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  • 1.
    Abelsson, J.
    et al.
    NU Hospital Organization, Uddevalla.
    Merup, M.
    Karolinska Universitetssjukhuset, Huddinge.
    Birgegård, G.
    Uppsala University.
    WeisBjerrum, O.
    Rigshospitalet, University of Copenhagen.
    Brinch, L.
    Rikshospitalet, Oslo University Hospital.
    Brune, M.
    Sahlgrenska Universitetssjukhuset, Göteborg.
    Johansson, P.
    NU Hospital Organization, Uddevalla.
    Kauppila, M.
    Turku University Hospital, Finland.
    Lenhoff, S.
    Skåne University Hospital.
    Liljeholm, M.
    Norrlands Universitetssjukhus, Umeå.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Remes, K.
    Turku University Hospital, Finland.
    Vindelöv, L.
    Rigshospitalet, University of Copenhagen.
    Andréasson, Björn
    NU Hospital Organization, Uddevalla.
    The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries2012Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 47, nr 3, s. 380-386Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.Bone Marrow Transplantation advance online publication, 9 May 2011; doi:10.1038/bmt.2011.91.

  • 2.
    Auner, H W.
    et al.
    University of London Imperial Coll Science Technology and Med, England .
    Szydlo, R
    University of London Imperial Coll Science Technology and Med, England .
    van Biezen, A
    Leiden University, Netherlands .
    Iacobelli, S
    University of Roma Tor Vergata, Italy .
    Gahrton, G
    Karolinska Institute, Sweden .
    Milpied, N
    Hop Haut Leveque, France .
    Volin, L
    University of Helsinki, Finland .
    Janssen, J
    Vrije University of Amsterdam, Netherlands .
    Nguyen Quoc, S
    Grp Hospital Pitie Salpetriere, France .
    Michallet, M
    Hop Edouard Herriot, France .
    Schoemans, H
    University Hospital Gasthuisberg, Belgium .
    el Cheikh, J
    Institute J Paoli I Calmettes, France .
    Petersen, E
    University of Medical Centre, Netherlands .
    Guilhot, F
    Hop La Miletrie, France .
    Schoenland, S
    Heidelberg University, Germany .
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Morris, C
    Queens University of Belfast, North Ireland .
    Garderet, L
    Hop St Antoine, France .
    de Witte, T
    Radboud University of Nijmegen, Netherlands .
    Kroeger, N
    University Hospital Eppendorf, Germany .
    Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation2013Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, nr 11, s. 1395-1400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

  • 3.
    Baron, F.
    et al.
    University of Liege, Belgium .
    Labopin, M.
    Hospital Saint Antoine / Pierre-and-Marie-Curie University, Paris, France.
    Blaise, D.
    CHU Marseille, France .
    Lopez-Corral, L.
    Hospital Clinico Universitario, Salamanca, Spain.
    Vigouroux, S.
    CHU Bordeaux, France .
    Craddock, C.
    Queen Elizabeth Hospital and School of Cancer Studies, University of Birmingham, UK .
    Attal, M.
    CHU Toulouse, France .
    Jindra, P.
    Charles University Medical School and Teaching Hospital, Pilsen, Czech Republic.
    Goker, H.
    Hacettepe University, Ankara,Turkey .
    Socie, G.
    Saint-Louis Hospital, Paris, France.
    Chevallier, P.
    CHU Nantes, France .
    Browne, P.
    St James Hospital, Dublin, Ireland.
    Sandstedt, A.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Duarte, R. F.
    Hospital Llobregat, Barcelona, Spain .
    Nagler, A.
    Tel Aviv University, Israel.
    Mohty, M.
    Hospital Saint Antoine / Pierre-and-Marie-Curie University, Paris, France.
    Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation2014Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 49, nr 3, s. 389-396Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (P less than 0.001). In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (P less than 0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of less than 6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR=1.1), whereas there was a suggestion for higher relapse risk in patients given greater than= 6 mg/kg ATG (HR=1.4, P=0.08). In summary, these data suggest that a certain amount of in vivo T-Cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC.

  • 4.
    Baron, F
    et al.
    University of Liege, Belgium .
    Labopin, M
    Hop St Antoine, France .
    Niederwieser, D
    University of Leipzig, Germany .
    Vigouroux, S
    University Hospital, France University of Bordeaux 2, France .
    Cornelissen, J J.
    Erasmus University, Netherlands .
    Malm, Claes
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Vindelov, L L.
    Rigshosp, Denmark .
    Blaise, D
    CHU Marseille, France .
    Janssen, J J W M
    Vrije University of Amsterdam, Netherlands .
    Petersen, E
    University of Medical Centre Utrecht, Netherlands .
    Socie, G
    Hop St Louis, France .
    Nagler, A
    Tel Aviv University, Israel .
    Rocha, V
    Eurocord, France EBMT ALWP, France .
    Mohty, M
    Hop St Antoine, France EBMT ALWP, France University of Nantes, France INSERM, France .
    Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation2012Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, nr 12, s. 2462-2468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR) 0.7, P = 0.02) translating into a trend for better overall survival (OS; HR 1.3; P = 0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR 0.4, P andlt; 0.0.001) owing to high risk of nonrelapse mortality (NRM; HR 5.2, P andlt; 0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR 0.72; P = 0.07) translating into a better OS (HR 1.8; P andlt; 0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR 0.65; P = 0.02) but also with higher NRM (HR 3.5; P andlt; 0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (P andlt; 0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR 0.65; P = 0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD. Leukemia (2012) 26, 2462-2468; doi: 10.1038/leu.2012.135

  • 5.
    Benner, Axel
    et al.
    German Cancer Research Centre, Germany.
    Mansouri, Larry
    Uppsala University, Sweden.
    Rossi, Davide
    Amedeo Avogadro University of Eastern Piedmont, Italy.
    Majid, Aneela
    University of Leicester, England.
    Willander, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Parker, Anton
    Royal Bournemouth Hospital, England.
    Bond, Gareth
    University of Oxford, England.
    Pavlova, Sarka
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Nueckel, Holger
    University of Duisburg Essen, Germany.
    Merkel, Olaf
    Paracelus Medical University, Austria.
    Ghia, Paolo
    University of Bita Salute San Raffaele, Italy.
    Montserrat, Emili
    University of Barcelona, Spain.
    Arifin Kaderi, Mohd
    Uppsala University, Sweden; Int Islamic University of Malaysia, Malaysia.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Gaidano, Gianluca
    Amedeo Avogadro University of Eastern Piedmont, Italy.
    Dyer, Martin J. S.
    University of Leicester, England.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Linderholm, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Oscier, David
    Royal Bournemouth Hospital, England.
    Tvaruzkova, Zuzana
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Pospisilova, Sarka
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Duehrsen, Ulrich
    University of Duisburg Essen, Germany.
    Greil, Richard
    Paracelus Medical University, Austria.
    Doehner, Hartmut
    University of Ulm, Germany.
    Stilgenbauer, Stephan
    University of Ulm, Germany.
    Zenz, Thorsten
    German Cancer Research Centre, Germany; University of Heidelberg Hospital, Germany.
    MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis2014Inngår i: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, nr 8, s. 1285-1291Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.

  • 6.
    Bjorkholm, M.
    et al.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Derolf, A.R.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Hultcrantz, M.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Kristinsson, S.Y.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Ekstrand, C.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Goldin, L.R.
    National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
    Andreasson, B.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Birgegard, G.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Linder, O.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Markevarn, B.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Nilsson, L.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Samuelsson, J.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Granath, F.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Landgren, O.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
    Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms2011Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, nr 17, s. 2410-2415Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). Methods: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. Results: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P32), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P32 greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. Conclusion: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P32 and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors. © 2011 by American Society of Clinical Oncology.

  • 7.
    Chevallier, P
    et al.
    CHU Hotel Dieu, France .
    Labopin, M
    University of Paris 06, France .
    Milpied, N
    CHU Bordeaux, France .
    Cornelissen, J J
    Erasmus MC Daniel den Hoed Cancer Centre, Netherlands .
    Blaise, D
    Institute Paoli Calmette, France .
    Petersen, E
    University of Medical Centre Utrecht, Netherlands .
    Sandstedt, A
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Goker, H
    Hacettepe University, Turkey .
    Socie, G
    Hop St Louis, France .
    Rocha, V
    Hop St Louis, France .
    Mohty, M
    n/a.
    Impact of cytogenetics risk on outcome after reduced intensity conditioning allo-SCT from an HLA-identical sibling for patients with AML in first CR: a report from the acute leukemia working party of EBMT2012Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 47, nr 11, s. 1442-1447Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    So far the impact of cytogenetics risk on outcome in the context of reduced intensity conditioning (RIC) allo-SCT has been poorly studied. We have identified 378 AML patients in first CR who underwent RIC allo-SCT from an HLA-matched sibling donor between 2000 and 2007 reported to the European Group for Bone and Marrow Transplantation and for whom detailed cytogenetics data were available (good risk: n = 21; intermediate risk: n = 304; and poor risk: n = 53). With a median follow-up of 24 months (range: 1-93), 2-year non-relapse mortality, relapse rate (RR), leukemia-free survival (LFS) and OS were 14%, 31%, 55% and 61%, respectively. Cytogenetics was significantly associated with RR (good risk: 10%; intermediate risk: 28%; and poor risk: 55% at 2 years, Pandlt;0.0001) and LFS (good risk: 64%; intermediate risk: 57%; and poor risk: 38% at 2 years, P = 0.003). In a multivariate analysis, RR and LFS were significantly higher and lower, respectively, in the high-risk cytogenetics group (P = 0.001, P = 0.004) and in patients with a higher WBC at diagnosis (andgt;10 x 10(9)/L) (Pandlt;0.001, P = 0.004). As documented in the setting of myeloablative allo-SCT, patients with poor cytogenetics had increased RR and decreased LFS after RIC allo-SCT, requiring new prospective strategies to improve results in this subgroup.

  • 8.
    Hoglund, Martin
    et al.
    University of Uppsala Hospital, Sweden .
    Sandin, Fredrik
    Regional Cancer Centre, Sweden .
    Hellstrom, Karin
    Regional Cancer Centre, Sweden .
    Bjoreman, Mats
    University Hospital, Sweden .
    Bjorkholm, Magnus
    Karolinska University Hospital, Sweden .
    Brune, Mats
    Sahlgrens University Hospital, Sweden .
    Dreimane, Arta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ekblom, Marja
    Skåne University Hospital, Sweden .
    Lehmann, Soren
    Karolinska University Hospital, Sweden .
    Ljungman, Per
    Karolinska University Hospital, Sweden .
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Markevarn, Berit
    Umeå University Hospital, Sweden .
    Myhr-Eriksson, Kristina
    Sunderby Luleå Hospital, Sweden .
    Ohm, Lotta
    Karolinska University Hospital, Sweden .
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital, Sweden .
    Sjalander, Anders
    Umeå University, Sweden .
    Wadenvik, Hans
    Sahlgrens University Hospital, Sweden .
    Simonsson, Bengt
    University of Uppsala Hospital, Sweden .
    Stenke, Leif
    Karolinska University Hospital, Sweden .
    Richter, Johan
    Skåne University Hospital, Sweden .
    Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, nr 7, s. 1284-1292Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 9.
    Hulegardh, E.
    et al.
    Sahlgrens University Hospital, Sweden .
    Hagglund, H.
    Karolinska University Hospital, Sweden .
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Karlsson, K.
    Skåne University Hospital, Sweden .
    Karbach, H.
    Umeå University Hospital, Sweden .
    Markuszewska, A.
    Umeå University Hospital, Sweden .
    Persson, I.
    Uppsala University, Sweden .
    Astrom, M.
    Örebro University Hospital, Sweden .
    Hallbook, H.
    Uppsala University, Sweden .
    Outcome after HSCT in Philadelphia chromosome positive acute lymphoblastic leukemia in Sweden: a population-based study2014Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 31, nr 8, s. 66-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Even in the tyrosine kinase inhibitor era, allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as standard care for adult Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL). In this retrospective national study, we have reviewed the outcome after HSCT in Sweden for adult Ph-positive ALL between 2000 and 2009. In total, 51 patients with median age 42 (range 20-66) years underwent HSCT. Mainly allogeneic HSCT was performed (24 related donor, 24 unrelated donor and one cord blood), and only two patients were treated with an autologous HSCT. The 5-year OS was 51 (37-64) %. The probabilities of morphological relapse and non-relapse mortality (NRM) at 5 years were 36 (23-49) and 18 (9-29) %, respectively. For the allogeneic transplanted, the 5-year OS was for patients less than40 years 70 (50-90) % and for patients greater than= 40 years 34 (16-52) %, p = 0.002. The 5-year probability of NRM was for patients less than40 years 10 (2-28) % compared to 25 (11-42) % for patients greater than= 40 years (p = 0.04). Patients with chronic graft-versus-host disease (GVHD) had a 5-year morphological relapse probability of 20 (6-40) % compared to 59 (35-77) % for patients without chronic GVHD (p = 0.03). Age greater than= 40 years and the absence of chronic GVHD were confirmed as independent negative prognostic factors for relapse and non-relapse mortality in a multivariate analysis although the impact of chronic GVHD was significant only in the older age cohort.

  • 10.
    Jakobsen Falk, Ingrid
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Willander, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Lund, Johan
    Division of hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome2014Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 genotyping may be useful tools for prognostication, risk stratification and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 11.
    Kozlowski, Piotr
    et al.
    Örebro University Hospital, Sweden .
    Astrom, Maria
    Örebro University Hospital, Sweden .
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Bernell, Per
    Karolinska University Hospital, Sweden .
    Hulegardh, Erik
    Sahlgrenska University, Sweden .
    Hagglund, Hans
    Karolinska University Hospital, Sweden .
    Karlsson, Karin
    Skåne University Hospital, Sweden .
    Markuszewska-Kuczymska, Alicja
    University Hospital, Sweden .
    Tomaszewska-Toporska, Beata
    Skåne University Hospital, Sweden .
    Smedmyr, Bengt
    Uppsala University, Sweden .
    Amini, Rose-Marie
    Uppsala University, Sweden .
    Hallbook, Helene
    Uppsala University, Sweden .
    High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden2014Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 92, nr 5, s. 377-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first-line therapy in patients with T-cell ALL (T-ALL). Patients and methods Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol. Results The median age was 32yr (range 18-72yr). Complete remission (CR) was obtained in 17 of 19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two- and 5-yr leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two- and 5-yr overall survival (OS) in whole cohort was 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-yr LFS for 15 patients who did not receive allogeneic SCT upfront were 20% (95% CI: 0-40), although 14 of 15 completed the protocol (eight cycles). Relapse occurred in 2 of 4 upfront-transplanted patients and in 12 of 15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age greater than= 35yr influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7). Conclusions Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden.

  • 12.
    Kozlowski, Piotr
    et al.
    Örebro University Hospital, Sweden .
    Astrom, Maria
    Örebro University Hospital, Sweden .
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Bernell, Per
    Karolinska University Hospital, Sweden .
    Hulegardh, Erik
    Sahlgrenska University, Sweden .
    Hagglund, Hans
    Karolinska University Hospital, Sweden .
    Karlsson, Karin
    Skåne University Hospital, Sweden .
    Markuszewska-Kuczymska, Alicja
    Umeå University Hospital, Sweden .
    Tomaszewska-Toporska, Beata
    Skåne University Hospital, Sweden .
    Smedmyr, Bengt
    Uppsala University, Sweden .
    Hallbook, Helene
    Uppsala University, Sweden .
    High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-20072012Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, nr 9, s. 1414-1421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background less thanbrgreater than less thanbrgreater thanA minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission. less thanbrgreater than less thanbrgreater thanDesign and Methods less thanbrgreater than less thanbrgreater thanBetween 2003-2007, 76 adults (andlt;66 years) with relapsed acute lymphoblastic leukemia (Burkitts leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated. less thanbrgreater than less thanbrgreater thanResults less thanbrgreater than less thanbrgreater thanReinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13-32) and 15% (95% CI: 7-24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2-8.3) after relapse, whereas all patients over 35 years old at diagnosis have died. less thanbrgreater than less thanbrgreater thanConclusions less thanbrgreater than less thanbrgreater thanAllogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis.

  • 13.
    Lazarevic, V.L.
    et al.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Remberger, M.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Hagglund, H.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Hallbook, H.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Juliusson, G.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Kimby, E.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Wahlin, A.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Omar, H.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Johansson, J.-E.
    Department of Hematology, University Hospital Lund, Lund University, Lund, Sweden.
    Letter: Myeloablative allogeneic stem cell transplantation for lymphoblastic lymphoma in Sweden: A retrospective study2011Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 86, nr 8, s. 709-710Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    [No abstract available]

  • 14.
    Lazarevic, Vladimir
    et al.
    Lund University.
    Remberger, Mats
    Karolinska Institute.
    Hagglund, Hans
    Karolinska University Hospital.
    Juliusson, Gunnar
    Lund University.
    Omar, Hamdy
    Karolinska University Hospital.
    Halbook, Helene
    University of Uppsala Hospital.
    Kimby, Eva
    Karolinska University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Wahlin, Anders
    Umeå University Hospital.
    Johansson, Jan-Erik
    Sahlgrens University Hospital.
    Letter: Long-term survival after allogeneic stem cell transplant for relapsed large B cell lymphomas: a retrospective study2012Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 53, nr 3, s. 503-505Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 15.
    Lyth, Johan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Frodin, U
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Pain assessments during autologous stem cell transplantation in BONE MARROW TRANSPLANTATION, vol 46, issue , pp S450-S4512011Inngår i: BONE MARROW TRANSPLANTATION, Nature Publishing Group , 2011, Vol. 46, s. S450-S451Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 16.
    Machaczka, Maciej
    et al.
    Karolinska University Hospital Huddinge, Sweden Karolinska Institute, Sweden .
    Johansson, Jan-Erik
    Sahlgrens University Hospital, Sweden .
    Remberger, Mats
    Karolinska Institute, Sweden .
    Hallbook, Helene
    University of Uppsala Hospital, Sweden .
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Lj Lazarevic, Vladimir
    Skåne University Hospital, Sweden Lund University, Sweden .
    Wahlin, Anders
    Umeå University, Sweden .
    Omar, Hamdy
    Karolinska University Hospital Huddinge, Sweden Karolinska Institute, Sweden .
    Juliusson, Gunnar
    Skåne University Hospital, Sweden Lund University, Sweden .
    Kimby, Eva
    Karolinska University Hospital Huddinge, Sweden Karolinska Institute, Sweden .
    Hagglund, Hans
    Karolinska University Hospital Huddinge, Sweden Karolinska Institute, Sweden .
    Allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning for chronic lymphocytic leukemia in Sweden: does donor T-cell engraftment 3 months after transplant predict survival?2012Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 53, nr 9, s. 1699-1705Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD were 29% and 47%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplant was measured in 31 out of 34 patients (91%) surviving beyond day + 100. Seventeen patients achieved andgt; 90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with andlt;= 90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, p = 0.002) and better long-term PFS and OS (p = 0.002 and 0.046, respectively). Donor T-cell engraftment of andgt; 90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome.

  • 17.
    Mellqvist, Ulf-Henrik
    et al.
    Sahlgrens University Hospital, Sweden .
    Gimsing, Peter
    Rigshosp, Denmark .
    Hjertner, Oyvind
    Norwegian University of Science and Technology, Norway .
    Lenhoff, Stig
    Skåne University Hospital, Sweden .
    Laane, Edward
    North Estonian Regional Hospital, Estonia .
    Remes, Kari
    Turku University, Finland .
    Steingrimsdottir, Hlif
    Landspitali University Hospital, Iceland .
    Abildgaard, Niels
    Odense University Hospital, Denmark .
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Blimark, Cecilie
    Sahlgrens University Hospital, Sweden .
    Dahl, Inger Marie
    University of North Norway, Norway .
    Forsberg, Karin
    Norrlands University Hospital, Sweden .
    Gedde-Dahl, Tobias
    Oslo University Hospital, Norway .
    Gregersen, Henrik
    Aalborg Hospital, Denmark .
    Gruber, Astrid
    Karolinska Institute, Sweden .
    Guldbrandsen, Nina
    Oslo University Hospital, Norway .
    Haukas, Einar
    Stavanger University Hospital, Norway .
    Carlson, Kristina
    Akad University Hospital, Sweden .
    Kvam, Ann Kristin
    Oslo University Hospital, Norway .
    Nahi, Hareth
    Karolinska Institute, Sweden .
    Lindas, Roald
    Haukeland Hospital, Norway .
    Frost Andersen, Niels
    Aarhus University Hospital, Denmark .
    Turesson, Ingemar
    Skåne University Hospital, Sweden .
    Waage, Anders
    Norwegian University of Science and Technology, Norway .
    Westin, Jan
    Sahlgrens University Hospital, Sweden .
    Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, nr 23, s. 4647-4654Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the andgt;= VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

  • 18.
    Mulligan, Stephen P.
    et al.
    Royal N Shore Hospital, Australia.
    -Karlsson, Karin
    Department of Hematology, Skåne University Hospital, Lund , Sweden.
    Stromberg, Mats
    Karolinska University Hospital, Sweden.
    Jonsson, Viggo
    National Hospital, Denmark.
    Gill, Devinder
    Princess Alexandra Hospital, Australia.
    Hammerstrom, Jens
    St Olavs University Hospital, Norway.
    Hertzberg, Mark
    Westmead Hospital, Australia.
    McLennan, Roger
    Ballarat Base Hospital, Australia.
    Uggla, Bertil
    University Hospital Örebro, Sweden.
    Norman, John
    Royal Adelaide Hospital, Australia.
    Wallvik, Jonas
    Department Med, Sweden.
    Sundstrom, Gunnel
    Norrlands University Hospital, Sweden.
    Johansson, Hemming
    Karolinska Institute, Sweden.
    Brandberg, Yvonne
    Karolinska Institute, Sweden.
    Liliemark, Jan
    Karolinska University Hospital, Sweden; Swedish Council Health Technology Assessment, Sweden.
    Juliusson, Gunnar
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US. Department of Hematology, Sk å ne University Hospital, Lund, Sweden.
    Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic2014Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, nr 12, s. 2769-2777Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

  • 19.
    Mustjoki, Satu
    et al.
    HUCH.
    Richter, Johan
    Skåne University Hospital.
    Barbany, Gisela
    Karolinska University Hospital.
    Ehrencrona, Hans
    Skåne University Hospital.
    Dybedal, Ingunn
    University of Oslo.
    Fioretos, Thoas
    Lund University.
    Gedde-Dahl, Tobias
    University Hospital, Oslo.
    Gjertsen, Bjorn
    Haukeland Hospital.
    Hovland, Randi
    Haukeland Hospital.
    E Jalkanen, Sari
    HUCH.
    Josefsen, Dag
    Norwegian Radium Hospital.
    Koskenvesa, Perttu
    HUCH.
    Lassen, Carin
    Skåne University Hospital.
    Latvala, Kirsi
    HUCH.
    Majeed, Waleed
    Stavanger University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Markevarn, Berit
    Umeå University Hospital.
    Mosfegh, Ali
    Karolinska University Hospital.
    Ohm, Lotta
    Karolinska University Hospital.
    Olofsson, Tor
    Skåne University Hospital.
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital.
    Rapakko, Katrin
    Oulu University Hospital.
    Remes, Karil
    Turku University.
    Stentoft, Jesper
    Aarhus University Hospital.
    Stenke, Leif
    Karolinska University Hospital.
    Suominen, Merja
    Kanta Hame Central Hospital.
    Thunberg, Sara
    Karolinska University Hospital.
    Weiss Bjerrum, Ole
    University of Copenhagen Hospital.
    Simonsson, Bengt
    University of Uppsala Hospital.
    Porkka, Kimmo
    HUCH.
    Hjorth-Hansen, Henrik
    St Olavs University Hospital.
    Favorable Therapeutic Responses in Newly Diagnosed CML-CP Patients Induced by Dasatinib Are Reflected At the CD34+CD38+Progenitor Cell but Not At the CD34+CD38-Stem Cell Level: Results From Randomized NordCML006 Study in BLOOD, vol 118, issue 21, pp 356-3562011Inngår i: BLOOD, American Society of Hematology , 2011, Vol. 118, nr 21, s. 356-356Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 20.
    Nagler, Arnon
    et al.
    Chaim Sheba Medical Centre, Israel .
    Labopin, Myriam
    UPMC University of Paris, France .
    Shimoni, Avichai
    Chaim Sheba Medical Centre, Israel .
    Mufti, Ghulam J
    Kings Coll London, England .
    Cornelissen, Jan J
    Erasmus Medical Centre Daniel den Hoed, Netherlands .
    Blaise, Didier
    Institute J Paoli I Calmettes, France .
    Janssen, Jeroen J W M
    Vrije University of Amsterdam, Netherlands .
    Milpied, Noel
    CHU Bordeaux, France .
    Vindelov, Lars
    Rigshosp, Denmark .
    Petersen, Eefke
    University of Medical Centre, Netherlands .
    Gribben, John
    St Bartholomews and Royal London Hospital, England .
    Bacigalupo, Andrea
    Osped San Martino Genova, Italy .
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Niederwieser, Dietger
    University Hospital Leipzig, Germany .
    Socie, Gerard J
    Hop St Louis, France .
    Arnold, Renate
    Charite, Germany .
    Brown, Paul
    St James Hospital, Ireland .
    Goker, Hakan
    Hacettepe University, Turkey .
    Rocha, Vanderson
    CHU Nantes, France .
    Mohty, Mohamad
    EBMT ALWP, France University of Paris 07, France .
    Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission: a retrospective analysis from the Acute Leukemia Working Party of EBMT2012Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 89, nr 3, s. 206-213Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reduced-intensity conditioning (RIC)-alloSCT is increasingly used for acute myelogenous leukemia. Limited data are available for the comparison of peripheral blood stem cells with bone marrow for RIC-alloSCT. We used the European Group for Blood and Marrow Transplantation (EBMT) ALWP data to compare the outcome of mobilized peripheral blood stem cells (PBSC) (n = 1430) vs. bone marrow (BM) (n = 107) for acute myelogenous leukemia (AML) patients with complete remission that underwent RIC-alloSCT from compatible sibling donors. The leukemia features, the disease status, and the time from diagnosis were similar between the two groups. Engraftment was achieved in 99% and 93% in the PBSC and BM groups, respectively (P andlt; 0.0001). The day of engraftment was significantly earlier for the PBSC vs. the BM group, 15 (159) and 19 (569), respectively (P andlt; 0.001). Acute GVHD, severe GVHD (grade IIIIV) and chronic GVHD did not differ between the groups. leukemia-free survival (LFS), relapse, and non-relapsed mortality (NRM) were 51 +/- 2%, 32 +/- 1%, and 17 +/- 1% vs. 50 +/- 6%, 38 +/- 6%, and 12 +/- 3% for the PBSC and BM groups, respectively. Our results indicate faster engraftment, but no difference in GVHD, LFS, relapse, and NRM when comparing PBSC to BM grafts from sibling donors following RIC conditioning. This is the first study comparing PBSC to BM grafts in the RIC setting, analyzing a homogeneous population of patients with AML in remission. Whether PBSC should be preferred for advanced phases of the disease, where the outcome is dominated by relapse incidences, needs further investigation.

  • 21.
    Simonsson, Bengt
    et al.
    Uppsala University.
    Gedde-Dahl, Tobias
    Oslo University Hospital.
    Markevarn, Berit
    Umea University.
    Remes, Kari
    Turku University Hospital.
    Stentoft, Jesper
    Aarhus University Hospital.
    Almqvist, Anders
    Vaasa Central Hospital.
    Bjoreman, Mats
    University Hospital, Hematol Unit, Orebro, Sweden .
    Flogegard, Max
    Falun Central Hospital.
    Koskenvesa, Perttu
    University of Helsinki.
    Lindblom, Anders
    Malmö University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Mustjoki, Satu
    University of Helsinki.
    Myhr-Eriksson, Kristina
    Luleå Centralral Hospital.
    Ohm, Lotta
    Karolinska Hospital.
    Rasanen, Anu
    Kymenlaakso Central Hospital.
    Sinisalo, Marjatta
    Tampere University Hospital.
    Sjalander, Anders
    Sundsvall Central Hospital.
    Stromberg, Ulla
    Uppsala University.
    Weiss Bjerrum, Ole
    University of Copenhagen.
    Ehrencrona, Hans
    Uppsala University.
    Gruber, Franz
    University of Tromso.
    Kairisto, Veli
    Turku University.
    Olsson, Karin
    Reg Oncol Centre, Uppsala.
    Sandin, Fredrik
    Reg Oncol Centre, Uppsala.
    Nagler, Arnon
    Chaim Sheba Medical Centre.
    Lanng Nielsen, Johan
    Aarhus University Hospital.
    Hjorth-Hansen, Henrik
    St Olavs Hospital Trondheim.
    Porkka, Kimmo
    University of Helsinki.
    Combination of pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia2011Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, nr 12, s. 3228-3235Artikkel i tidsskrift (Fagfellevurdert)
    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 (andlt; 12-week MMR rate 67%, andgt; 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.

  • 22.
    Willander, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The present thesis is focused on the prognostic value of genetic variations and alterations in the initiation and development of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) patients. Several prognostic markers based on genetic or chromosomal aberrations are today used in clinic in these heterogeneous diseases. Novel biomarkers have been identified through next generation sequencing techniques and some of them may be useful as prognostic markers in clinical diagnostic. In papers I-IV we have investigated some of this markers in CLL and AML tumor cells.

    In papers I and III we investigated the prognostic value of the MDM2 SNP309 in relation to the presence of TP53 mutations in tumor cells from CLL and AML patients. The SNP309 G-allele was associated with a shorter overall survival in TP53 wildtype CLL and non-normal karyotype AML patients. Mutations in the TP53 gene were found in 6.2% in CLL and 21.7% in AML and were always associated with adverse overall survival. This was most significant observed among the AML patients, where the three year survival was zero.

    In paper II we investigated mutations in NOTCH1 and NOTCH2 as prognostic biomarkers in CLL. Notch1 and Notch2 play critical roles in lineage differentiation of white blood cells. We found mutation only in NOTCH1 in a frequency of 6.7% and our analysis revealed a shorter overall survival for these. NOTCH1 mutations were almost mutually exclusive with TP53 mutations and represented together 12.9% in CLL patients, and they may both be strong prognostic biomarkers in CLL.

    In paper IV we studied mutations in the tricarboxylic acid cycle. Metabolic disturbances in cancer cells have been known for many years, but recently mechanistic explanations have been identified. Hot spot mutations in IDH1/2 genes, result in neomorphic enzyme activities that results in global hypermethylation of the cancer cell genome. We found mutations in 21% of the AML patients. Among the CN-AML patients there is a lack of prognostic markers and in this subgroup we found patients with IDH2 mutations to have a shorter overall survival (3 vs. 21 months (p=0.009) for mutated and wild-type patients, respectively). Additionally, we also studied a SNP in the IDH1 gene, and both the IDH2 mutations and the SNP showed to have a potential as a new prognostic markers in CN-AML.

    In summary, the results in papers I-IV have a potential to function as novel prognostic biomarkers in the clinic for therapeutic considerations and may also be targets for novel drugs for CLL and AML patients.

    Delarbeid
    1. MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia
    Vise andre…
    2010 (engelsk)Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 85, nr 3, s. 251-256Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: The single nucleotide polymorphism SNP309 with a change from T to G in the promoter region of the MDM2 gene is shown to increase the MDM2 protein levels and attenuate the p53 levels and associates with disease progression in several tumors. OBJECTIVE: In this study, the role of the polymorphism was investigated with regard to the clinical outcome in B-cell chronic lymphocytic leukemia (B-CLL). PATIENTS: A total of 210 patients with B-CLL were followed for up to 19 yr. RESULTS: The overall survival (OS) of patients with at least one G-allele was significantly shorter when compared with those with two T-alleles (P = 0.024) with a more pronounced difference in patients below the median age. Age at onset of B-CLL was similar irrespective of MDM2 status. The presence of a G-allele in combination with TP53 mutations or unmutated IgVH gene status resulted in an additive risk of death. CONCLUSION: In this report, with a high proportion of B-CLL patients with an advanced Binet stage and with an unmutated IgVH gene, MDM2 SNP309 was found to be independently associated with OS. The survival difference was more pronounced in younger patients.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58806 (URN)10.1111/j.1600-0609.2010.01470.x (DOI)000280996400010 ()20491880 (PubMedID)
    Tilgjengelig fra: 2010-08-27 Laget: 2010-08-27 Sist oppdatert: 2017-12-12
    2. NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients
    Åpne denne publikasjonen i ny fane eller vindu >>NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients
    Vise andre…
    2013 (engelsk)Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background

    NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.

    Methods

    In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.

    Results

    In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).

    Conclusions

    Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.

    sted, utgiver, år, opplag, sider
    BioMed Central, 2013
    Emneord
    Chronic lymphocytic leukemia; NOTCH1 mutations; TP53 mutations; Prognostic markers
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-96472 (URN)10.1186/1471-2407-13-274 (DOI)000319998800001 ()
    Tilgjengelig fra: 2013-08-23 Laget: 2013-08-20 Sist oppdatert: 2017-12-06
    3. TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome
    Åpne denne publikasjonen i ny fane eller vindu >>TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome
    Vise andre…
    2014 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 genotyping may be useful tools for prognostication, risk stratification and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

    Emneord
    AML, TP53, MDM2, SNP309, prognostic markers
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-104948 (URN)
    Tilgjengelig fra: 2014-03-04 Laget: 2014-03-04 Sist oppdatert: 2015-04-14bibliografisk kontrollert
    4. Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
    Vise andre…
    2014 (engelsk)Inngår i: Biomarker Research, ISSN 2050-7771, Vol. 2, nr 18Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The isocitrate dehydrogenase (IDH1/IDH2) genes are frequently mutated and reported to associate with poor prognosis in acute myeloid leukemia (AML). We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP  105C>T (rs11554137) in 207 unselected de novo AML patients. IDH1 codon 132 mutations were present in 7.7%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 10.1% and 2.9%, respectively. The SNP 105C>T was present in 10.1% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p=0.009) was observed in the intermediate risk patient group with cytogenetically normal karyotype (CN-AML). Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative CN-AML, (p=0.007). Our results indicate that IDH2 mutations and the IDH1 SNP 105C>T variant may represent a new subgroup for risk stratification and may indicate new treatment options.

    Emneord
    AML, IDH1, IDH2, SNP, prognostic markers
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-104949 (URN)10.1186/2050-7771-2-18 (DOI)
    Tilgjengelig fra: 2014-03-04 Laget: 2014-03-04 Sist oppdatert: 2018-12-19bibliografisk kontrollert
  • 23.
    Willander, Kerstin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Paul, Esbjörn
    Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia2014Inngår i: Biomarker Research, ISSN 2050-7771, Vol. 2, nr 18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The isocitrate dehydrogenase (IDH1/IDH2) genes are frequently mutated and reported to associate with poor prognosis in acute myeloid leukemia (AML). We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP  105C>T (rs11554137) in 207 unselected de novo AML patients. IDH1 codon 132 mutations were present in 7.7%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 10.1% and 2.9%, respectively. The SNP 105C>T was present in 10.1% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p=0.009) was observed in the intermediate risk patient group with cytogenetically normal karyotype (CN-AML). Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative CN-AML, (p=0.007). Our results indicate that IDH2 mutations and the IDH1 SNP 105C>T variant may represent a new subgroup for risk stratification and may indicate new treatment options.

  • 24.
    Willander, Kerstin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Kumar Dutta, Ravi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ungerbäck, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Rebeqa
    Lund University, Sweden.
    Juliusson, Gunnar
    Lund University, Sweden.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Linderholm, Mats
    Stockholms Sjukhem, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients2013Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.

    Methods

    In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.

    Results

    In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).

    Conclusions

    Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.

1 - 24 of 24
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