typic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC population in chronic phase chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CML at diagnosis and demonstrate differences in response to subsequent TKI treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI therapy compared with subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CML stem cell markers CD25, CD26, and IL1RAP is high in all subpopulations at diagnosis but downregulated and unevenly distributed across subpopulations in response to TKI treatment. The most TKI-insensitive cells of the LSC compartment can be captured within the CD45RA(-) fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Together, our results expose a considerable heterogeneity of the CML stem cell population and propose a Lin(-) CD34(+) CD38(-/low) CD45RA(-) cKIT(-) CD26(+) population as a potential therapeutic target for improved therapy response.

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