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  • 1. Axdorph, Ulla
    et al.
    Stenke, Leif
    Grimfors, Gunnar
    Carneskog, Jan
    Hansen, Jan
    Linder, Olle
    Ljungman, Per
    Löfvenberg, Eva
    Malm, Claes
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Simonsson, Bengt
    Turesson, Ingemar
    Vilén, Lars
    Udén, Anne-Marie
    Björkholm, Magnus
    Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase - A report from the Swedish CML Group2002Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 118, nr 4, s. 1048-1054Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In attempting to restore the chronic phase (CP) of chronic myelogenous leukaemia (CML), the Swedish CML group utilized an intensive chemotherapy protocol for 83 patients (aged 16-79 years) in accelerated (AP, n = 22) or blastic phase (BC, n = 61). Most patients received a combination of mitoxantrone (12 mg/m2/d) and etoposide (100 mg/m2/d) together with cytosine arabinoside (1 g/m2 b.i.d) for 4 d. Overall, 39 patients (47%) achieved a second CP (CP2)/partial remission (PR). Responding patients <65 years were eligible for ablative chemotherapy followed by an allogeneic (SCT) or a double autologous stem cell transplant (ASCT). Seventeen of 34 responders <65 years failed to proceed to transplantation as a result of early disease progression (n = 15) or disease-related complications (n = 2). The remaining 17 patients underwent SCT (n = 9, including four unrelated donor SCT) or ASCT (n = 8). Only one of the eight ASCT patients had a second ASCT, the remaining seven failed because of progression (n = 5) or hypoplasia (n = 2). The median duration of CP2/PR was 6 months (range 1-72 months). Five patients achieved a longer CP2/PR than CP1. The 1 year survival was 70% for SCT/ASCT patients (median survival 21 months), 50% for responding patients overall, but only 7% for non-responders (P < 0.001). Three SCT/ASCT patients are long-term survivors (65+, 66+ and 73+ months). In conclusion, approximately half of the patients achieved a CP2/PR after intensive chemotherapy, with a clear survival advantage for responders vs non-responders. Subsequent SCT/ASCT was feasible for half of the responders (<65 years), and one individual underwent double ASCT. Novel therapeutic options for CML patients in AP/BP are needed.

  • 2.
    Baudet, Anna
    et al.
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden; Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden .
    Ek, Fredrik
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Davidsson, Josef
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Soneji, Shamit
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Olsson, Roger
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Magnusson, Mattias
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Cammenga, Jörg
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden;Department of Chemical Biology and Therapeutics Lund University Lund Sweden .
    Juliusson, Gunnar
    Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden; Departments of Haematology Skanes University Hospital Lund University Lund Sweden.
    Small molecule screen identifies differentiation-promoting compounds targeting genetically diverse acute myeloid leukaemia2016Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 175, nr 2, s. 342-346Artikel i tidskrift (Övrigt vetenskapligt)
  • 3.
    Berggren, Daniel Moreno
    et al.
    Uppsala Univ, Sweden.
    Folkvaljon, Yasin
    Uppsala Univ Hosp, Sweden.
    Engvall, Marie
    Uppsala Univ, Sweden.
    Sundberg, Johan
    Uppsala Univ, Sweden.
    Lambe, Mats
    Uppsala Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Antunovic, Petar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Garelius, Hege
    Sahlgrens Univ Hosp, Sweden.
    Lorenz, Fryderyk
    Umea Univ, Sweden.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Rasmussen, Bengt
    Orebro Univ Hosp, Sweden.
    Lehmann, Soren
    Uppsala Univ, Sweden.
    Hellstrom-Lindberg, Eva
    Karolinska Inst, Sweden.
    Jadersten, Martin
    Karolinska Inst, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register2018Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, nr 5, s. 614-627Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (Pamp;lt;0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;05) and for WPSS compared to IPSS (P=0amp;lt;boldamp;gt;amp;lt;/boldamp;gt;07). IPSS-R was superior to both IPSS and WPSS for patients aged 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

  • 4. Dawei, X
    et al.
    Areström, I
    Virtala, R
    Pisa, P
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Gruber, A
    High level of lung resistance related protein mRNA in leukaemic cells from patinets with acute myelogenous leukaemia are associated with inferior response to chemotherapy and prior treatment with mitoxantrone.1999Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 106, s. 627-633Artikel i tidskrift (Refereegranskat)
  • 5.
    Frandsen, Thomas L
    et al.
    Rigshospitalet, Copenhagen.
    Abrahamsson, Jonas
    Queen Silvias Childrens Hospital, Gothenburg.
    Lausen, Birgitte
    Rigshospitalet, Copenhagen.
    Vettenranta, Kim
    University of Tampere, Finland.
    Heyman, Mats
    Astrid Lindgrens Barnsjukhus, Stockholm.
    Behrentz, Michael
    Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Castor, Anders
    Lund University Hospital.
    Wehner, Peder S
    Syddanmarks University Hospital, Odense, Denmark.
    Frost, Britt-marie
    University Hospital of Uppsala.
    Andersen, Elisabeth W
    University of Copenhagen.
    Schmiegelow, Kjeld
    Rigshospitalet, Copenhagen.
    Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, nr 2, s. 244-247Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m(2), x3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m(2) per day if they did not develop myelotoxicity within 2 weeks after HDM. 6MP could be increased in 31 patients (81%). Toxicity was acceptable and did not differ significantly between groups. Patients receiving 75 mg/m(2) per day had significantly shorter duration of treatment interruptions of 6MP than the remaining patients (P = 0.03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity.

  • 6.
    Friesen, C.
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Herr, I.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Los, Marek Jan
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Debatin, K. M.
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Drug induced cytotoxicity in leukemia cells involves the CD95 (APO-1/FAS) pathway of apoptosis1996Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 93, s. 367-367Artikel i tidskrift (Refereegranskat)
  • 7.
    Grovdal, Michael
    et al.
    Karolinska Institute.
    Karimi, Mohsen
    Karolinska Institute.
    Khan, Rasheed
    Karolinska Institute.
    Aggerholm, Anni
    Aarhus University Hospital.
    Antunovic, Petar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Astermark, Jan
    Malmö University Hospital.
    Bernell, Per
    Malmö University Hospital.
    Engstrom, Lena-Maria
    University Norrland, Umeå.
    Kjeldsen, Lars
    Rigshospital, Copenhagen.
    Linder, Olle
    Örebro University Hospital.
    Nilsson, Lars
    Lund University Hospital.
    Olsson, Anna
    Sahlgrens University Hospital.
    Holm, Mette S.
    Aarhus University Hospital.
    Tangen, Jon M.
    Ullevaal University Hospital.
    Wallvik, Jonas
    Sundsvall Hospital.
    Oberg, Gunnar
    Academy Hospital, Uppsala.
    Hokland, Peter
    Aarhus University Hospital.
    E. Jacobsen, Sten
    Univ Lund Hosp, Haematopoiet Stem Cell Lab, S-22185 Lund, Sweden.
    Porwit, Anna
    Karolinska University Hospital.
    Hellstrom-Lindberg, Eva
    Karolinska Institute.
    Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy2010Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 150, nr 3, s. 293-302Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pgreater thanThis prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13 center dot 5 months, greater than 24 months in 17% of the patients, and 18-30 center dot 5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0 center dot 003). 5-azacytidine treatment, at a dose of 60 mg/m2 was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9 center dot 5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.

  • 8.
    Gunnarsson, Niklas
    et al.
    Umeå University, Sweden.
    Stenke, Leif
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Hoglund, Martin
    University of Uppsala Hospital, Sweden; University of Uppsala Hospital, Sweden.
    Sandin, Fredrik
    Regional Cancer Centre, Sweden.
    Bjorkholm, Magnus
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Dreimane, Arta
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Lambe, Mats
    Regional Cancer Centre, Sweden; Karolinska Institute, Sweden.
    Markevarn, Berit
    Umeå University Hospital, Sweden.
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital, Sweden; University of Uppsala Hospital, Sweden.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Wadenvik, Hans
    Sahlgrens University Hospital, Sweden.
    Wallvik, Jonas
    Umeå University, Sweden.
    Sjalander, Anders
    Umeå University, Sweden.
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, nr 5, s. 683-688Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 9. Hallböök, Helene
    et al.
    Simonsson, Bengt
    Ahlgren, Thomas
    Björkholm, Magnus
    Carneskog, Jan
    Grimfors, Gunnar
    Hast, Robert
    Karlsson, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Kimby, Eva
    Lerner, Richard
    Linder, Olle
    Linderholm, Mats
    Löfvenberg, Eva
    Malm, Claes
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Nilsson, Per-Gunnar
    Paul, Christer
    Stenke, Leif
    Stockelberg, Dick
    Tidefelt, Ulf
    Turesson, Ingemar
    Uden-Blome, Ann-Marie
    Vilen, Lars
    Wahlin, Anders
    Winquist, Ingemar
    Smedmyr, Bengt
    High-dose cytarabine in upfront therapy for adult patients with acute lymphoblastic leukaemia2002Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 118, s. 748-754Artikel i tidskrift (Refereegranskat)
  • 10.
    Hellstrom-Lindberg, E.
    et al.
    Hellström-Lindberg, E., Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden, Department of Medicine, Karolinska Institute, Huddinge University Hospital, 141 86 Stockholm, Sweden.
    Gulbrandsen, N.
    Department of Haematology, Ullevål Hospital, Oslo, Norway.
    Lindberg, G.
    Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Ahlgren, T.
    Depts. Med./Haematol. the Hospitals, Malmö, Sweden.
    Dahl, I.M.S.
    Depts. Med./Haematol. the Hospitals, Tromsö, Norway.
    Dybedal, I.
    Depts. Med./Haematol. the Hospitals, Trondheim, Norway.
    Grimfors, G.
    Karolinska Hospital, Stockholm, Sweden.
    Hesse-Sundin, E.
    Karolinska Hospital, Eskilstuna, Sweden.
    Hjorth, M.
    Karolinska Hospital, Lidköping, Sweden.
    Kanter-Lewensohn, L.
    Department of Pathology, Karolinska Hospital, Stockholm, Sweden.
    Linder, O.
    Karolinska Hospital, Örebro, Sweden.
    Luthman, M.
    St. Göran Hospital, Stockholm, Sweden.
    Lofvenberg, E.
    Löfvenberg, E., St. Göran Hospital, Umeå, Sweden.
    Oberg, G.
    Öberg, G., St. Göran Hospital, Uppsala, Sweden.
    Porwit-MacDonald, A.
    Department of Pathology, Karolinska Hospital, Stockholm, Sweden.
    Rådlund, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Samuelsson, J.
    Southern Hospital, Stockholm, Sweden.
    Tangen, J.M.
    Department of Haematology, Ullevål Hospital, Oslo, Norway.
    Winquist, I.
    Southern Hospital, Lund, Sweden.
    Wisloff, F.
    Department of Haematology, Ullevål Hospital, Oslo, Norway.
    A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: Significant effects on quality of life2003Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 120, nr 6, s. 1037-1046Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo = 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S-Epo > 500 U/l and =2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

  • 11.
    Jakobsen Falk, Ingrid
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Fyrberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Paul, Esbjorn
    Karolinska Institute, Sweden.
    Nahi, Hareth
    Karolinska Institute, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Hoglund, Martin
    Uppsala University, Sweden.
    Palmqvist, Lars
    University of Gothenburg, Sweden.
    Stockelberg, Dick
    Sahlgrens University Hospital, Sweden.
    Wei, Yuan
    Sahlgrens University Hospital, Sweden.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. KTH Royal Institute Technology, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, nr 5, s. 671-680Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 12.
    Juliusson, Gunnar
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Celsing, Fredrik
    Turesson, Ingemar
    Lenhoff, Stig
    Adriansson, Magnus
    Malm, Claes
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma2000Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 109, nr 1, s. 89-96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR, nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15- 50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.

  • 13.
    Juliusson, Gunnar
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Höglund, Martin
    Karlsson, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Löfgren, Christina
    Möllgård, Lars
    Paul, Christer
    Tidefelt, Ulf
    Björkholm, Magnus
    Increased remissions from one course for intermediate-dose cytosine arabinoside and idarubicin in elderly acute myeloid leukaemia when combined with cladribine. A randomized population-based phase II study2003Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 123, nr 5, s. 810-818Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cladribine has single-drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara-CTP) of cytosine arabinoside (ara-C). To evaluate the feasibility of adding intermittent cladribine to intermediate-dose ara-C (1 g/m2/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty-three patients (median 71 years, range 60-84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38░C, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two-drug therapy (P = 0.014). The median survival with a 2-year follow-up was 14 months, and the 2-year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population-based approach, the overall results are encouraging.

  • 14.
    Karlsson, Karin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Strömberg, Mats
    Liliemark, Jan
    Delannoy, André
    Johnson, S A N
    Porwit, Anja
    Kimby, Eva
    Lärfars, Gerd
    Cristiansen, Ilse
    Nilsson, Göran
    Celsing, Fredrik
    Sundström, Gunnel
    Luthman, Mikaela
    Tidefelt, Ulf
    Wallvik, Jonas
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Hematologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Oral cladribine for B-cell chronic lymphocytic leukaemia: Report of a phase II trial with a 3-d, 3-weekly schedule in untreated and pretreated patients, and a long-term follow-up of 126 previously untreated patients2002Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 116, nr 3, s. 538-548Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin < 11.0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival.

  • 15.
    Lenhoff, S.
    et al.
    Lund University Hospital, Lund, Sweden, Department of Haematology, University Hospital, SE-221 85 Lund, Sweden.
    Hjorth, M.
    Department of Internal Medicine, Lidköping Hospital, Lidköping, Sweden.
    Westin, J.
    Lund University Hospital, Lund, Sweden.
    Brinch, L.
    Rikshospitalet, Oslo, Norway.
    Backstrom, B.
    Bäckström, B., Norrland University Hospital, Umeå, Sweden.
    Carlson, K.
    Uppsala University Hospital, Uppsala, Sweden.
    Christiansen, I.
    Odense University Hospital, Odense, Denmark.
    Dahl, I.M.
    Tromsö University Hospital, Tromsö, Norway.
    Gimsing, P.
    Rigshospitalet, Copenhagen, Denmark.
    Hammerstrom, J.
    Hammerström, J., Trondheim University Hospital, Trondheim, Norway.
    Johnsen, H.E.
    Copenhagen University Hospital, Herlev, Denmark.
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Linder, O.
    Örebro University Hospital, Örebro, Sweden.
    Mellqvist, U.-H.
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Nesthus, I.
    Haukeland Hospital, Bergen, Norway.
    Nielsen, J.L.
    Århus University Hospital, Århus, Denmark.
    Tangen, J.M.
    Ullevål Hospital, Oslo, Norway.
    Turesson, I.
    Malmö University Hospital, Malmö, Sweden.
    Impact of age on survival after intensive therapy for multiple myeloma: A population-based study by the Nordic Myeloma Study Group2006Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 133, nr 4, s. 389-396Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60-64 years) on survival in a prospective, population-based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population-based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta-2-microglobulin and age <60 years vs. 60-64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0.001) and 60-64 years (median 50 months vs. 27 months, P = 0.001). We conclude that in a population-based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60-64 years but with less superiority than in younger patients. © 2006 Blackwell Publishing Ltd.

  • 16. Lietz, Andreas
    et al.
    Janz, Martin
    Sigvardsson, Mikael
    Lund University.
    Jundt, Franziska
    Dörken, Bernd
    Mathas, Stephan
    Loss of bHLH transcription factor E2A activity in primary effusion lymphoma confers resistance to apoptosis2007Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 137, nr 4, s. 342-348Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Similar to classical Hodgkin lymphoma (HL) tumour cells, primary effusion lymphoma (PEL) originates from mature B cells but displays a non-B cell phenotype, the mechanisms and consequences of which are not yet understood. This study showed that PEL lacked DNA binding activity of the B cell-determining transcription factors E2A, EBF and Pax5. PEL overexpressed the E2A antagonists ABF-1 and Id2, which have been described to block the B-cell differentiation program in classical HL. However, in contrast to HL cells, B lineage-inappropriate genes were not similarly upregulated in PEL, and reconstitution of B cell-specific E2A homodimer activity in PEL induced apoptosis. These data demonstrate that lineage infidelity in PEL is not as pronounced as in HL, and that the loss of the B cell-specific transcription factor E2A in PEL is implicated in apoptosis protection.

  • 17.
    Lonnerholm, G.
    et al.
    Lönnerholm, G., Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden, Department of Women's and Children's Health, University Children's Hospital, SE-751 85 Uppsala, Sweden.
    Frost, B.-M.
    Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.
    Abrahamsson, J.
    Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Castor, A.
    Department of Paediatrics, University Hospital, Lund, Sweden.
    Forestier, E.
    Department of Clinical Sciences, Paediatrics, University of Umeå, Umeå, Sweden.
    Heyman, M.
    Childhood Cancer Research Unit, Karolinska University Hospital, Stockholm, Sweden.
    Uges, D.R.A.
    Department of Pharmacy, University Hospital, Groningen, Netherlands.
    De, Graaf S.S.N.
    De Graaf, S.S.N., Department of Pediatrics, University Medical Centre St. Radboud, Nijmegen, Netherlands.
    Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia2008Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 142, nr 4, s. 616-621Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10.5 years, range 7.3-12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m2 and the area under the plasma concentration-time curve (AUC) was 4.49 and 5.40 mg/l x min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5.2, P = 0.036), or AUC values below median (RR 5.8, P = 0.025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies. © 2008 The Authors.

  • 18.
    Lotfi, Kourosh
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Månsson, Emma
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Stockholm, Sweden.
    Chandra, Joya
    Oncology Department, Mayo Clinic, Rochester, Minnesota, USA.
    Wang, Yuyinh
    Department of Oncology-Pathology, Karolinska Hospital Stockholm, Sweden.
    Xu, Dawei
    Department of Internal Medicine, Karolinska Hospital Stockholm, Sweden.
    Knaust, Eva
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Spasokoukotskaja, Tanja
    Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University of Medicine, Budapest, Hungary.
    Liliemark, Eva
    Department of Oncology-Pathology, Karolinska Hospital Stockholm, Sweden.
    Eriksson, Staffan
    Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Uppsala, Sweden.
    Albertioni, Freidoun
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Stockholm, Sweden.
    Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide2001Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 113, nr 2, s. 339-346Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cross-resistance between different classes of anti-neoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P < 0·001) and β protein (P < 0·026), formed substantially lower amounts of the topo II–DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P < 0·001) for the high Km and 134% (P < 0·331) for the low Km 5′-NT in resistant cells. The high Km 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′-triphosphate [40% decreased (P < 0·045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P < 0·001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

  • 19.
    Lundin, Catarina
    et al.
    Lund University Hospital.
    Davidsson, Josef
    Lund University Hospital.
    Hjorth, Lars
    Lund University Hospital.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Johansson, Bertil
    Lund University Hospital.
    Tiling resolution array-based comparative genomic hybridisation analyses of acute lymphoblastic leukaemias in children with Down syndrome reveal recurrent gain of 8q and deletions of 7p and 9p2009Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 146, nr 1, s. 113-115Artikel i tidskrift (Övrigt vetenskapligt)
  • 20. Merup, M
    et al.
    Lazarevic, V
    Nahi, H
    Andreasson, B
    Malm, Claes
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Nilsson, L
    Brune, M
    LeBlanc, K
    Kutti, J
    Birgegard, G
    Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens2006Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 135, nr 3, s. 367-373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment-related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced-intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty-seven patients were transplanted, 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5-63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low-risk patients according to Cervantes score or between sibling and unrelated donor transplantations. © 2006 The Authors.

  • 21.
    Nordigården, Amanda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Zetterblad, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Druid, Pia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Ronnstrand, Lars
    Lund University.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, nr 2, s. 198-208Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

  • 22.
    Olsson, Linda
    et al.
    Lund University, Sweden; Department Clin Genet, Sweden.
    Zettermark, Sofia
    Lund University, Sweden.
    Biloglav, Andrea
    Lund University, Sweden.
    Castor, Anders
    Skåne University Hospital, Sweden.
    Behrendtz, Mikael
    Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Forestier, Erik
    Umeå University, Sweden.
    Paulsson, Kajsa
    Lund University, Sweden.
    Johansson, Bertil
    Lund University, Sweden; Department Clin Genet, Sweden.
    The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes2016Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, nr 2, s. 292-301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFBMYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed amp;gt;= 1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML.

  • 23. Waage, Anders
    et al.
    Gimsing, Peter
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Turesson, Ingemar
    Gulbrandsen, Nina
    Eriksson, Tommy
    Hjorth, Martin
    Lanng Nielsen, Johan
    Lenhoff, Stig
    Westin, Jan
    Wislöff, Finn
    Early response predicts thalidomide efficiency in patients with advanced multiple myeloma2004Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 125, nr 2, s. 149-155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sixty-five patients who were primary or secondary refractory to melphalan/ prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M-protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half-life were calculated to be 0.200/h, 0.140/h, 0.886 l/kg, 0.126 l/h/kg and 4.98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks.

  • 24.
    Xu, D.
    et al.
    Department of Internal Medicine, Section of Haematology and Immunology and Department of Clinical Pharmacology, Karolinska Hospital.
    Knaust, Eva
    Department of Clinical Pharmacology, Karolinska Hospital.
    Pisa, P.
    Department of Internal Medicine, Section of Haematology and Immunology, Karolinska Hospital.
    Palucka, K.
    Department of Internal Medicine, Section of Haematology and Immunology, Karolinska Hospital.
    Lundeberg, J.
    The Royal Institute of Technology, Stockholm, Sweden.
    Areström, I.
    Department of Clinical Pharmacology, Karolinska Hospital.
    Peterson, C.
    Department of Clinical Pharmacology, Karolinska Hospital.
    Gruber, A.
    Department of Internal Medicine, Section of Haematology and Immunology and Department of Clinical Pharmacology, Karolinska Hospital.
    Levels of mdr1 and mrp mRNA in leukaemic cell populations from patients with acute myelocytic leukaemia are heterogenous and inversely correlated to cellular daunorubicin accumulation1996Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 92, nr 4, s. 847-854Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multidrug resistance gene (mdr1) expression is associated with a poor prognosis in acute myelocytic leukaemia (AML). Whether expression of the recently described multidrug resistance-associated gene (mrp) has any prognostic importance in AML is still unclear. The aim of the present study was to investigate the functional role of the mdr1 and mrp mRNA levels in peripheral leukaemic cell populations from patients with AML. Peripheral leukaemic cells from 10 patients with AML were incubated with daunorubicin (DNR). Cellular DNR content was analysed with a fluorescence-activated cell sorter (FACS). From each cell population the 20–25% cells with the lowest and highest DNR content were sorted out, and mdr1 and mrp RNA were quantified in these subpopulations with competitive polymerase chain reaction. The ratio between the mean DNR content in the cell populations with high and low DNR content varied between 1.9 and 6.6. The cell fraction with low DNR content had higher (3.8–40 times) mdr1 mRNA levels in 10/10 patients and higher (1.4–26 times) mrp mRNA levels in 8/10, as compared to the cell fraction with high DNR accumulation.

    In conclusion, mdr1 and mrp mRNA expressions are heterogenous in leukaemic cell populations from patients with AML. The mdr1 expression, and to some extent mrp expression, is inversely correlated to DNR accumulation in vitro.

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