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  • 301.
    Pfirrmann, M.
    et al.
    Univ Munich, Inst Med Informationsverarbeitung Biometrie & Epi, Marchioninistr 15, D-81377 Munich, Germany..
    Baccarani, M.
    Univ Bologna, S Orsola Malpighi Hosp, Hematol & Oncol L&A Seragnoli, Bologna, Italy..
    Saussele, S.
    Heidelberg Univ, Med Fak Mannheim, Univ Med Mannheim, Med Klin 3, Mannheim, Germany..
    Guilhot, J.
    CHU Poitiers, INSERM, CIC 1402, Clin Invest Ctr, Poitiers, France..
    Cervantes, F.
    Univ Barcelona, IDIBAPS, Hosp Clin, Hematol Dept, Barcelona, Spain..
    Ossenkoppele, G.
    Vrije Univ Amsterdam, Med Ctr, Dept Hematol, Amsterdam, Netherlands..
    Hoffmann, V. S.
    Univ Munich, Inst Med Informationsverarbeitung Biometrie & Epi, Marchioninistr 15, D-81377 Munich, Germany..
    Castagnetti, F.
    Univ Bologna, S Orsola Malpighi Hosp, Hematol & Oncol L&A Seragnoli, Bologna, Italy..
    Hasford, J.
    Univ Munich, Inst Med Informationsverarbeitung Biometrie & Epi, Marchioninistr 15, D-81377 Munich, Germany..
    Hehlmann, R.
    Heidelberg Univ, Med Fak Mannheim, Univ Med Mannheim, Med Klin 3, Mannheim, Germany..
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 1, p. 48-56Article in journal (Refereed)
    Abstract [en]

    In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate-and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

  • 302.
    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)
  • 303. Pfirrmann, M.
    et al.
    Saussele, S.
    Baccarani, M.
    Guilhot, J.
    Cervantes, F.
    Ossenkoppele, G.
    Lindoerfer, D.
    Hoffmann, V. S.
    Castagnetti, F.
    Hehlmann, R.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Overall survival and prognosis in patients with chronic myeloid leukaemia allocated to first-line imatinib treatment - new results from the EUTOS "In-Study" registry2013In: Onkologie (Basel), ISSN 0378-584X, E-ISSN 1423-0240, Vol. 36, no Suppl. 7, p. 100-100Article in journal (Other academic)
  • 304. Pfirrmann, M.
    et al.
    Saussele, S.
    Baccarani, M.
    Guilhot, J.
    Cervantes, F.
    Ossenkoppele, G.
    Lindoerfer, D.
    Hoffmann, Vs
    Castagnetti, F.
    Hehlmann, R.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Overall Survival and Prognosis in 2190 Patients with First-Line Imatinib Treatment Considering Death Due to Chronic Myeloid Leukaemia as the Only Event2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 531-532Article in journal (Other academic)
  • 305.
    Pfirrmann, Markus
    et al.
    Univ Munich, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany..
    Hasford, Joerg
    Univ Munich, Inst Med Informat Verarbeitung Biometrie & Epidem, Munich, Germany..
    Saussele, Susanne
    Heidelberg Univ, Med Fak Mannheim, Mannheim, Germany..
    Turkina, Anna
    Natl Res Ctr Hematol, Moscow, Russia..
    Prejzner, Witold
    Med Univ Gdansk, Dept Hematol, Gdansk, Poland..
    Luis Steegmann, Juan
    Hosp Univ Princesa, Dept Hematol, Madrid, Spain..
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Zaritskey, Andrey
    St Petersburg State Med Univ, St Petersburg, Russia..
    Colita, Adriana
    Federat Ctr Hematol & Bone Marrow Transplantat, Fundeni Clin Inst, Bucharest, Romania..
    Zackova, Daniela
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Brno, Czech Republic..
    Janssen, Jeroen
    Vrije Univ Amsterdam, Med Ctr, Dept Hematol, Amsterdam, Netherlands..
    Cervantes, Francisco
    Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain..
    Indrak, Karel
    Univ Palackianae, Dept Hematooncol, Olomouc, Czech Republic..
    Guilhot, Joelle
    CHU Poitiers, INSERM CIC 1402, Clin Invest Ctr, Poitiers, France..
    Hehlmann, Ruediger
    Heidelberg Univ, Med Fak Mannheim, Mannheim, Germany..
    Baccarani, Michele
    Univ Bologna, S Orsola Malpighi Hosp, Clin Dept Hematol & Oncol L&A Seragnoli, Bologna, Italy..
    The EUTOS Survival Score Is Preferable over the Sokal Score for Prognosis of Long-Term Survival of Patients with Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 306. Pfirrmann, Markus
    et al.
    Saussele, Susanne
    Baccarani, Michele
    Guilhot, Joelle
    Cervantes, Francisco
    Ossenkoppele, Gert J.
    Lindoerfer, Doris
    Hoffmann, Verena S.
    Castagnetti, Fausto
    Hehlmann, Ruediger
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Survival and Prognosis in Patients with First-Line Imatinib Treatment Under Particular Consideration of Death Due to Chronic Myeloid Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 307. Pietersz, R. N. I.
    et al.
    Reesink, H. W.
    Panzer, S.
    Gilbertson, M. P.
    Borosak, M. E.
    Wood, E. M.
    Leitner, G. C.
    Rabitsch, W.
    Ay, C.
    Lambermont, M.
    Deneys, V.
    Sondag, D.
    Compernolle, V.
    Legrand, D.
    Francois, A.
    Tardivel, R.
    Garban, F.
    Sawant, R. B.
    Rebulla, P.
    Handa, M.
    Ohto, H.
    Kerkhoffs, J. -LH.
    Brand, A.
    Zhiburt, E.
    Cid, J.
    Escolar, G.
    Lozano, M.
    Puig, L.
    Knutson, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hallbook, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Estcourt, L.
    Stanworth, S.
    Murphy, M. F.
    Williams, L.
    Mraz, D. L.
    Ross, R. L.
    Snyder, E.
    Prophylactic platelet transfusions2012In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 103, no 2, p. 159-176Article in journal (Refereed)
  • 308. Press, R
    et al.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, A
    Andersen, O
    Axelson, Hans W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Strömberg, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wahlin, A
    Isaksson, C
    Johansson, J-E J
    Hägglund, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP2014In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 6, p. 618-624Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Only 70-80% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) respond satisfactorily to the established first-line immunomodulatory treatments. Autologous haematopoietic stem cell transplantation (AHSCT) has been performed as a last treatment resort in a few therapy-refractory cases with CIDP. We describe the results of AHSCT in 11 consecutive Swedish patients with therapy-refractory CIDP with a median follow-up time of 28 months.

    METHOD: Case data were gathered retrospectively for AHSCT treatments in 11 patients with CIDP refractory to the first-line immunomodulatory treatments, intravenous high-dose immunoglobulin, corticosteroids and plasma exchange and to one or more second-line treatments used in 10 of the 11 patients.

    RESULTS: The median Inflammatory Neuropathy Cause and Treatment (INCAT) score within 1 month prior to AHSCT was 6 and the Rankin score 4. Total INCAT and Rankin scores improved significantly within 2-6 months after AHSCT and continued to do so at last follow-up. The motor action potential amplitudes (CMAP) improved already within 4 months (median) after AHSCT. Three of the 11 patients relapsed during the follow-up period, requiring retransplantation with AHSCT in one. Eight of the 11 patients maintained drug-free remission upon last follow-up. AHSCT was safe but on the short term associated with a risk of cytomegalovirus (CMV) and Epstein-Barr virus reactivation, CMV disease, haemorrhagic cystitis and pancreatitis.

    CONCLUSIONS: Our results though hampered by the limited number of patients and the lack of a control group suggest AHSCT to be efficacious in therapy-refractory CIDP, with a manageable complication profile. Confirmation of these results is necessary through randomised controlled trials.

  • 309.
    Qu, Y.
    et al.
    Karolinska Inst, Ctr Hematol & Regenerat Med HERM, Stockholm, Sweden..
    Siggens, L.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Cordeddu, L.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Ekwall, K.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Ctr Hematol & Regenerat Med HERM, Stockholm, Sweden..
    Lennartsson, A.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Differential Dna Methylation In Cytogenetically Normal Acute Myeloid Leukemia Is Linked To Altered Gene Expression Of Enhancer Target Genes2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 209-210Article in journal (Other academic)
  • 310. Qu, Ying
    et al.
    Lennartsson, Andreas
    Gaidzik, Verena I.
    Deneberg, Stefan
    Karimi, Mohsen
    Bengtzen, Sofia
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bullinger, Lars
    Doehner, Konstanze
    Lehmann, Soren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 8, p. 1108-1119Article in journal (Refereed)
    Abstract [en]

    The extent and role of aberrant DNA methylation in promoter CpG islands (CGIs) have been extensively studied in leukemia and other malignancies. Still, CGIs represent only a small fraction of the methylome. We aimed to characterize genome-wide differential methylation of cytogenetically normal AML (CN-AML) cells compared with normal CD34(+) bone marrow cells using the Illumina (R) 450K methylation array. Differential methylation in CN-AML was most prominent in genomic areas far from CGIs, in so called open sea regions. Furthermore, differential methylation was specifically found in genes encoding transcription factors (TFs), with WT1 being the most differentially methylated TF. Among genetic mutations in AML, DNMT3A mutations showed the most prominent association with the DNA methylation pattern, characterized by hypomethylation of CGIs (as compared with DNMT3A wild type cases). The differential methylation in DNMT3A mutant cells vs. wild type cells was predominantly found in HOX genes, which were hypomethylated. These results were confirmed and validated in an independent CN-AML cohort. In conclusion, we show that, in CN-AML, the most pronounced changes in DNA methylation occur in non-CGI regions and that DNMT3A mutations confer a pattern of global hypomethylation that specifically targets HOX genes.

  • 311.
    Qu, Ying
    et al.
    Ctr Hematol & Regenerat Med, Dept Med Huddinge, Huddinge, Sweden.
    Siggens, Lee
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Cordeddu, Lina
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Gaidzik, Verena I
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany.
    Karlsson, Kasper
    Karolinska Inst, Dept Med Biochem & Biophys, Mol Neurobiol Lab, Stockholm, Sweden.
    Bullinger, Lars
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany.
    Döhner, Konstanze
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany.
    Ekwall, Karl
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Ctr Hematol & Regenerat Med, Dept Med Huddinge, Huddinge, Sweden; Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden.
    Lennartsson, Andreas
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Cancer specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 7, p. e13-e25Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. Here we have analyzed 57 AML patients with normal karyotype using Illuminas 450 k array and show that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, ChIP-seq analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is not therefore sufficient for enhancer activation. Some sites of hypomethylation occur at weak / poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation, causing perturbed enhancer activity in CN-AML that contributes to a leukemic transcriptome.

  • 312.
    Raj, K.
    et al.
    GKT Sch Med, London, England.
    Olavarria, E.
    Hammersmith Hosp, London, England.
    Eikema, D-J
    Dept Med Stat & Bioinoformat, Leiden, Netherlands.
    Blok, H-J
    Dept Med Stat & Bioinoformat, Leiden, Netherlands.
    Bregante, S.
    Osped San Martino Genova, Genoa, Italy.
    Ciceri, F.
    Osped San Raffaele Srl, Segrate, Italy.
    Passweg, J.
    Univ Hosp, Basel, Switzerland.
    Ljungmann, P.
    Karolinska Univ Hosp, Stockholm, Sweden.
    Schaap, M.
    Radboud Univ Nijmegen, Nijmegen Med Ctr, Nijmegen, Netherlands.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Zuckerman, T.
    Rambam Med Ctr, Haifa, Israel.
    Volin, L.
    HUCH Comprehens Canc Ctr, Helsinki, Finland.
    Koc, Yener
    Med Pk Hosp, Antalya, Turkey.
    Diez-Martin, J.
    Hosp Gregorio Maranon, Madrid, Spain.
    Brossart, P.
    Univ Bonn, Bonn, Germany.
    Blaise, D.
    Inst Paoli Calmettes, Marseille, France.
    Natale, A.
    Osped Civile, Pescara, Italy.
    Vitek, A.
    Inst Hematol & Blood Transfus, Prague, Czech Republic.
    Mclornan, D.
    GKT Sch Med, London, England.
    Robin, M.
    Hop St Louis, Paris, France.
    Chalandon, Y.
    Hop Univ Geneve, Geneva, Switzerland.
    Kroger, N.
    Univ Hosp Eppendorf, Hamburg, Germany.
    Family mismatched allogeneic stem cell transplantationfor myelofibrosis: Report from the chronic malignancies working party of EBMT2017In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 52, no Supplement: 1, p. S182-S183Article in journal (Other academic)
  • 313.
    Rank, Cecilie Utke
    et al.
    Univ Copenhagen, Rigshosp, Pediat Oncol Res Lab, Copenhagen, Denmark;Univ Copenhagen, Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Toft, Nina
    Univ Copenhagen, Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Tuckuviene, Ruta
    Aalborg Univ Hosp, Dept Pediat, Aalborg, Denmark.
    Grell, Kathrine
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Sect Biostat, Copenhagen, Denmark.
    Nielsen, Ove Juul
    Univ Copenhagen, Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Frandsen, Thomas Leth
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
    Marquart, Hanne Vibeke Hansen
    Univ Copenhagen, Rigshosp, Dept Clin Immunol, Copenhagen, Denmark.
    Albertsen, Birgitte Klug
    Aarhus Univ Hosp, Dept Pediat, Aarhus, Denmark.
    Tedgard, Ulf
    Lund Univ Hosp, Dept Pediat & Coagulat Disorders, Malmo, Sweden.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Ruud, Ellen
    Oslo Univ Hosp, Rikshosp, Dept Paediat Med, Oslo, Norway.
    Jarvis, Kirsten Brunsvig
    Oslo Univ Hosp, Rikshosp, Dept Paediat Med, Oslo, Norway.
    Quist-Paulsen, Petter
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Hematol, Trondheim, Norway.
    Huttunen, Pasi
    Helsinki Univ Hosp, Childrens Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Helsinki, Finland.
    Wartiovaara-Kautto, Ulla
    Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland;Univ Helsinki, Helsinki, Finland.
    Jonsson, Olafur Gisli
    Univ Hosp, Landspitali, Childrens Hosp, Reykjavik, Iceland.
    Trakymiene, Sonata Saulyte
    Vilnius Univ Hosp Santaros Klin, Childrens Hosp, Ctr Pediat Oncol & Hematol, Vilnius, Lithuania.
    Griskevicius, Laimonas
    Vilnius Univ Hosp Santaros Klin, Dept Hematol Oncol & Transfus Med Ctr, Vilnius, Lithuania;Vilnius Univ, Vilnius, Lithuania.
    Saks, Kadri
    Tallinn Childrens Hosp, Dept Oncohematol, Tallinn, Estonia.
    Punab, Mari
    Tartu Univ Hosp, Dept Hematol & Oncol, Tartu, Estonia.
    Schmiegelow, Kjeld
    Univ Copenhagen, Rigshosp, Pediat Oncol Res Lab, Copenhagen, Denmark;Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Blegdamsvej 9, DK-2100 Copenhagen, Denmark;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark.
    Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 131, no 22, p. 2475-2484Article in journal (Refereed)
    Abstract [en]

    Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged (lymph nodes), 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P <= .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.

  • 314.
    Ravindran, Avinash
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    Rönnberg, Elin
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    Mazzurana, Luca
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden.
    Säfholm, Jesper
    Karolinska Inst, Inst Environm Med, Unit Expt Asthma & Allergy Res, Ctr Allergy Res, Stockholm, Sweden.
    Orre, Ann-Charlotte
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Thorac Surg, Stockholm, Sweden.
    Al-Ameri, Mamdoh
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Thorac Surg, Stockholm, Sweden.
    Peachell, Peter
    Univ Sheffield, Royal Hallamshire Hosp, Acad Unit Resp Med, Sheffield, S Yorkshire, England.
    Adner, Mikael
    Karolinska Inst, Inst Environm Med, Unit Expt Asthma & Allergy Res, Ctr Allergy Res, Stockholm, Sweden.
    Dahlen, Sven-Erik
    Karolinska Inst, Inst Environm Med, Unit Expt Asthma & Allergy Res, Ctr Allergy Res, Stockholm, Sweden.
    Mjösberg, Jenny
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    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 Solna, Immunol & Allergy Unit, Stockholm, Sweden.
    An Optimized Protocol for the Isolation and Functional Analysis of Human Lung Mast Cells2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2193Article in journal (Refereed)
    Abstract [en]

    Background: Mast cells are tissue-resident inflammatory cells defined by their high granularity and surface expression of the high-affinity IgE receptor, Fc + RI, and CD117/KIT, the receptor for stem cell factor (SCF). There is a considerable heterogeneity among mast cells, both phenotypically and functionally. Human mast cells are generally divided into two main subtypes based on their protease content; the mucosa-associated MCT (tryptase positive and chymase negative mast cell) and the connective tissue associated-residing MCTC (tryptase and chymase positive mast cell). Human lung mast cells exhibit heterogeneity in terms of cellular size, expression of cell surface receptors, and secreted mediators. However, knowledge about human lung mast cell heterogeneity is restricted to studies using immunohistochemistry or purified mast cells. Whereas the former is limited by the number of cellular markers that can be analyzed simultaneously, the latter suffers from issues related to cell yield.

    Aim: To develop a protocol that enables isolation of human lung mast cells at high yields for analysis of functional properties and detailed analysis using single-cell based analyses of protein (flow cytometry) or RNA (RNA-sequencing) expression.

    Methods: Mast cells were isolated from human lung tissue by a sequential combination of washing, enzymatic digestion, mechanical disruption, and density centrifugation using Percoll (WEMP). As a comparison, we also isolated mast cells using a conventional enzyme-based protocol. The isolated cells were analyzed by flow cytometry.

    Results: We observed a significant increase in the yield of total human lung CD45(+) immune cells and an even more pronounced increase in the yield of CD117(+) mast cells with the WEMP protocol in comparison to the conventional protocols. In contrast, the frequency of the rare lymphocyte subset innate lymphoid cells group 2 (ILC2) did not differ between the two methods.

    Conclusion: The described WEMP protocol results in a significant increase in the yield of human lung mast cells compared to a conventional protocol. Additionally, the WEMP protocol enables simultaneous isolation of different immune cell populations such as lymphocytes, monocytes, and granulocytes while retaining their surface marker expression that can be used for advanced single-cell analyses including multi-color flow cytometry and RNA-sequencing.

  • 315.
    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)
  • 316. 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)
  • 317.
    Rosengren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mellqvist, U-H
    South Elvsborg Hosp, Dept Hematol, Boras, Sweden.
    Nahi, H
    Karolinska Inst, Dept Hematol, Stockholm, Sweden.
    Forsberg, K
    Norrlands Univ Hosp, Dept Hematol, Umeå, Sweden.
    Lenhoff, S
    Skåne Univ Hosp, Dept Hematol, Lund, Sweden.
    Strömberg, O
    Karolinska Inst, Dept Hematol, Stockholm, Sweden.
    Ahlberg, L
    Linköping Univ Hosp, Dept Hematol, Linköping, Sweden.
    Linder, O
    Örebro Univ Hosp, Dept Hematol, Örebro, Sweden.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation in Sweden, long-term results from all patients treated in 1994-2009.2016In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 51, no 12, p. 1569-1572Article in journal (Refereed)
    Abstract [en]

    High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) is widely used in immunoglobulin light chain (AL) amyloidosis, but the benefit is debated mainly because of the high treatment-related mortality (24% in a randomised study comparing HDM/ASCT with oral melphalan/dexamethasone). We report here on the long-term outcome of all patients treated with HDM/ASCT for AL amyloidosis in Sweden between 1994 and 2009. Seventy-two patients were treated at eight Swedish centres. Median follow-up was 67.5 months. At least partial response (organ or haematological) was seen in 64% of the patients. Median overall survival was 98 months or 8.2 years, with 5-year survival 63.9% and 10-year survival 43.4%. In patients with cardiac involvement or multiple organ involvement, survival was significantly shorter, median overall survival 49 and 56 months, respectively. All mortality within 100 days from ASCT was 12.5% for all patients and 17.2% in the patients with cardiac involvement. For patients treated in the earlier time period (1994-2001), 100-day mortality was 23.8% compared with 7.8% in the later period (2002-2009). In conclusion, long survival times can be achieved in patients with AL amyloidosis treated with HDM/ASCT, also in smaller centres. Early mortality is high, but with a decreasing trend over time.

  • 318.
    Rudd, S. G.
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Paulin, C. B.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Nikolaos, T.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Sanjiv, K.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Juliane, K.
    Univ Hosp Heidelberg, Dept Infect Dis, Heidelberg, Germany..
    Myrberg, I. Hed
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Axelsson, H.
    Karolinska Inst, Chem Biol Consortium Sweden, Stockholm, Sweden..
    Rasti, A.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Witta, E.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Lee, S.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Rassidakis, G. Z.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Tamm, K. Pokrovskaja
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Heyman, M.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Grander, D.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Lundback, T.
    Karolinska Inst, Chem Biol Consortium Sweden, Stockholm, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Helleday, T.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Henter, J. I.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Schaller, T.
    Univ Hosp Heidelberg, Dept Infect Dis, Heidelberg, Germany..
    Herold, N.
    Karolinska Inst, Childhood Canc Res Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    CRISPR Screen Identifies MAD1L1, CDC27 and CDC42 as Determinants of Sensitivity to Sonic Hedgehog Inhibitor Sonidegib in Medulloblastoma Cell Lines2018In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 65, no Suppl. 2, p. S419-S420Article in journal (Other academic)
  • 319. Russell, Nigel
    et al.
    Douglas, Kenny
    Ho, Anthony
    Mohty, Mohamad
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Ossenkoppele, Gert J
    Milone, Giuseppe
    Pareja, Macarena Ortiz
    Shaheen, Daniel J
    Willemsen, Arnold
    Whitaker, Nicky
    Chabannon, Christian
    Plerixafor and granulocyte colony-stimulating factor for first-line steady-state autologous peripheral blood stem cell mobilization in lymphoma and multiple myeloma: results of the prospective PREDICT trial2013In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 98, no 2, p. 172-178Article in journal (Refereed)
    Abstract [en]

    In Europe, the combination of plerixafor + granulocyte colony-stimulating factor is approved for the mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and myeloma whose cells mobilize poorly. The purpose of this study was to further assess the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization in European patients with lymphoma or myeloma. In this multicenter, open label, single-arm study, patients received granulocyte colony-stimulating factor (10 μg/kg/day) subcutaneously for 4 days; on the evening of day 4 they were given plerixafor (0.24 mg/kg) subcutaneously. Patients underwent apheresis on day 5 after a morning dose of granulocyte colony-stimulating factor. The primary study objective was to confirm the safety of mobilization with plerixafor. Secondary objectives included assessment of efficacy (apheresis yield, time to engraftment). The combination of plerixafor + granulocyte colony-stimulating factor was used to mobilize hematopoietic stem cells in 118 patients (90 with myeloma, 25 with non-Hodgkin's lymphoma, 3 with Hodgkin's disease). Treatment-emergent plerixafor-related adverse events were reported in 24 patients. Most adverse events occurred within 1 hour after injection, were grade 1 or 2 in severity and included gastrointestinal disorders or injection-site reactions. The minimum cell yield (≥2×106 CD34+ cells/kg) was harvested in 98% of patients with myeloma and in 80% of those with non-Hodgkin's lymphoma in a median of one apheresis. The optimum cell dose (≥5×106 CD34+ cells/kg for non-Hodgkin's lymphoma or ≥6×106 CD34+ cells/kg for myeloma) was harvested in 89% of myeloma patients and 48% of non-Hodgkin's lymphoma patients. In this prospective, multicenter European study, mobilization with plerixafor + granulocyte colony-stimulating factor allowed the majority of patients with myeloma or non-Hodgkin's lymphoma to undergo transplantation with minimal toxicity, providing further data supporting the safety and efficacy of plerixafor + granulocyte colony-stimulating factor for front-line mobilization of hematopoietic stem cells in patients with non-Hodgkin's lymphoma or myeloma.

  • 320.
    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.

  • 321.
    Scherber, R.
    et al.
    OHSU, Hematol & Oncol, Portland, OR USA.;Mayo Clin, Hematol & Oncol, Scottsdale, AZ USA..
    Dueck, A.
    Mayo Clin, Phoenix, AZ USA..
    Geyer, H.
    Mayo Clin, Phoenix, AZ USA.;Mayo Clin, Internal Med, Scottsdale, AZ USA..
    Kosiorek, H.
    Mayo Clin, Phoenix, AZ USA..
    Kiladjian, J. J.
    Hosp St Louis, Paris, France..
    Slot, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Zweegman, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Boekhorst, P.
    Erasmus Med Cener, Rotterdam, Netherlands..
    Schouten, H.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands..
    Sackmann, F.
    Fundaleu, Buenos Aires, DF, Argentina..
    Fuentes, A.
    Univ Hosp La Paz, Madrid, Spain..
    Hernandez-Maraver, D.
    Univ Hosp La Paz, Madrid, Spain..
    Pahl, H.
    Univ Hosp Freiburg, Freiburg, Germany..
    Stegelmann, F.
    Univ Hosp Ulm, Ulm, Germany..
    Doehner, K.
    Univ Hosp Ulm, Ulm, Germany..
    Bonatz, K.
    Med Klin, Mannheim, Germany..
    Reiter, A.
    Med Klin, Mannheim, Germany..
    Boyer, F.
    Ctr Hosp Univ, Angers, France..
    Etienne, G.
    Ctr Hosp Univ, Angers, France..
    Ianotto, J. C.
    Univ Hosp, Brest, France..
    Ranta, D.
    Univ Hosp, Nancy, France..
    Roy, L.
    Ctr Hosp Univ, Poitiers, France..
    Cahn, J. Y.
    Ctr Hosp Univ, Grenoble, France..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, London, England..
    Radia, D.
    Guys & St Thomas NHS Fdn Trust, London, England..
    Muxi, P.
    Hosp Britanico, Montevideo, Uruguay..
    Maldonado, N.
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Besses, C.
    Hosp Mar, Barcelona, Spain..
    Cervantes, F.
    Univ Barcelona, Barcelona, Spain..
    Johansson, P.
    NU Hosp Org, Uddevalla, Sweden..
    Barosi, G.
    IRCCS Policlin S Matteo Fdn, Pavia, Italy..
    Vannucchi, A.
    Osped Circolo Varese, Varese, Italy..
    Passamonti, F.
    Fdn IRCCS Policlin San Matteo, Pavia, Italy..
    Andreasson, B.
    NU Hosp Org, Uddevalla, Sweden..
    Samuelsson, J.
    Stockholm South Hosp, Stockholm, Sweden..
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sun, X.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, J.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Zhang, P.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, Z.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Barbui, T.
    Osped Riuniti Bergamo, Bergamo, Italy.;Osped Riuniti Bergamo, Bergamo, Italy..
    Senyak, Z.
    MPN Forum, Asheville, NC USA..
    Grieshammer, M.
    Johannes Wesling Klinikum, Minden, Germany..
    Rambaldi, A.
    Osped Riuniti Bergamo, Bergamo, Italy..
    Ferrari, M.
    Osped Riuniti Bergamo, Bergamo, Italy..
    Lehmann, T.
    Univ Basel Hosp, Basel, Switzerland..
    Mesa, R.
    Mayo Clin, Phoenix, AZ USA..
    SYMPTOMS, RISK CLASSIFICATION, AND SPLEEN SIZE IN JAK2 INHIBITOR-NAIVE MYELOFIBROSIS: IMPLICATIONS FOR JAK2 INHIBITOR TREATMENT2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 557-558Article in journal (Other academic)
  • 322. Scotch, Allison H
    et al.
    Kosiorek, Heidi
    Scherber, Robyn
    Dueck, Amylou C
    Slot, Stefanie
    Zweegman, Sonja
    Boekhorst, Peter A W Te
    Commandeur, Suzan
    Schouten, Harry
    Sackmann, Federico
    Fuentes, Ana Kerguelen
    Hernández-Maraver, Dolores
    Pahl, Heike L
    Griesshammer, Martin
    Stegelmann, Frank
    Döhner, Konstanze
    Lehmann, Thomas
    Bonatz, Karin
    Reiter, Andreas
    Boyer, Francoise
    Etienne, Gabriel
    Ianotto, Jean-Christophe
    Ranta, Dana
    Roy, Lydia
    Cahn, Jean-Yves
    Harrison, Claire N
    Radia, Deepti
    Muxi, Pablo
    Maldonado, Norman
    Besses, Carlos
    Cervantes, Francisco
    Johansson, Peter L
    Barbui, Tiziano
    Barosi, Giovanni
    Vannucchi, Alessandro M
    Paoli, Chiara
    Passamonti, Francesco
    Andreasson, Bjorn
    Ferrari, Maria L
    Rambaldi, Alessandro
    Samuelsson, Jan
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Xiao, Zhijian
    Xu, Zefeng
    Zhang, Yue
    Sun, Xiujuan
    Xu, Junqing
    Kiladjian, Jean-Jacques
    Zhang, Peihong
    Gale, Robert Peter
    Mesa, Ruben A
    Geyer, Holly L
    Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 34-40Article in journal (Refereed)
    Abstract [en]

    Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n = 89) and without (n = 329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count < 100 x10(9)/L (moderate 51-100 x 10(9)/L; severe <= 50 x10(9)/L), was associated with anemia (76% vs. 45%, p < 0.001), leukopenia (29% vs. 11%, p < 0.001), and need for red blood cell transfusion (35% vs. 19%, p = 0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p < 0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p = 0.04), leukopenia (40% vs. 20%, p = 0.04), and transfusion requirements (51% vs. 20%, p = 0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

  • 323.
    Sevov, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Bunikis, Ignas
    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.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cavelier, Lucia
    Targeted RNA Sequencing Assay Efficiently Identifies Cryptic KMT2A (MLL)-Fusions in Acute Leukemia Patients2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 324.
    Simonson, Oscar E.
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Mougiakakos, Dimitrios
    Univ Erlangen Nurnberg, Dept Internal Med Hematol & Oncol, D-91054 Erlangen, Germany..
    Heldring, Nina
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Bassi, Giulio
    Univ Verona, Dept Med, Sect Hematol, Stem Cell Res Lab, I-37100 Verona, Italy..
    Johansson, Henrik J.
    Karolinska Inst, Dept Oncol Pathol, Canc Prote Mass Spectrometry, Sci Life Lab, Stockholm, Sweden..
    Dalen, Magnus
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden..
    Jitschin, Regina
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Rodin, Sergey
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden.;Vaccine & Gene Therapy Inst Florida, Ctr Dis Aging, Port St Lucie, FL USA..
    El Andaloussi, Samir
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Wiklander, Oscar P. B.
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Nordin, Joel Z.
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Skog, Johan
    Exosome Diagnost Inc, New York, NY USA..
    Romain, Charlotte
    Exosome Diagnost Inc, New York, NY USA..
    Koestler, Tina
    Exosome Diagnost Inc, New York, NY USA..
    Johansson Hellgren, Laila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Schiller, Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Joachimsson, Per-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Uppsala Hosp, Dept Hematol, Uppsala, Sweden..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Uppsala Hosp, Dept Hematol, Uppsala, Sweden..
    Lentio, Janne
    Faridani, Omid R.
    Ludwig Inst Canc Res, S-10401 Stockholm, Sweden..
    Sandberg, Rickard
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.;Ludwig Inst Canc Res, S-10401 Stockholm, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krampera, Mauro
    Univ Verona, Dept Med, Sect Hematol, Stem Cell Res Lab, I-37100 Verona, Italy..
    Weiss, Daniel J.
    Univ Vermont, Dept Med, Hlth Sci Res Facil, Burlington, VT USA..
    Grinnemo, Karl-Henrik
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden.;Vaccine & Gene Therapy Inst Florida, Ctr Dis Aging, Port St Lucie, FL USA..
    Le Blanc, Katarina
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome2015In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 4, no 10, p. 1199-1213Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2 x 10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1199-1213

  • 325.
    Simonsson, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gedde-Dahl, Tobias
    Markevarn, Berit
    Remes, Kari
    Stentoft, Jesper
    Almqvist, Anders
    Bjoreman, Mats
    Flogegard, Max
    Koskenvesa, Perttu
    Lindblom, Anders
    Malm, Claes
    Mustjoki, Satu
    Myhr-Eriksson, Kristina
    Ohm, Lotta
    Rasanen, Anu
    Sinisalo, Marjatta
    Sjalander, Anders
    Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bjerrum, Ole Weiss
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gruber, Franz
    Kairisto, Veli
    Olsson, Karin
    Sandin, Fredrik
    Nagler, Arnon
    Nielsen, Johan Lanng
    Hjorth-Hansen, Henrik
    Porkka, Kimmo
    Combination of pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 12, p. 3228-3235Article in journal (Refereed)
    Abstract [en]

    Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha 2b (Peg-IFN-alpha 2b) 50 mu g weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha 2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha 2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-alpha 2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha 2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha 2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

  • 326. 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.

  • 327. Snarski, E
    et al.
    Snowden, J A
    Oliveira, M C
    Simoes, B
    Badoglio, M
    Carlson, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Moore, J
    Rovira, M
    Clark, R E
    Saiz, A
    Hadj-Khelifa, S
    Tan, J
    Crescimanno, A
    Musso, M
    Martin, T
    Farge, D
    Onset and outcome of pregnancy after autologous haematopoietic SCT (AHSCT) for autoimmune diseases: a retrospective study of the EBMT autoimmune diseases working party (ADWP)2015In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 50, no 2, p. 216-220Article in journal (Refereed)
    Abstract [en]

    Autologous haematopoietic SCT (AHSCT) is increasingly used to control severe and refractory autoimmune diseases (AD). Many patients are women of reproductive age with a potential desire for children. We present a multicentre retrospective analysis of pregnancy and childbirth in patients who underwent AHSCT for AD. The databases of the European Blood and Marrow Transplantation and University of Sao Paulo, Ribeirão Preto, Brazil were searched for female patients aged 18-50 years who had received AHSCT for AD between 1994-2011. In 324 adult female patients, 22 pregnancies were reported in 15 patients between 1997-2011. Indications for AHSCT included multiple sclerosis (n=7), systemic sclerosis (n=5), rheumatoid arthritis (n=1), juvenile idiopathic arthritis (n=1) and Takayasu disease (n=1). Of the 22 reported pregnancies, 20 followed natural conception. 15 pregnancies (68%) resulted in healthy life births, whereas 7 (32%) failed. Exacerbations of AD occurred in two patients during second pregnancies. No maternal mortality was associated with pregnancy or postpartum. There were no reports of congenital, developmental or any other disease in the children. This retrospective analysis confirms the possibility of pregnancy and childbirth following AHSCT for severe AD. The outcome of pregnancy is generally good and most led to the birth of a healthy child.

  • 328.
    Sohrabian, Donia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Linder, Marie
    Karolinska Inst, Med, Stockholm, Sweden..
    Ekstrand, Charlotta
    Karolinska Inst, Med, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Med, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Med, Stockholm, Sweden..
    Infection and Anti-Infective Treatment Preceding a Diagnosis of Primary Persisting Immune Thrombocytopenia2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 88-88, article id Abstr. 143Article in journal (Refereed)
  • 329.
    Strese, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Velander, Ebba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6341-6352Article in journal (Refereed)
    Abstract [en]

    The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34(+) progenitor cells and a more differentiated CD34(+) derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

  • 330.
    Svanberg, Anncarin
    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 Public Health and Caring Sciences, Caring Sciences.
    Mucositis Prevention for Patients Receiving High Dose Chemotherapy and Stem Cell Transplantation: Preventive Strategies - There is Always More to do2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to investigate oral cryotherapy (OC) as prophy-laxis against oral mucositis (OM) in patients given high-dose chemotherapy for stem cell transplantation (SCT). A new mouth rinse device was tested for possible additive effect to OC.

    For study I-III, 78 patients were randomised to OC or standard oral care (SOC). Papers I and II showed that OC patients had significantly less severe mucositis, pain, opioid use, lower C-reactive protein and less parenteral nutrition treatment (TPN).

    There was no difference in relapse rate, and 5-year survival was unexpectedly significantly better in the OC group (Paper III). In paper IV, the local effect of OC on the mucosa of the mouth was investigated by the use of an infrared thermograph. Change in surface temperature in eight areas of the mouth cavity was measured after cooling of the mouth in healthy volunteers. A substantial lowering of the temperature (-12.9 °C, mean) was seen which could explain the efficacy of OC. To exclude that acute cooling in itself is traumatic, the proinflammatory cytokine IL-6 was measured in saliva and showed no increase after cooling. Paper V reported a study in 40 allogeneic SCT patients. 20 were given SOC including OC and 20 in addition received Caphosol®, a calcium phosphate mouth rinse, during chemotherapy and until day 21. Severity of mucositis, use of opioids and TPN, effects on nutrition and CRP levels were measured. No significant difference was found between the groups in any of these variables, but a non-significant trend for an advantage for the combination could be seen. IL-6 saliva levels were measured. There was a substantial increase (more than 10-fold), in mean IL-6 levels from baseline to beginning of mucositis and a weak correlation between increased IL-6 levels and severity of OM, suggesting that IL-6 in saliva may be a useful marker of the inflammatory mucosal process.

    This thesis demonstrates that OC is effective as prophylaxis against chemotherapy-induced OM. As a consequence of this work, OC has been introduced as the standard of care in all SCT patients in our institution.

    List of papers
    1. Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy-a randomized controlled trial
    Open this publication in new window or tab >>Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy-a randomized controlled trial
    2007 (English)In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 15, no 10, p. 1155-1161Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Mucositis is a major complication in myeloablative therapy, which often necessitates advanced pharmacological pain treatment, including i.v. opioids. Attempts to prevent oral mucositis have included oral cryotherapy, which has been shown to reduce mucositis, but there is a lack of knowledge concerning the effect of oral cryotherapy on opioid use by reducing the mucositis for patients treated with myeloablative therapy before bone marrow transplantation (BMT). Aim: The aim of the present study was to evaluate if oral cryotherapy could delay or alleviate the development of mucositis and thereby reduce the number of days with i.v. opioids among patients who receive myeloablative therapy before BMT. Materials and methods: Eighty patients 18 years and older, scheduled for BMT, were included consecutively and randomised to oral cryotherapy or standard oral care. A stratified randomisation was used with regard to type of transplantation. Intensity of pain, severity of mucositis and use of opioids were recorded using pain visual analogue scale (VAS) scores, mucositis index scores and medical and nursing charts. Results: This study showed that patients receiving oral cryotherapy had less pronounced mucositis and significantly fewer days with i.v. opioids than the control group. In the autologous setting, cryotherapy patients also needed significantly lower total dose of opioids. Conclusion: Oral cryotherapy is an effective and well-tolerated therapy to alleviate mucositis and consequently reduce the number of days with i.v. opioids among patients treated with myeloablative therapy before BMT.

    Keywords
    Oral cryotherapy, Bone marrow transplantation, Mucositis, Oral pain, Opioid use
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-11834 (URN)10.1007/s00520-007-0245-8 (DOI)000249632900004 ()17393189 (PubMedID)
    Available from: 2007-10-26 Created: 2007-10-26 Last updated: 2017-12-11Bibliographically approved
    2. Oral cryotherapy reduces mucositis and improves nutrition: a randomised controlled trial
    Open this publication in new window or tab >>Oral cryotherapy reduces mucositis and improves nutrition: a randomised controlled trial
    2010 (English)In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 19, no 15-16, p. 2146-2151Article in journal (Refereed) Published
    Abstract [en]

    Aim and objective. To investigate if oral cryotherapy during myeloablative therapy may influence frequency and severity of mucositis, nutritional status and infection rate after bone marrow transplantation. Background. Patients treated with intensive myeloablative treatment before bone marrow transplantation are all at risk to develop mucositis. Oral mucositis causes severe pain and oral dysfunction, which can contribute to local and systemic infections and bleeding; it may even interrupt cancer therapy. Oral mucositis also decreases the oral food intake, which increases the risk for malnutrition and infection. Reduced food intake, loss of fat and muscles, alterations in energy and substrate metabolism leads to malnutrition. Design. A randomised controlled trial with a random assignment to experimental or control group. Method. A stratified randomisation was used with regard to the type of transplantation. Mucositis was measured on WHO mucositis scale. Number of days of total parenteral nutrition, infection rate, weight, albumin levels and days at hospital was compared. Results. There were significantly fewer patients in the experimental group with mucositis grade 3-4 than in the control group and significantly lower number of days in the hospital (allogeneic patients). Less total parenteral nutrition was needed in the experimental group in both settings, and the S-albumin level was significantly better preserved. No significant difference could be found with regard to infection rate. Conclusion. Oral cryotherapy reduced mucositis, number of hospital days, the need for total parenteral nutrition and resulted in a better nutritional status. Relevance to clinical practice. Nurses caring for patients treated with myeloablative therapy should place high priority to prevent oral mucositis and hereby reduce its side effects.

    Keywords
    bone marrow transplantation, infection rate, mucositis, nutritional status, oral cryotherapy, total parenteral nutrition
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-135665 (URN)10.1111/j.1365-2702.2010.03255.x (DOI)000279937600009 ()
    Available from: 2010-12-08 Created: 2010-12-07 Last updated: 2017-12-11Bibliographically approved
    3. Five year follow-up of survival and relapse in patients who received cryotherapy during high dose chemotherapy for stem cell transplantation shows no safety concerns
    Open this publication in new window or tab >>Five year follow-up of survival and relapse in patients who received cryotherapy during high dose chemotherapy for stem cell transplantation shows no safety concerns
    2012 (English)In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 21, no 6, p. 822-828Article in journal (Refereed) Published
    Abstract [en]

    We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high-dose chemotherapy for stem cell transplantation. The present study is a 5-year follow-up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high-dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5-year follow-up study gave no support for safety concerns with cryotherapy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179505 (URN)10.1111/ecc.12009 (DOI)000314038700016 ()22967016 (PubMedID)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
    4. The effect of cryotherapy on oral mucosa: a study in healthy volunteers
    Open this publication in new window or tab >>The effect of cryotherapy on oral mucosa: a study in healthy volunteers
    2012 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 5, p. 3587-3591Article in journal (Refereed) Published
    Abstract [en]

    Oral cryotherapy causes local vasoconstriction, which reduces blood flow and reduces the cytotoxic damage to the oral mucosa, has been shown to reduce oral mucositis after intense cytostatic treatment. The main object of this study was to investigate the effect of oral cryotherapy on the temperature in the oral mucosa, the level of proinflammatory cytokine interleukin-6 (IL-6) in saliva and the effect on blood pressure in healthy volunteers, before and after 1 h of cooling the oral cavity with crushed ice. Twelve healthy volunteers [mean age 32.4 (SD 13.2) (20-56) years] were treated with oral cryotherapy in the form of crushed ice. Temperature measurements were performed in the oral mucosa using infrared thermograph following a flowchart protocol. Blood pressure (BP) was measured with a sphygmomanometer. Saliva was analysed for inflammatory cytokine IL-6, using an enzyme-linked immunosorbent assay (ELISA). All participants fulfilled the cooling session. The temperature in the oral cavity decreased significantly (mean 12.9 degrees C, p < .002). The systolic BP was marginally but significantly higher after cooling (similar to 5 mmHg, p = .019). We could not detect any differences in cytokine IL-6 levels before and after oral cooling. We conclude that cryotherapy during 1 h lowers the mucosal temperature as much as similar to 12.9 degrees C, which explains the significant protective effect against mucosal damage by cytostatic drugs. The cooling caused no increase in IL-6 levels. Systemic blood pressure was marginally increased.

    Keywords
    oral cooling, thermographic measurement, interleukin (IL)-6, oral cavity temperature, blood pressure
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179504 (URN)10.1007/s12032-012-0230-z (DOI)000311513800085 ()22476810 (PubMedID)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
    5. Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation: A pilot study
    Open this publication in new window or tab >>Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation: A pilot study
    2015 (English)In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 19, p. 50-53Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: To investigate if adding Caphosol(®), a mouthwash solution, to oral cryotherapy (OC) further protects against oral mucositis (OM), a toxic painful complication to high dose chemotherapy.

    METHOD: The study was a randomised, controlled, study design. Patients ≥16 years scheduled for allogeneic stem cell transplantation were included consecutively and randomised to experimental group receiving OC combined with Caphosol(®) (n = 20) or control group receiving OC only (n = 20). OC was given from start to end of HDCT. Caphosol(®), from day 0 to day 21.

    RESULT: There were no significant differences regarding age or gender between the groups. Mucositis was assessed with the World Health Organisation (WHO) grading scale. Pain was assessed with a 10 cm visual analogue scale (VAS) from 0 = no pain to 10 = worst imaginable pain. Start and duration of therapy with pain relieving drugs, serum C-reactive protein values, and number of days of hospitalisation were collected from the medical records. Data on OM, oral pain, use of i.v. opioids and total parenteral nutrition were collected during 22 days. There was no significant difference between the groups on OM, oral pain, use of i.v. opioids or TPN between the groups.

    CONCLUSION: The study showed no additional effect of combining Caphosol(®) with OC.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-179503 (URN)10.1016/j.ejon.2014.07.011 (DOI)000350074400009 ()25224595 (PubMedID)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
  • 331.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Addition of aprepitant (Emend (R)) to standard antiemetic care for seven days post-chemotherapy before stem cell transplantation gives significant reduction of vomiting2013In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, no Suppl.2, p. S463-S463Article in journal (Other academic)
  • 332.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Addition of Aprepitant (Emend®) to Standard Antiemetic Regimen Continued for 7 Days after Chemotherapy for Stem Cell Transplantation Provides Significant Reduction of Vomiting2015In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 89, no 1, p. 31-36Article in journal (Refereed)
    Abstract [en]

    Chemotherapy-induced nausea/vomiting (CINV) is a major problem for patients treated with high-dose chemotherapy (HDCT) conditioning before stem cell transplantation (SCT), both during chemotherapy and afterwards (delayed nausea/vomiting). The standard of care (5-HT3 antagonist and dexamethasone) appears to be ineffective against delayed nausea and vomiting. The objective of this study was to compare standard antiemetic treatment with standard treatment plus prolonged treatment with aprepitant (Emend®) until 7 days after the end of chemotherapy in patients treated with HDCT before autologous SCT. Ninety-six patients were randomized to the experiment (EXP) group receiving Emend in addition to standard antiemetics or to the control (CTR) group receiving placebo. Emend or placebo treatment started 1 h before the first HDCT dose for SCT and ended 7 days after HDCT. Thirty-eight patients in the EXP group experienced complete response (no vomiting) compared to 16 patients in the CTR group. There was a significant difference between the EXP (0.63 ± 2.71) and the CTR (3.72 ± 4.91) group during 10 days after the end of HDCT (p = 0.001) with regard to the number of vomiting episodes. No difference with regard to days of nausea or in the use of antiemetic rescue was noted between the groups. We conclude that standard antiemetic treatment can be improved by addition of aprepitant continued for 7 days after the end of chemotherapy.

  • 333.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Öhrn, Kerstin
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation: A pilot study2015In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 19, p. 50-53Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate if adding Caphosol(®), a mouthwash solution, to oral cryotherapy (OC) further protects against oral mucositis (OM), a toxic painful complication to high dose chemotherapy.

    METHOD: The study was a randomised, controlled, study design. Patients ≥16 years scheduled for allogeneic stem cell transplantation were included consecutively and randomised to experimental group receiving OC combined with Caphosol(®) (n = 20) or control group receiving OC only (n = 20). OC was given from start to end of HDCT. Caphosol(®), from day 0 to day 21.

    RESULT: There were no significant differences regarding age or gender between the groups. Mucositis was assessed with the World Health Organisation (WHO) grading scale. Pain was assessed with a 10 cm visual analogue scale (VAS) from 0 = no pain to 10 = worst imaginable pain. Start and duration of therapy with pain relieving drugs, serum C-reactive protein values, and number of days of hospitalisation were collected from the medical records. Data on OM, oral pain, use of i.v. opioids and total parenteral nutrition were collected during 22 days. There was no significant difference between the groups on OM, oral pain, use of i.v. opioids or TPN between the groups.

    CONCLUSION: The study showed no additional effect of combining Caphosol(®) with OC.

  • 334.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Öhrn, Kerstin
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Five year follow-up of survival and relapse in patients who received cryotherapy during high dose chemotherapy for stem cell transplantation shows no safety concerns2012In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 21, no 6, p. 822-828Article in journal (Refereed)
    Abstract [en]

    We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high-dose chemotherapy for stem cell transplantation. The present study is a 5-year follow-up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high-dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5-year follow-up study gave no support for safety concerns with cryotherapy.

  • 335.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Öhrn, Kerstin
    Broström, Hans
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The effect of cryotherapy on oral mucosa: a study in healthy volunteers2012In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 5, p. 3587-3591Article in journal (Refereed)
    Abstract [en]

    Oral cryotherapy causes local vasoconstriction, which reduces blood flow and reduces the cytotoxic damage to the oral mucosa, has been shown to reduce oral mucositis after intense cytostatic treatment. The main object of this study was to investigate the effect of oral cryotherapy on the temperature in the oral mucosa, the level of proinflammatory cytokine interleukin-6 (IL-6) in saliva and the effect on blood pressure in healthy volunteers, before and after 1 h of cooling the oral cavity with crushed ice. Twelve healthy volunteers [mean age 32.4 (SD 13.2) (20-56) years] were treated with oral cryotherapy in the form of crushed ice. Temperature measurements were performed in the oral mucosa using infrared thermograph following a flowchart protocol. Blood pressure (BP) was measured with a sphygmomanometer. Saliva was analysed for inflammatory cytokine IL-6, using an enzyme-linked immunosorbent assay (ELISA). All participants fulfilled the cooling session. The temperature in the oral cavity decreased significantly (mean 12.9 degrees C, p < .002). The systolic BP was marginally but significantly higher after cooling (similar to 5 mmHg, p = .019). We could not detect any differences in cytokine IL-6 levels before and after oral cooling. We conclude that cryotherapy during 1 h lowers the mucosal temperature as much as similar to 12.9 degrees C, which explains the significant protective effect against mucosal damage by cytostatic drugs. The cooling caused no increase in IL-6 levels. Systemic blood pressure was marginally increased.

  • 336.
    Svensson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Infectious and bleeding complications in patients with hematological malignancies: Studies on diagnosis and prevention2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS).

    Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted.

    There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL.

    Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests.

    Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.

    List of papers
    1. Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia
    Open this publication in new window or tab >>Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia
    2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 7, p. 537-542Article in journal (Refereed) Published
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) and hypogammaglobulinemia who suffer from recurrent infections can be offered prophylactic intravenous immunoglobulin (Ig) substitution. Our aim was to assess the prevalence of pure IgG subclass deficiency (with normal Ig levels), its correlation to risk of infection, and the clinical value of routine measurement of serum IgG subclass levels in patients with CLL. Methods: Serum levels of Ig and IgG subclasses were determined in patients with CLL at Uppsala University Hospital. Clinical data were collected through patient records and questionnaires. Results: Hypogammaglobulinemia occurred in 52.3% out of 111 patients. These patients did not have a higher annual risk of infection than patients without hypogammaglobulinemia (79.5% vs 79.1%, p = 0.706 for all infections; 13.4% vs 11.2%, p = 0.394 for severe infection; and 1.7% vs 3.4%, p = 0.083 for sepsis). Pure subclass deficiency was uncommon and occurred in 6 patients (5.4%). The annual overall risk of infection, of severe infection, and of sepsis for these patients did not differ as compared to patients with no hypogammaglobulinemia and no subclass deficiency (70.8% vs 80.7%, p = 0.334; 11.8% vs 11.1%, p = 0.497; and 8.9% vs 2.3%, p = 0.067, respectively). Conclusions: Pure IgG subclass deficiency is rare in patients with CLL. In this heterogeneous cohort of patients, neither hypogammaglobulinemia nor pure IgG subclass deficiency were significant risk factors for infectious complications. Measurement of serum levels of Ig may be justified in patients with recurrent severe infections, but routine analysis of IgG subclass levels in patients with CLL is probably not warranted.

    Keywords
    Hypogammaglobulinemia, IgG subclass, chronic lymphocytic leukemia, immunodeficiency
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-203524 (URN)10.3109/00365548.2013.769279 (DOI)000320380900007 ()
    Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
    2. Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group
    Open this publication in new window or tab >>Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group
    Show others...
    2018 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 36, no 25, p. 3701-3707Article in journal (Refereed) Published
    Abstract [en]

    Aim: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent conjugated pneumococcal vaccine (PCV13), Prevenar13®, compared with a 23-valent capsular polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response.

     

    Background: Patients with CLL have an increased risk for infection and Streptococcus pneumoniae is one of the most common pathogens with high morbidity.  Patients with CLL are known to respond poorly to the traditionally used polysaccharide vaccines. Conjugation of polysaccharide to protein carriers renders a thymus-dependent, memory-inducing and more immunogenic vaccine. In patients with CLL, there is no consensus on a recommendation for pneumococcal vaccination, due to a lack of comparative studies.

     

    Methods: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n=63) or PPSV23 (n=65) after stratification by IgG levels and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, at one and at six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA).

     

    Results: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. The proportion of patients with good response (defined as response in 8 of 12 common serotypes according to predefined response criteria) was higher in PCV13 recipients than in PPSV23 recipients after one month (40% vs. 22%, p=0.034) as well as after six months (33% vs. 17%, p=0.041). Never did PPSV23 trigger a better immune response for any of the serotypes, than PCV13, regardless of analysis. For two of the serotypes, OPA GMTs were lower at the six months than at the one-month follow up. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated.

     

    Conclusions: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for many serotypes common for the two vaccines. PCV13 should be considered as a part in vaccination programs against Streptococcus pneumoniae for these patients and administered as early as possible during the course of the disease. 

    Keywords
    Chronic lymphocytic leukemia (CLL), vaccine, Pneumococci, Pneumococcal vaccine, Polysaccharide vaccine, protein-conjugate vaccine, immunogenicity
    National Category
    Immunology in the medical area Infectious Medicine
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-316457 (URN)10.1016/j.vaccine.2018.05.012 (DOI)000436202800022 ()
    Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2019-02-01Bibliographically approved
    3. Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?
    Open this publication in new window or tab >>Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?
    2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 56-60Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine the diagnostic yield of BAL in patients treated for hematological malignancies and how often it contributed to a modification of the anti-infectious therapy.

    METHODS: We reviewed records from 151 consecutive BAL procedures in 133 adult patients with hematological malignancies, treated at a tertiary hematology unit from 2004 to 2013. Extensive microbiological work-ups on BAL samples had been performed according to a standardized protocol.

    RESULTS: A microbiological finding causing the infectious episode could be identified in 59 (39%) cases. In 44 (29%) of the cases, results from BAL had an impact on clinical management either by contributing to a specific diagnosis (25%) or by leading to cessation of ongoing microbiological therapy. The most common diagnoses were invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). Diagnoses of IPA and PJP were based on results from BAL in 65% and 93% of cases, respectively. Several microbiological tests on BAL samples rendered no positive results. Complications were few and mainly mild.

    CONCLUSION: BAL is still important for either verifying or excluding some of the most important respiratory tract pathogens in patients with hematological malignancies, particularly IPA and PJP. Standardized procedures for BAL sampling should be continually revised to exclude unnecessary microbiological tests.

    Keywords
    Aspergillosis, bronchoalveolar lavage, hematological malignancies, immunodeficiency, invasive fungal disease, neutropenia, Pneumocystis jirovecii pneumonia, pulmonary infiltrates
    National Category
    General Practice Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-310816 (URN)10.1080/03009734.2016.1237595 (DOI)000396476600008 ()27739337 (PubMedID)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-02-26Bibliographically approved
    4. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
    Open this publication in new window or tab >>A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
    Show others...
    2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 5, p. 439-445Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.

    PATIENTS AND METHODS:

    Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 109/L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.

    RESULTS:

    Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.

    CONCLUSION:

    The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-233787 (URN)10.1111/ejh.12383 (DOI)000343970700011 ()24853277 (PubMedID)
    Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-12-05Bibliographically approved
  • 337.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    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.
    Answer to "Letter to the Editor, Scandinavian Journal of Infectious Diseases"2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 9, p. 730-730Article in journal (Refereed)
  • 338.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Chowdhury, Onima
    Garelius, Hege
    Lorenz, Fryderyk
    Saft, Leonie
    Jacobsen, Sten-Eirik
    Hellström-Lindberg, Eva
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine2014In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 5, p. 439-445Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.

    PATIENTS AND METHODS:

    Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 109/L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.

    RESULTS:

    Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.

    CONCLUSION:

    The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

  • 339.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 7, p. 537-542Article in journal (Refereed)
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) and hypogammaglobulinemia who suffer from recurrent infections can be offered prophylactic intravenous immunoglobulin (Ig) substitution. Our aim was to assess the prevalence of pure IgG subclass deficiency (with normal Ig levels), its correlation to risk of infection, and the clinical value of routine measurement of serum IgG subclass levels in patients with CLL. Methods: Serum levels of Ig and IgG subclasses were determined in patients with CLL at Uppsala University Hospital. Clinical data were collected through patient records and questionnaires. Results: Hypogammaglobulinemia occurred in 52.3% out of 111 patients. These patients did not have a higher annual risk of infection than patients without hypogammaglobulinemia (79.5% vs 79.1%, p = 0.706 for all infections; 13.4% vs 11.2%, p = 0.394 for severe infection; and 1.7% vs 3.4%, p = 0.083 for sepsis). Pure subclass deficiency was uncommon and occurred in 6 patients (5.4%). The annual overall risk of infection, of severe infection, and of sepsis for these patients did not differ as compared to patients with no hypogammaglobulinemia and no subclass deficiency (70.8% vs 80.7%, p = 0.334; 11.8% vs 11.1%, p = 0.497; and 8.9% vs 2.3%, p = 0.067, respectively). Conclusions: Pure IgG subclass deficiency is rare in patients with CLL. In this heterogeneous cohort of patients, neither hypogammaglobulinemia nor pure IgG subclass deficiency were significant risk factors for infectious complications. Measurement of serum levels of Ig may be justified in patients with recurrent severe infections, but routine analysis of IgG subclass levels in patients with CLL is probably not warranted.

  • 340.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kättström, Magdalena
    Hammarlund, Ylva
    Roth, Daniel
    Andersson, Per-Ola
    Svensson, Magnus
    Nilsson, Ingmar
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kimby, Eva
    Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group2018In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 36, no 25, p. 3701-3707Article in journal (Refereed)
    Abstract [en]

    Aim: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent conjugated pneumococcal vaccine (PCV13), Prevenar13®, compared with a 23-valent capsular polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response.

     

    Background: Patients with CLL have an increased risk for infection and Streptococcus pneumoniae is one of the most common pathogens with high morbidity.  Patients with CLL are known to respond poorly to the traditionally used polysaccharide vaccines. Conjugation of polysaccharide to protein carriers renders a thymus-dependent, memory-inducing and more immunogenic vaccine. In patients with CLL, there is no consensus on a recommendation for pneumococcal vaccination, due to a lack of comparative studies.

     

    Methods: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n=63) or PPSV23 (n=65) after stratification by IgG levels and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, at one and at six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA).

     

    Results: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. The proportion of patients with good response (defined as response in 8 of 12 common serotypes according to predefined response criteria) was higher in PCV13 recipients than in PPSV23 recipients after one month (40% vs. 22%, p=0.034) as well as after six months (33% vs. 17%, p=0.041). Never did PPSV23 trigger a better immune response for any of the serotypes, than PCV13, regardless of analysis. For two of the serotypes, OPA GMTs were lower at the six months than at the one-month follow up. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated.

     

    Conclusions: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for many serotypes common for the two vaccines. PCV13 should be considered as a part in vaccination programs against Streptococcus pneumoniae for these patients and administered as early as possible during the course of the disease. 

  • 341.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lundström, Kristina Lamberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 56-60Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine the diagnostic yield of BAL in patients treated for hematological malignancies and how often it contributed to a modification of the anti-infectious therapy.

    METHODS: We reviewed records from 151 consecutive BAL procedures in 133 adult patients with hematological malignancies, treated at a tertiary hematology unit from 2004 to 2013. Extensive microbiological work-ups on BAL samples had been performed according to a standardized protocol.

    RESULTS: A microbiological finding causing the infectious episode could be identified in 59 (39%) cases. In 44 (29%) of the cases, results from BAL had an impact on clinical management either by contributing to a specific diagnosis (25%) or by leading to cessation of ongoing microbiological therapy. The most common diagnoses were invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). Diagnoses of IPA and PJP were based on results from BAL in 65% and 93% of cases, respectively. Several microbiological tests on BAL samples rendered no positive results. Complications were few and mainly mild.

    CONCLUSION: BAL is still important for either verifying or excluding some of the most important respiratory tract pathogens in patients with hematological malignancies, particularly IPA and PJP. Standardized procedures for BAL sampling should be continually revised to exclude unnecessary microbiological tests.

  • 342.
    Sylvan, Sandra Eketorp
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Asklid, Anna
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden.
    Johansson, Hemming
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Klintman, Jenny
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden;Lund Univ, Dept Translat Med, Lund, Sweden.
    Bjellvi, Jenny
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden.
    Tolvgård, Staffan
    Ostersunds Hosp, Dept Internal Med, Ostersund, Sweden.
    Kimby, Eva
    Karolinska Inst, Dept Internal Med Huddinge, Stockholm, Sweden.
    Norin, Stefan
    Karolinska Inst, Dept Internal Med Huddinge, Stockholm, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hosp, Dept Hematol, Boras, Sweden.
    Karlsson, Claes
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Karlsson, Karin
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Lauri, Birgitta
    Sunderby Hosp, Dept Hematol, Sunderbyn Lulea, Sweden.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandstedt, Anna Bergendahl
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden.
    Strandberg, Maria
    Sundsvall Hosp, Dept Med, Sundsvall, Sweden.
    Österborg, Anders
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Hansson, Lotta
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    First-line therapy in chronic lymphocytic leukemia: a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 20132019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 4, p. 797-805Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections >= grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified.

  • 343.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clinical and Immunological Studies in Chronic Myeloid Leukaemia2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic myeloid leukaemia (CML) is characterised by the constitutively active tyrosine kinase BCR-ABL. Standard treatment with tyrosine kinase inhibitors (TKI) in the chronic phase (CP) of CML conveys excellent long-term prognosis but is associated with side effects and costs. Treatment free remission (TFR) is possible in a proportion of patients discontinuing treatment after obtaining deep treatment responses but it is not fully known how to select the right patients for stopping attempts. Treatment of accelerated phase (AP) and blast crisis (BC) is more complicated and the prognosis more dismal. In this thesis, we have studied factors of importance for outcome in CML patients with focus on immunological factors and clinical management.

    In a cohort of 32 newly diagnosed CP-CML patients, evidence of active immune escape mechanisms were found. These declined with the course of TKI treatment and at the same time, effector lymphocyte responses were elicited. These anti-leukaemia immune responses might help in the long-term control of CML. Multiple plasma protein markers were also measured with three multiplex platforms in a smaller cohort of patients (n=14). Inflammatory cytokines and other plasma proteins were affected by TKI treatment and multiplexing seems useful for finding potential biomarkers with biologic or prognostic significance in CML.

    Patients progressing to AP/BC were studied in a population-based material from the Swedish CML register. Approximately 4% of TKI-treated CP-CML patients transformed to AP/BC within 2 years of diagnosis. Monitoring of treatment responses was suboptimal in 1/3 of these patients and the median survival was 1.4 years after diagnosis of AP/BC. Thus, minimising the risk of disease progression through strict adherence to guidelines for monitoring and treatment is essential.

    In a cohort of patients (n=50) discontinuing TKI treatment within a large European trial, musculoskeletal pain was reported by 30% of patients, starting within 1- 6 weeks of TKI discontinuation and spontaneously resolving over time in most cases. Patients (n=56) were also evaluated with a multiplex platform with a total of 162 inflammation- and cancer-related plasma proteins. No predictive protein biomarkers for successful TKI discontinuation could be found. However, profound effects of TKI-treatment were seen and plasma proteomics could be useful for understanding effects of long-term TKI-treatment.

    List of papers
    1. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?
    Open this publication in new window or tab >>Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?
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    2014 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 25, p. 2821-2823Article in journal (Refereed) Published
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-233785 (URN)10.1200/JCO.2014.55.6910 (DOI)000341562600033 ()25071107 (PubMedID)
    Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-12-05Bibliographically approved
    2. The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
    Open this publication in new window or tab >>The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
    Show others...
    2015 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed) Published
    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. 

    National Category
    Hematology Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-269778 (URN)10.1158/1535-7163.MCT-14-0849 (DOI)000358053000010 ()25761894 (PubMedID)
    Available from: 2015-12-18 Created: 2015-12-18 Last updated: 2017-12-01Bibliographically approved
    3. Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli
    Open this publication in new window or tab >>Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli
    Show others...
    2016 (English)In: 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) Published
    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.

    Keywords
    Proteomics, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Th1, Angiogenesis
    National Category
    Cancer and Oncology Hematology
    Identifiers
    urn:nbn:se:uu:diva-310831 (URN)10.1016/j.leukres.2016.09.019 (DOI)000388315500015 ()27710869 (PubMedID)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2017-11-29Bibliographically approved
    4. Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register
    Open this publication in new window or tab >>Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register
    Show others...
    2017 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 57-66Article in journal (Refereed) Published
    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.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-310827 (URN)10.1111/ejh.12785 (DOI)000393166600009 ()27428357 (PubMedID)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-02-26Bibliographically approved
    5. Proximity extension assay-based plasma proteomics cannot predict relapse in chronic myeloid leukaemia patients stopping treatment with tyrosine kinase inhibitors (TKI) but reveal profound effects of long-term TKI treatment on plasma protein profiles
    Open this publication in new window or tab >>Proximity extension assay-based plasma proteomics cannot predict relapse in chronic myeloid leukaemia patients stopping treatment with tyrosine kinase inhibitors (TKI) but reveal profound effects of long-term TKI treatment on plasma protein profiles
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Hematology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-327172 (URN)
    Available from: 2017-08-05 Created: 2017-08-05 Last updated: 2017-08-05
  • 344.
    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)
  • 345.
    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.

  • 346.
    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)
  • 347.
    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.

  • 348.
    Tobiasson, Magnus
    et al.
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Abdulkadir, Hani
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Lennartsson, Andreas
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Katayama, Shintaro
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Marabita, Francesco
    Karolinska Inst, Dept Med, Ctr Mol Med, Unit Computat Med, Stockholm, Sweden.;Natl Bioinformat Infrastruct Sweden, Stockholm, Sweden..
    De Paepe, Ayla
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Karimi, Mohsen
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Krjutskov, Kaarel
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden.;Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland.;Competence Ctr Hlth Technol, Tartu, Estonia..
    Einarsdottir, Elisabet
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden.;Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland..
    Grövdal, Michael
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Jansson, Monika
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Ben Azenkoud, Asmaa
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Corddedu, Lina
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden.
    Ekwall, Karl
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Kere, Juha
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden.;Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland..
    Hellström-Lindberg, Eva
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Ungerstedt, Johanna
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 17, p. 28812-28825Article in journal (Refereed)
    Abstract [en]

    Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.

  • 349.
    Toft, N.
    et al.
    Herlev Univ Hosp, Dept Hematol, Herlev, Denmark.;Rigshosp, Univ Hosp, Dept Hematol, Copenhagen, Denmark..
    Birgens, H.
    Herlev Univ Hosp, Dept Hematol, Herlev, Denmark..
    Abrahamsson, J.
    Queen Silvias Childrens Hosp, Dept Clin Sci, Gothenburg, Sweden..
    Griskevicius, L.
    Vilnius Univ Hosp, Santariskiu Klin, Hematol Oncol & Transfus Med Ctr, Vilnius, Lithuania..
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Heyman, M.
    Karolinska Inst, Karolinska Univ Hosp, Astrid Lindgrens Childrens Hosp, Childhood Canc Res Unit, Stockholm, Sweden..
    Klausen, T. W.
    Herlev Univ Hosp, Dept Hematol, Herlev, Denmark..
    Jonsson, O. G.
    Landspitali Univ Hosp, Childrens Hosp, Reykjavk, Iceland..
    Palk, K.
    North Estonia Med Ctr, Dept Hematol, Tallinn, Estonia..
    Pruunsild, K.
    Tallinn Childrens Hosp, Tallinn, Estonia..
    Quist-Paulsen, P.
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Vaitkeviciene, G.
    Vilnius Univ Hosp, Santariskiu Klin, Childrens Hosp, Ctr Pediat Oncol & Hematol, Vilnius, Lithuania..
    Vettenranta, K.
    Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland..
    Asberg, A.
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Pediat, Trondheim, Norway..
    Frandsen, T. Leth
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark..
    Marquart, H. V.
    Rigshosp, Univ Hosp, Sect 7631, Dept Clin Immunol, Copenhagen, Denmark..
    Madsen, H. O.
    Rigshosp, Univ Hosp, Sect 7631, Dept Clin Immunol, Copenhagen, Denmark..
    Noren-Nystrom, U.
    Umea Univ, Dept Clin Sci, Pediat, Umea, Sweden..
    Schmiegelow, K.
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark..
    Adults And Children (1-45 Years) With Ph-Negative All Have Almost Identical Outcome In Risk-Stratified Analysis Of Nopho All20082016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 35-35Article in journal (Other academic)
  • 350. Toft, N
    et al.
    Birgens, H
    Abrahamsson, J
    Griškevičius, L
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Heyman, M
    Klausen, T W
    Jónsson, Ó G
    Palk, K
    Pruunsild, K
    Quist-Paulsen, P
    Vaitkeviciene, G
    Vettenranta, K
    Åsberg, A
    Frandsen, T L
    Marquart, H V
    Madsen, H O
    Norén-Nyström, U
    Schmiegelow, K
    Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, p. 606-615Article in journal (Refereed)
    Abstract [en]

    Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P = 0.53). Event-free survival rates (pEFS(5y)) were 89 +/- 1% (A), 80 +/- 3% (B) and 74 +/- 4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

45678 301 - 350 of 377
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