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  • 1.
    Ahlstrand, Erik
    et al.
    Orebro Univ, Sweden.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindgren, Marie
    Kalmar Cty Hosp, Sweden.
    Pettersson, Helna
    NU Hosp Grp, Sweden.
    Liljeholm, Maria
    Univ Hosp Nouthern Sweden, Sweden.
    Ravn-Landtblom, Anna
    Karolinska Inst, Sweden; Stockholm South Hosp, Sweden.
    Scheding, Stefan
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Andreasson, Bjorn
    NU Hosp Grp, Sweden.
    Highly reduced survival in essential thrombocythemia and polycythemia vera patients with vascular complications during follow-up2020In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 104, no 3, p. 271-278Article in journal (Refereed)
    Abstract [en]

    Objective To explore the relative importance of risk factors, treatments, and blood counts for the occurrence of vascular complications and their impact on life expectancy in essential thrombocythemia (ET) and polycythemia vera (PV). Methods Nested case-control study within the Swedish MPN registry. From a cohort of 922 ET patients and 763 PV patients, 71 ET and 81 PV cases with vascular complications were compared with matched controls. Results Incidence of vascular complications was 2.0 and 3.4 events per 100 patient-years in ET and PV, respectively. At diagnosis, no significant risk factor differences were observed between cases and controls in neither of the diseases. At the time of vascular event, ET complication cases did not differ significantly from controls but in PV, cases had significantly higher WBCs and were to a lesser extent treated with anti-thrombotic and cytoreductive therapy. Life expectancy was significantly decreased in both ET and PV cases compared with controls. Conclusions The risk of vascular complications is high in both ET and PV, and these complications have a considerable impact on life expectancy. The protective effect of anti-thrombotic and cytoreductive therapy for vascular complications in PV underscores the importance of avoiding undertreatment.

  • 2.
    Baliakas, Panagiotis
    et al.
    Uppsala Univ, Sweden.
    Tesi, Bianca
    Karolinska Univ Hosp, Sweden.
    Wartiovaara-Kautto, Ulla
    Helsinki Univ Hosp, Finland.
    Stray-Pedersen, Asbjorg
    Oslo Univ Hosp, Norway.
    Friis, Lone Smidstrup
    Copenhagen Univ Hosp, Denmark.
    Dybedal, Ingunn
    Oslo Univ Hosp, Norway.
    Hovland, Randi
    Haukeland Hosp, Norway.
    Jahnukainen, Kirsi
    Helsinki Univ Hosp, Finland.
    Raaschou-Jensen, Klas
    Odense Univ Hosp, Denmark.
    Ljungman, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Rustad, Cecilie F.
    Oslo Univ Hosp, Norway.
    Lautrup, Charlotte K.
    Aalborg Univ Hosp, Denmark.
    Kilpivaara, Outi
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Kittang, Astrid Olsnes
    Haukeland Hosp, Norway.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Denmark.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Hellstrom-Lindberg, Eva
    Karolinska Univ Hosp, Sweden.
    Andersen, Mette K.
    Copenhagen Univ Hosp, Denmark.
    Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up2019In: HemaSphere, E-ISSN 2572-9241, Vol. 3, no 6, article id UNSP e321Article in journal (Refereed)
    Abstract [en]

    Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow-up of at-risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo-HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.

  • 3.
    Behrens, Kira
    et al.
    Leibniz Institute Expt Virol, Germany; Walter and Eliza Hall Institute Medical Research, Australia.
    Maul, Katrin
    Leibniz Institute Expt Virol, Germany.
    Tekin, Nilguen
    Leibniz Institute Expt Virol, Germany; Leibniz Institute Expt Virol, Germany.
    Kriebitzsch, Neele
    Leibniz Institute Expt Virol, Germany.
    Indenbirken, Daniela
    Leibniz Institute Expt Virol, Germany.
    Prassolov, Vladimir
    Engelhardt Institute Molecular Biol, Russia.
    Mueller, Ursula
    Leibniz Institute Expt Virol, Germany.
    Serve, Hubert
    Goethe University of Frankfurt, Germany.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Stocking, Carol
    Leibniz Institute Expt Virol, Germany.
    RUNX1 cooperates with FLT3-ITD to induce leukemia2017In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, no 3, p. 737-752Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression. FLT3-ITD directly impacts on RUNX1 activity, whereby up-regulated and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in tumors releases the differentiation block and down-regulates genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML. We predict that blocking RUNX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors.

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  • 4.
    Bergfelt, Emma
    et al.
    Uppsala University, Sweden.
    Kozlowski, Piotr
    University of Örebro, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Hulegardh, Erik
    Sahlgrens University Hospital, Sweden.
    Hagglund, Hans
    Karolinska Institute, Sweden.
    Karlsson, Karin
    Skåne University Hospital, Sweden.
    Markuszewska-Kuczymska, Alicja
    University of Umeå Hospital, Sweden.
    Tomaszewska-Toporska, Beata
    Skåne University Hospital, Sweden.
    Smedmyr, Bengt
    Uppsala University, Sweden.
    Astrom, Maria
    University of Örebro, Sweden.
    Amini, Rose-Marie
    Uppsala University, Sweden.
    Hallbook, Helene
    Uppsala University, Sweden.
    Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study2015In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, p. 135-Article in journal (Refereed)
    Abstract [en]

    The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status greater than= 2. MRD less than 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

  • 5.
    Bergfelt Lennmyr, Emma
    et al.
    Uppsala Univ Hosp, Sweden.
    Kozlowski, Piotr
    Orebro Univ, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Bernell, Per
    Karolinska Univ Hosp, Sweden.
    Hulegardh, Erik
    Sahlgrens Univ Hosp, Sweden.
    Izarra, Antonio Santamaria
    Univ Hosp Umeå, Sweden.
    Karlsson, Karin
    Skane Univ Hosp, Sweden.
    Tomaszewska-Toporska, Beata
    Skane Univ Hosp, Sweden.
    Åström, Maria
    Orebro Univ, Sweden.
    Hallbook, Helene
    Uppsala Univ Hosp, Sweden.
    Real-world data on first relapse of acute lymphoblastic leukemia in patients > 55 years2018In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 59, no 10, p. 2470-2473Article in journal (Other academic)
    Abstract [en]

    n/a

  • 6.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    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 register2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, no 5, p. 614-627Article in journal (Refereed)
    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.

  • 7.
    Berggren, Daniel Moreno
    et al.
    Uppsala Univ, Sweden.
    Garelius, Hege
    Sahlgrens Univ Hosp, Sweden.
    Willner Hjelm, Petter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Rasmussen, Bengt
    Orebro Univ, Sweden.
    Weibull, Caroline E.
    Karolinska Inst, Sweden.
    Lambe, Mats
    Karolinska Inst, Sweden; Reg Canc Ctr Cent Sweden, Sweden.
    Lehmann, Soren
    Uppsala Univ, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hellstrom-Lindberg, Eva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jadersten, Martin
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Therapy-related MDS dissected based on primary disease and treatment-a nationwide perspective2023In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 37, p. 1103-1112Article in journal (Refereed)
    Abstract [en]

    In this population-based study, we aimed to characterize and compare subgroups of therapy-related Myelodysplastic syndromes (t-MDS) and define the implications of type of previous treatment and primary disease. We combined data from MDS patients, diagnosed between 2009 and 2017 (n = 2705), in the nationwide Swedish MDS register, with several health registers. Furthermore, using matched population controls, we investigated the prevalence of antecedent malignancies in MDS patients in comparison with the general population. This first ever nationwide study on t-MDS confirms a shorter median survival for t-MDS compared to de novo MDS (15.8 months vs 31.1 months, p < 0.001). T-MDS patients previously treated with radiation only had disease characteristics with a striking resemblance to de novo-MDS, in sharp contrast to patients treated with chemotherapy who had a significantly higher risk profile. IPSS-R and the WHO classification differentiated t-MDS into different risk groups. As compared with controls, MDS patients had a six-fold increased prevalence of a previous hematological malignancy but only a 34% increased prevalence of a previous solid tumor. T-MDS patients with a previous hematological malignancy had a dismal prognosis, due both to mortality related to their primary disease and to high-risk MDS.

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  • 8.
    Bernhardsson, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Dietrich, Franciele
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tätting, Love
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Depletion of cytotoxic (CD8+) T cells impairs implant fixation in rat cancellous bone2019In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 37, no 4, p. 805-811Article in journal (Refereed)
    Abstract [en]

    As cytotoxic (CD8(+)) T cells seem to impair shaft fracture healing, we hypothesized that depletion of CD8(+) cells would instead improve healing of cancellous bone. Additionally, we also tested if CD8-depletion would influence the healing of ruptured Achilles tendons. Rats received a single injection of either anti-CD8 antibodies or saline and put through surgery 24 h later. Three different surgical interventions were performed as follows: (1) a drill hole in the proximal tibia with microCT (BV/TV) to assess bone formation; (2) a screw in the proximal tibia with mechanical evaluation (pull-out force) to assess fracture healing; (3) Achilles tendon transection with mechanical evaluation (force-at-failure) to assess tendon healing. Furthermore, CD8-depletion was confirmed with flow cytometry on peripheral blood. Flow cytometric analysis confirmed depletion of CD8(+) cells (p amp;lt; 0.001). Contrary to our hypothesis, depletion of CD8(+) cells reduced the implant pull-out force by 19% (p amp;lt; 0.05) and stiffness by 34% (p amp;lt; 0.01), although the bone formation in the drill holes was the same as in the controls. Tendon healing was unaffected by CD8-depletion. Our results suggest that CD8(+) cells have an important part in cancellous bone healing.

  • 9.
    Birgegard, Gunnar
    et al.
    Uppsala Univ, Sweden.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ahlstrand, Erik
    Orebro Univ, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Enevold, Christian
    Copenhagen Univ Hosp, Denmark.
    Ghanima, Waleed
    Ostfold Hosp, Norway.
    Hasselbalch, Hans
    Zealand Univ Hosp, Denmark.
    Nielsen, Claus H.
    Zealand Univ Hosp, Denmark.
    Knutsen, Havar
    Ulleval Hosp, Norway.
    Pedersen, Ole B.
    Naestved Hosp, Denmark.
    Sorensen, Anders
    Copenhagen Univ Hosp, Denmark; Zealand Univ Hosp, Denmark.
    Andreasson, Bjorn
    NU Hosp Grp, Sweden.
    Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group2019In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 102, no 3, p. 235-240Article in journal (Refereed)
    Abstract [en]

    Objectives The study investigates the hypothesis that inflammation in myelofibrosis (MF) like in myeloma and lymphoma, may disturb iron distribution and contribute to anaemia. Methods A cross-sectional study of 80 MF and 23 ET patients was performed. Results About 35% of anaemic MF patients had functional iron deficiency (FID) with transferrin saturation amp;lt;20 and normal or elevated S-ferritin (amp;lt;500 mu g/L). In ET, FID was rare. In MF patients with FID, 70.6% were anaemic, vs 29.4% in patients without FID (P = 0.03). Hepcidin was significantly higher in MF patients with anaemia, including transfusion-dependent patients, 50.6 vs 24.4 mu g/L (P = 0.01). There was a significant negative correlation between Hb and inflammatory markers in all MF patients: IL-2, IL-6 and TNF-alpha, (P amp;lt; 0.01-0.03), LD (P = 0.004) and hepcidin (P = 0.03). These correlations were also seen in the subgroup of anaemic MF patients (Table ). Tsat correlated negatively with CRP (P amp;lt; 0.001). Symptom burden was heavier in MF patients with FID, and MPN-SAF quality of life scores correlated with IL-6 and CRP. Conclusions The inflammatory state of MF disturbs iron turnover, FID is common and contributes to anaemia development and impairment of QoL. Anaemic MF patients should be screened for FID.

  • 10.
    Bjerrum, Ole Weis
    et al.
    Rigshosp, Denmark.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ghanima, Waleed
    Univ Oslo, Norway; Univ Oslo, Norway.
    Kauppila, Marjut
    Turku Univ Hosp, Finland.
    Andersen, Christen Lykkegaard
    Rigshosp, Denmark; Roskilde Hosp, Denmark.
    Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 5, p. 475-478Article in journal (Refereed)
    Abstract [en]

    Background: Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs. Objectives: The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems. Results: The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients. Conclusions: The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector.

  • 11.
    Björn, Niclas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jakobsen, Ingrid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Laboratory Medicine, Örebro University Hospital.
    Lotfi, Kourosh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Gréen, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping.
    Single-Cell RNA Sequencing of Hematopoietic Stem and Progenitor Cells Treated with Gemcitabine and Carboplatin.2020In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, no 5, article id E549Article in journal (Refereed)
    Abstract [en]

    Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The understanding of how human bone marrow is affected on a transcriptional level leading to the development of myelosuppression is required for the implementation of personalized treatments in the future. In this study, we treated human hematopoietic stem and progenitor cells (HSPCs) harvested from a patient with chronic myelogenous leukemia (CML) with gemcitabine/carboplatin. Thereafter, scRNA-seq was performed to distinguish transcriptional effects induced by gemcitabine/carboplatin. Gene expression was calculated and evaluated among cells within and between samples compared to untreated cells. Cell cycle analysis showed that the treatments effectively decrease cell proliferation, indicated by the proportion of cells in the G2M-phase dropping from 35% in untreated cells to 14.3% in treated cells. Clustering and t-SNE showed that cells within samples and between treated and untreated samples were affected differently. Enrichment analysis of differentially expressed genes showed that the treatments influence KEGG pathways and Gene Ontologies related to myeloid cell proliferation/differentiation, immune response, cancer, and the cell cycle. The present study shows the feasibility of using scRNA-seq and chemotherapy-treated HSPCs to find genes, pathways, and biological processes affected among and between treated and untreated cells. This indicates the possible gains of using single-cell toxicity studies for personalized medicine.

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  • 12.
    Blimark, Cecilie Hveding
    et al.
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden.
    Turesson, Ingemar
    Skåne University Hospital, Lund-Malmö, Sweden.
    Genell, Anna
    Western Sweden Hlth Care Reg, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Björkstrand, Bo
    Karolinska Inst, Sweden.
    Carlson, Kristina
    Uppsala Univ Hosp, Sweden.
    Forsberg, Karin
    Umeå Univ Hosp, Sweden.
    Juliusson, Gunnar
    Lund Univ, Sweden.
    Linder, Olle
    Örebro Univ Hosp, Sweden.
    Mellqvist, Ulf-Henrik
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden; Boras Hosp, Sweden.
    Nahi, Hareth
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kristinsson, Sigurdur Y.
    Karolinska Inst, Sweden; Univ Iceland, Iceland; Karolinska Univ Hosp, Sweden.
    Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 3, p. 506-513Article in journal (Refereed)
    Abstract [en]

    Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent real-world patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabi-ants per year. Among initially symptomatic patients (n= 3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (Pamp;lt;0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95% CI: 0.77-0.92; Pamp;lt;0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95% CI: 0.87-0.99; Pamp;lt;0.05). We report here on a near complete real-world population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.

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  • 13.
    Boknäs, Niklas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Laine, Cia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Hillarp, Andreas
    Oslo Univ Hosp, Norway.
    Macwan, Ankit
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Kerstin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Lindahl, Tomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Holmström, Margareta
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Associations between hemostatic markers and mortality in COVID-19-Compounding effects of D-dimer, antithrombin and PAP complex2022In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 213, p. 97-104Article in journal (Refereed)
    Abstract [en]

    In this single-center cohort study, we applied a panel of laboratory markers to characterize hemostatic function in 217 consecutive patients that underwent testing for COVID-19 as they were admitted to Linkoping ¨ University Hospital between April and June 2020. In the 96 patients that tested positive for SARS-CoV-2 (COVID-19+), the cumulative incidences of death and venous thromboembolism were 24.0% and 19.8% as compared to 12.4% (p = 0.031) and 11.6% (p = 0.13) in the 121 patients that tested negative (COVID-19− ). In COVID-19+ patients, we found pronounced increases in plasma levels of von Willebrand factor (vWF) and fibrinogen. Excess mortality was observed in COVID-19+ patients with the following aberrations in hemostatic markers: high D-dimer, low antithrombin or low plasmin-antiplasmin complex (PAP) formation, with Odds Ratios (OR) for death of 4.7 (95% confidence interval (CI95) 1.7–12.9; p = 0.003) for D-dimer >0.5 mg/L, 5.9 (CI95 1.8–19.7; p = 0.004) for antithrombin (AT) ˂0.85 kIU/l and 4.9 (CI95 1.3–18.3; p = 0.019) for PAP < 1000 μg/L. Compounding increases in mortality was observed in COVID-19+ patients with combined defects in markers of fibrinolysis and coagulation, with ORs for death of 15.7 (CI95 4.3–57; p < 0.001) for patients with PAP <1000 μg/L and D-dimer >0.5 mg/L and 15.5 (CI95 2.8–87, p = 0.002) for patients with PAP <1000 μg/L and AT ˂0.85 kIU/L. We observed an elevated fraction of incompletely degraded D-dimer fragments in COVID-19+ patients with low PAP, indicating impaired fibrinolytic breakdown of cross-linked fibrin. 

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  • 14.
    Boknäs, Niklas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
    Macwan, Ankit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Södergren, Anna L.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Örebro University, School of Medical Sciences, Örebro, Sweden.
    Platelet function testing at low platelet counts: When can you trust your analysis?2019In: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, ISSN 2475-0379, Vol. 3, no 2, p. 285-290Article in journal (Refereed)
    Abstract [en]

    Background: Although flow cytometry is often brought forward as a preferable method in the setting of thrombocytopenia, the relative effects of low sample counts on results from flow cytometry-based platelet function testing (FC-PFT) in comparison with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) has not been reported. Objectives: To compare the effects of different sample platelet counts (10, 50, 100, and 200x10(9)L(-1)) on platelet activation measured with FC-PFT, LTA, and MEA using the same anticoagulant and agonist concentrations as for the commercial MEA test. Methods: Platelets were stimulated with two commonly used platelet agonists (ADP [6.5 mu molL(-1)] and PAR1-AP [TRAP, 32 mu molL(-1)]). The specified sample platelet counts were obtained by combining platelet-rich and platelet poor hirudinized plasma in different proportions with or without red blood cells. Results: For FC, P-selectin exposure and PAC-1 binding was reduced at 10x10(9)L(-1) after stimulation with PAR1-AP (by approximately 20% and 50%, respectively), but remained relatively unchanged when ADP was used as agonist (n=9). The platelet count-dependent effects observed with PAR1-AP were eliminated when samples were pre-incubated with apyrase, implying that reduced purinergic signaling was the main underlying factor (n=5). Both aggregometry-based PFTs showed a 50% reduction at 50x10(9)L(-1) and more than 80% reduction at 10x10(9)L(-1), irrespective of agonist used (n=7). Conclusions: Although FC-PFT is generally preferable to aggregometry-based PFTs in situations with low sample platelet counts, a careful optimization of experimental parameters is still required in order to eliminate platelet count-related effects.

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  • 15.
    Boknäs, Niklas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Orebro Univ, Sweden.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 5, p. 512-519Article in journal (Refereed)
    Abstract [en]

    Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole-blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p=0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole-blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis.

  • 16.
    Christensen, Mathilde Egelund
    et al.
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Siersma, Volkert
    Univ Copenhagen, Denmark.
    Kriegbaum, Margit
    Univ Copenhagen, Denmark.
    Lind, Bent Struer
    Univ Copenhagen, Denmark; Copenhagen Univ Hosp, Denmark.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ostgard, Lene Sofie Granfeldt
    Odense Univ Hosp, Denmark; Aarhus Univ, Denmark.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Andersen, Christen Lykkegaard
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Monocytosis in primary care and risk of haematological malignancies2023In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609Article in journal (Refereed)
    Abstract [en]

    Monocytosis (&gt;= 0.5 x 10(9)/L in peripheral blood) is the hallmark of chronic myelomonocytic leukaemia (CMML) but may be present in a spectrum of diseases including other haematological malignancies. In the primary care sector, monocytosis is a relatively common finding, but its predictive value for haematological malignancy is unknown. We included 663 184 adult primary care patients from the greater Copenhagen area with one or more differential cell counts registered between 2000 and 2016 and followed them in the extensive nationwide Danish health data registers for 3 years after blood sampling. We used logistic regression to model the risk of haematological malignancy and death following monocytosis. Monocytosis was associated with an increased risk of all types of haematological malignancy with the greatest relative risk increase observed in CMML with an OR of 105.22 (95% confidence interval: 38.27-289.30). Sustained monocytosis (at least two requisitions in 3 months) further increased CMML risk, although the diagnosis was still very rare, that is, observed in only 0.1% of these individuals. Outside the haematological setting, the absolute risk of haematological malignancy associated with monocytosis is low and haematological malignancy should mainly be suspected when monocytosis is sustained or the clinical presentation raises suspicion of malignancy.

  • 17.
    Czerw, Tomasz
    et al.
    Maria Sklodowska Curie Natl Res Inst Oncol, Poland.
    Iacobelli, Simona
    Tor Vergata Univ, Italy.
    Malpassuti, Vittoria
    Tor Vergata Univ, Italy.
    Koster, Linda
    EBMT Data Off, Netherlands.
    Kroeger, Nicolaus
    Univ Hosp Eppendorf, Germany.
    Robin, Marie
    Univ Paris, France.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Chevallier, Patrice
    CHU Nantes, France.
    Watz, Emma
    Karolinska Univ Hosp, Sweden.
    Poire, Xavier
    Clin Univ St Luc, Belgium.
    Snowden, John A.
    Sheffield Teaching Hosp NHS Trust, England.
    Kuball, Jurgen
    Univ Med Ctr, Netherlands.
    Kinsella, Francesca
    Univ Hosp Birmingham NHS Trust, England.
    Blaise, Didier
    Inst Paoli Calmettes, France.
    Remenyi, Peter
    Del Pesti Centrumkorhaz, Hungary.
    Mear, Jean-Baptiste
    Ctr Hosp Univ Rennes, France.
    Cammenga, Jörg
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Rubio, Marie Therese
    CHRU BRABOIS, France.
    Maury, Sebastien
    Hop Henri Mondor, France.
    Daguindau, Etienne
    Hop Jean Minjoz, France.
    Finnegan, Damian
    Belfast City Hosp, North Ireland.
    Hayden, Patrick
    St James Hosp, Ireland.
    Carlos Hernandez-Boluda, Juan
    Univ Valencia, Spain.
    McLornan, Donal
    Guys & St Thomas NHS Fdn Trust, England; Univ Coll London Hosp, England.
    Yakoub-Agha, Ibrahim
    Univ Lille, France.
    Impact of donor-derived CD34+infused cell dose on outcomes of patients undergoing allo-HCT following reduced intensity regimen for myelofibrosis: a study from the Chronic Malignancies Working Party of the EBMT2022In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 57, p. 261-270Article in journal (Refereed)
    Abstract [en]

    The optimal CD34 + cell dose in the setting of RIC allo-HCT for myelofibrosis (MF) remains unknown. We retrospectively analyzed 657 patients with primary or secondary MF transplanted with use of peripheral blood (PB) stem cells after fludarabine/melphalan or fludarabine/busulfan RIC regimen. Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34 + cells (&gt;7.0 x 10(6)/kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46; P &lt; 0.001) and platelet engraftment (HR, 1.43; P &lt; 0.001). In a model with interaction, for patients transplanted from a MSD, higher CD34 + dose was associated with improved overall survival (HR, 0.63; P = 0.04) and relapse-free survival (HR, 0.61; P = 0.02), lower risk of non-relapse mortality (HR, 0.57; P = 0.04) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34 + dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM. Our analysis suggests a potential benefit for MF patients undergoing RIC PB-allo-HCT receiving more than 7.0 x 10(6)/kg CD34 + cells.

  • 18.
    Czerw, Tomasz
    et al.
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Labopin, Myriam
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Schmid, Christoph
    University of Munich, Germany.
    Cornelissen, Jan J.
    Erasmus University, Netherlands.
    Chevallier, Patrice
    CHU Nantes, France.
    Blaise, Didier
    Institute J Paoli I Calmettes, France.
    Kuball, Juergen
    University of Medical Centre, Netherlands.
    Vigouroux, Stephane
    Hop Haut Leveque, France.
    Garban, Frederic
    Hop A Michallon, France.
    Lioure, Bruno
    Nouvel Hop Civil, France.
    Fegueux, Nathalie
    CHU Lapeyronie, France.
    Clement, Laurence
    Centre Hospital University of CHU Nancy, France.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Maertens, Johan
    University Hospital Gasthuisberg, Belgium.
    Guillerm, Gaelle
    CHU Morvan, France.
    Bordessoule, Dominique
    CHRU Limoges, France.
    Mohty, Mohamad
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Nagler, Arnon
    Hop St Antoine, France; Chaim Sheba Medical Centre, Israel.
    High CD3+and CD34+peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 19, p. 27255-27266Article in journal (Refereed)
    Abstract [en]

    Inconsistent results have been reported regarding the influence of graft composition on the incidence of graft versus host disease (GVHD), disease control and survival after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation (allo-PBSCT). These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. The current retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose on the outcome of RIC allo-PBSCT in patients with acute myelogenous leukemia (AML) in first complete remission, allografted from HLA-matched unrelated donors (10 of 10 match). We included 203 adults. In univariate analysis, patients transplanted with the highest CD3+ and CD34+ doses (above the third quartile cut-off point values, amp;gt;347 x 10amp;lt;^amp;gt;6/kg and amp;gt;8.25 x 10amp;lt;^amp;gt;6/kg, respectively) had an increased incidence of grade III-IV acute (a) GVHD (20% vs. 6%, P = .003 and 18% vs. 7%, P = .02, respectively). There was no association between cellular composition of grafts and transplant-related mortality, AML relapse, incidence of chronic GVHD and survival. Neither engraftment itself nor the kinetics of engraftment were affected by the cell dose. In multivariate analysis, CD3+ and CD34+ doses were the only adverse predicting factors for grade III-IV aGVHD (HR = 3.6; 95% CI: 1.45-9.96, P = .006 and 2.65 (1.07-6.57), P = .04, respectively). These results suggest that careful assessing the CD3+ and CD34+ graft content and tailoring the cell dose infused may help in reducing severe acute GVHD risk without negative impact on the other transplantation outcomes.

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  • 19.
    Dahlen, Torsten
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Flygt, Hjalmar
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Lubking, Anna
    Skane Univ Hosp, Sweden.
    Olsson-Stromberg, Ulla
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Dreimane, Arta
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Sjalander, Anders
    Umea Univ, Sweden.
    Leach, Susannah
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Gisslen, Magnus
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Li, Huiqi
    Univ Gothenburg, Sweden.
    Hoglund, Martin
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden.
    Nyberg, Fredrik
    Univ Gothenburg, Sweden.
    The impact of Covid-19 in patients with chronic myeloid leukemia-a nationwide population-based study2023In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551Article in journal (Other academic)
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  • 20.
    Dahlén, Torsten
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Edgren, Gustaf
    Karolinska Inst, Sweden; Soder Sjukhuset, Sweden.
    Ljungman, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Flygt, Hjalmar
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Olsson-Strömberg, Ulla
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Sweden.
    Dreimane, Arta
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Myhr-Eriksson, Kristina
    Sunderby Hosp, Sweden.
    Zhao, Jingcheng
    Karolinska Inst, Sweden.
    Själander, Anders
    Umea Univ, Sweden.
    Höglund, Martin
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Adverse outcomes in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Follow-up of patients diagnosed 2002-2017 in a complete coverage and nationwide agnostic register study2022In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 97, no 4, p. 421-430Article in journal (Refereed)
    Abstract [en]

    Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort-study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002-2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near-complete nationwide coverage were utilized for data acquisition. Median follow-up was 6 (IQR, 3-10) years with a total follow-up of 8510 person-years for the full cohort. Among 670 analyzed disease categories, the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5-2.6), heart failure 2.6 (2.2-3.2), pneumonia 2.8 (2.3-3.5), and unspecified sepsis 3.5 (2.6-4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within-cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5-5.6) and chronic ischemic heart disease (2.2; 1.2-3.9), dasatinib for pleural effusion (11.6; 7.6-17.7) and infectious complications, for example, acute upper respiratory infections (3.0; 1.4-6.0). Our extensive real-world data reveal significant risk increases of severe morbidity in TKI-treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored.

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  • 21.
    Davidsson, Josef
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Puschmann, Andreas
    Lund Univ, Sweden.
    Tedgard, Ulf
    Skane Univ Hosp, Sweden.
    Bryder, David
    Lund Univ, Sweden.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 5, p. 1106-1115Article, review/survey (Refereed)
    Abstract [en]

    Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9Ls normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutations effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.

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  • 22.
    Deb, Suryyani
    et al.
    Maulana Abul Kazam Azad Univ Technol, India.
    Boknäs, Niklas
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry.
    Sjöström, Clara
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Tharmakulanathan, Anjana
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Lotfi, Kourosh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ramström, Sofia
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Orebro Univ, Sweden.
    Varying effects of tyrosine kinase inhibitors on platelet function-A need for individualized CML treatment to minimize the risk for hemostatic and thrombotic complications?2020In: Cancer Medicine, E-ISSN 2045-7634, Vol. 9, no 1, p. 313-323Article in journal (Refereed)
    Abstract [en]

    Since their introduction, tyrosine kinase inhibitors (TKIs, eg, imatinib, nilotinib, dasatinib, bosutinib, ponatinib) have revolutionized the treatment of chronic myeloid leukemia (CML). However, long-term treatment with TKIs is associated with serious adverse events including both bleeding and thromboembolism. Experimental studies have shown that TKIs can cause platelet dysfunction. Herein, we present the first side-by-side investigation comparing the effects of currently used TKIs on platelet function and thrombin generation when used in clinically relevant concentrations. A flow cytometry multiparameter protocol was used to study a range of significant platelet activation events (fibrinogen receptor activation, alpha granule, and lysosomal exocytosis, procoagulant membrane exposure, and mitochondrial permeability changes). In addition, thrombin generation was measured in the presence of TKIs to assess the effects on global hemostasis. Results show that dasatinib generally inhibited platelet function, while bosutinib, nilotinib, and ponatinib showed less consistent effects. In addition to these general trends for each TKI, we observed a large degree of interindividual variability in the effects of the different TKIs. Interindividual variation was also observed when blood from CML patients was studied ex vivo with whole blood platelet aggregometry, free oscillation rheometry (FOR), and flow cytometry. Based on the donor responses in the side-by-side TKI study, a TKI sensitivity map was developed. We propose that such a sensitivity map could potentially become a valuable tool to help in decision-making regarding the choice of suitable TKIs for a CML patient with a history of bleeding or atherothrombotic disease.

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  • 23.
    Derolf, Asa
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Juliusson, Gunnar
    Skane Univ Hosp, Sweden.
    Benson, Lina
    Epidemiol and Reg Oncol Ctr Stockholm, Sweden.
    Floisand, Yngvar
    Oslo Univ Hosp, Norway.
    Lazarevic, Vladimir
    Skane Univ Hosp, Sweden.
    Antunovic, Petar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Lehmann, Soren
    Uppsala Univ, Sweden.
    Uggla, Bertil
    Orebro Univ Hosp, Sweden.
    Wahlin, Anders
    Umea Univ, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Letter: Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor in BRITISH JOURNAL OF HAEMATOLOGY, vol 188, issue 1, pp 187-1912020In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, no 1, p. 187-191Article in journal (Other academic)
    Abstract [en]

    n/a

  • 24.
    Eichhorst, Barbara
    et al.
    Univ Cologne, Germany.
    Niemann, Carsten U.
    Copenhagen Univ Hosp, Denmark.
    Kater, Arnon P.
    Univ Amsterdam, Netherlands.
    Fuerstenau, Moritz
    Univ Cologne, Germany.
    von Tresckow, Julia
    Univ Duisburg Essen, Germany.
    Zhang, Can
    Univ Cologne, Germany.
    Robrecht, Sandra
    Univ Cologne, Germany.
    Gregor, Michael
    Luzerner Kantonsspital, Switzerland.
    Juliusson, Gunnar
    Lund Univ, Sweden.
    Thornton, Patrick
    Blackrock Hlth Member Hosp, Ireland.
    Staber, Philipp B.
    Med Univ Vienna, Austria.
    Tadmor, Tamar
    Bnai Zion Med Ctr, Israel.
    Lindstrom, Vesa
    Helsinki Univ Hosp, Finland.
    da Cunha-Bang, Caspar
    Copenhagen Univ Hosp, Denmark.
    Schneider, Christof
    Univ Ulm, Germany.
    Poulsen, Christian B.
    Zealand Univ Hosp, Denmark.
    Illmer, Thomas
    Grp Practice Hematol & Oncol, Germany.
    Schoettker, Bjoern
    Hematol Oncol Ctr, Germany.
    Noesslinger, Thomas
    Hanusch Hosp, Austria.
    Janssens, Ann
    Univ Ziekenhuis Leuven, Belgium.
    Christiansen, Ilse
    Aalborg Univ Hosp, Denmark.
    Baumann, Michael
    Kantonsspital St Gallen, Switzerland.
    Frederiksen, Henrik
    Odense Univ Hosp, Denmark.
    van der Klift, Marjolein
    Amphia Hosp, Netherlands.
    Jaeger, Ulrich
    Med Univ Vienna, Austria.
    Leys, Maria B. L.
    Maasstad Ziekenhuis, Netherlands.
    Hoogendoorn, Mels
    Med Ctr Leeuwarden, Netherlands.
    Lotfi, Kourosh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Hebart, Holger
    Specialist Med Practice Hematol & Oncol, Germany.
    Gaska, Tobias
    Bruderhosp St Josef, Germany.
    Koene, Harry
    St Antonius Hosp Utrecht, Netherlands.
    Enggaard, Lisbeth
    Rigshosp, Denmark.
    Goede, Jereon
    Kantonsspital Hosp Winterthur, Switzerland.
    Regelink, Josien C.
    Meander Med Ctr, Netherlands.
    Widmer, Anouk
    Univ Hosp Zurich, Switzerland.
    Simon, Florian
    Univ Cologne, Germany.
    De Silva, Nisha
    UCL, England.
    Fink, Anna-Maria
    Univ Cologne, Germany.
    Bahlo, Jasmin
    Univ Cologne, Germany.
    Fischer, Kirsten
    Univ Cologne, Germany.
    Wendtner, Clemens-Martin
    Ludwig Maximilians Univ Munchen, Germany.
    Kreuzer, Karl A.
    Univ Cologne, Germany.
    Ritgen, Matthias
    Univ Hosp Schleswig Holstein, Germany.
    Brueggemann, Monika
    Univ Hosp Schleswig Holstein, Germany.
    Tausch, Eugen
    Univ Ulm, Germany.
    Levin, Mark-David
    Albert Schweitzer Hosp, Netherlands.
    van Oers, Marinus
    Univ Amsterdam, Netherlands.
    Geisler, Christian
    Copenhagen Univ Hosp, Denmark.
    Stilgenbauer, Stephan
    Univ Ulm, Germany.
    Hallek, Michael
    Univ Cologne, Germany.
    First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia2023In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 388, no 19, p. 1739-1754Article in journal (Refereed)
    Abstract [en]

    Background Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. Methods In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, &lt;10(-4) [i.e., &lt;1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. Results A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P&lt;0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P=0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P&lt;0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P&lt;0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P=0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). Conclusions Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.

  • 25.
    Eketorp Sylvan, Sandra
    et al.
    Karolinska Inst, Sweden.
    Asklid, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Johansson, Hemming
    Karolinska Inst, Sweden.
    Klintman, Jenny
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Bjellvi, Jenny
    Sahlgrens Univ Hosp, Sweden.
    Tolvgard, Staffan
    Ostersunds Hosp, Sweden.
    Kimby, Eva
    Karolinska Inst, Sweden.
    Norin, Stefan
    Karolinska Inst, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hosp, Sweden.
    Karlsson, Claes
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Karlsson, Karin
    Skane Univ Hosp, Sweden.
    Lauri, Birgitta
    Sunderby Hosp, Sweden.
    Mattsson, Mattias
    Uppsala Univ Hosp, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Strandberg, Maria
    Sundsvall Hosp, Sweden.
    Osterborg, Anders
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hansson, Lotta
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    First-line therapy in chronic lymphocytic leukemia: a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 20132019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 4, p. 797-805Article in journal (Refereed)
    Abstract [en]

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

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  • 26.
    El-Serafi, Ahmed
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Suez Canal Univ, Egypt.
    He, Rui
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Zheng, Wenyi
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Benkossou, Fadwa
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Oerther, Sandra
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Zhao, Ying
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Mellgren, Karin
    Sahlgrens Univ Hosp, Sweden.
    Gustafsson, Britt
    Karolinska Inst, Sweden.
    Heilmann, Carsten
    Natl Univ Hosp, Denmark.
    Kanerva, Jukka
    HUS Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Lotfi, Kourosh
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology.
    Toporski, Jacek
    Skane Univ Hosp, Sweden.
    Sundin, Mikael
    Karolinska Inst, Sweden; Astrid Lindgren Childrens Hosp, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    Mattsson, Jonas
    Univ Toronto, Canada; Princess Margaret Canc Ctr, Canada; Karolinska Inst, Sweden.
    El-Serafi, Ibrahim
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Hassan, Moustapha
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study2021In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 56, p. 807-817Article in journal (Refereed)
    Abstract [en]

    Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P &lt; 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

  • 27.
    Engert, Andreas
    et al.
    University of Cologne, Germany.
    Balduini, Carlo
    IRCCS Policlin San Matteo Fdn, Italy.
    Brand, Anneke
    Leids University, Netherlands.
    Coiffier, Bertrand
    University of Lyon 1, France.
    Cordonnier, Catherine
    Hop University of Henri Mondor, France.
    Doehner, Hartmut
    University of Klinikum Ulm, Germany.
    Duyvene de Wit, Thom
    European Hematol Assoc, Netherlands.
    Eichinger, Sabine
    Medical University of Wien, Austria.
    Fibbe, Willem
    Leids University, Netherlands.
    Green, Tony
    Cambridge Institute Medical Research, England.
    de Haas, Fleur
    European Hematol Assoc, Netherlands.
    Iolascon, Achille
    University of Naples Federico II, Italy.
    Jaffredo, Thierry
    University of Paris 06, France.
    Rodeghiero, Francesco
    Osped San Bortolo, Italy.
    Salles, Gilles
    University of Lyon, France.
    Jacob Schuringa, Jan
    University of Groningen, Netherlands.
    Andre, Marc
    Catholic University of Louvain, Belgium.
    Andre-Schmutz, Isabelle
    University of Paris 05, France.
    Bacigalupo, Andrea
    Osped San Martino Genova, Italy.
    Bochud, Pierre-Yves
    University of Lausanne, Switzerland.
    den Boer, Monique
    Erasmus MC, Netherlands.
    Bonini, Chiara
    University of Milan, Italy.
    Camaschella, Clara
    San Raffaele Institute, Italy.
    Cant, Andrew
    Great North Childrens Hospital, England.
    Domenica Cappellini, Maria
    University of Milan, Italy.
    Cazzola, Mario
    University of Pavia, Italy.
    Lo Celso, Cristina
    Imperial Coll London, England.
    Dimopoulos, Meletios
    University of Athens, Greece.
    Douay, Luc
    University of Paris 06, France.
    Dzierzak, Elaine
    University of Edinburgh, Scotland.
    Einsele, Hermann
    University of Wurzburg, Germany.
    Ferreri, Andres
    Ist Science San Raffaele, Italy.
    De Franceschi, Lucia
    University of Verona, Italy.
    Gaulard, Philippe
    Hop Henri Mondor, France.
    Gottgens, Berthold
    University of Cambridge, England.
    Greinacher, Andreas
    University of Medical Greifswald, Germany; Ernst Moritz Arndt University of Greifswald, Germany.
    Gresele, Paolo
    University of Perugia, Italy.
    Gribben, John
    Queen Mary University of London, England.
    de Haan, Gerald
    University of Groningen, Netherlands.
    Hansen, John-Bjarne
    University of Tromso, Norway.
    Hochhaus, Andreas
    University of Klinikum Jena, Germany.
    Kadir, Rezan
    Royal Free Hospital, England.
    Kaveri, Srini
    Institute National Sante and Rech Med, France.
    Kouskoff, Valerie
    University of Manchester, England.
    Kuehne, Thomas
    University of Kinderspital Beider Basel, Switzerland.
    Kyrle, Paul
    Medical University of Wien, Austria.
    Ljungman, Per
    Karolinska Institute, Sweden.
    Maschmeyer, Georg
    Klinikum Ernst Von Bergmann, Germany.
    Mendez-Ferrer, Simon
    University of Cambridge, England.
    Milsom, Michael
    Deutsch Krebsforschungszentrum Neuenheimer Feld, Germany.
    Mummery, Christine
    Leids University, Netherlands.
    Ossenkoppele, Gert
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Pecci, Alessandro
    University of Pavia, Italy.
    Peyvandi, Flora
    University of Milan, Italy.
    Philipsen, Sjaak
    Erasmus MC, Netherlands.
    Reitsma, Pieter
    Leids University, Netherlands.
    Maria Ribera, Jose
    Institute Catala Oncol, Spain.
    Risitano, Antonio
    University of Naples Federico II, Italy.
    Rivella, Stefano
    Weill Medical Coll, NY USA.
    Ruf, Wolfram
    Johannes Gutenberg University of Mainz, Germany.
    Schroeder, Timm
    Swiss Federal Institute Technology, Switzerland.
    Scully, Marie
    University of Coll London Hospital, England.
    Socie, Gerard
    Hop St Louis, France.
    Staal, Frank
    Leids University, Netherlands.
    Stanworth, Simon
    John Radcliffe Hospital, England.
    Stauder, Reinhard
    Medical University of Innsbruck, Austria.
    Stilgenbauer, Stephan
    University of Klinikum Ulm, Germany.
    Tamary, Hannah
    Schneider Childrens Medical Centre Israel, Israel.
    Theilgaard-Monch, Kim
    University of Copenhagen, Denmark.
    Lay Thein, Swee
    Kings Coll London, England.
    Tilly, Herve
    University of Rouen, France.
    Trneny, Marek
    Charles University of Prague, Czech Republic.
    Vainchenker, William
    Institute Gustave Roussy, France.
    Maria Vannucchi, Alessandro
    University of Florence, Italy.
    Viscoli, Claudio
    University of Genoa, Italy.
    Vrielink, Hans
    Sanquin Research, Netherlands.
    Zaaijer, Hans
    Sanquin Research, Netherlands.
    Zanella, Alberto
    Osped Maggiore Policlin, Italy.
    Zolla, Lello
    University of Tuscia, Italy.
    Jan Zwaginga, Jaap
    Leids University, Netherlands.
    Aguilar Martinez, Patricia
    Hop St Eloi, France.
    van den Akker, Emile
    Sanquin Research, Netherlands.
    Allard, Shubha
    Barts Health NHS Trust and NHS Blood and Transplant, England.
    Anagnou, Nicholas
    University of Athens, Greece.
    Andolfo, Immacolata
    University of Naples Federico II, Italy.
    Andrau, Jean-Christophe
    Institute Genet Molecular Montpellier, France.
    Angelucci, Emanuele
    Osp A Businco, Italy.
    Anstee, David
    NHSBT Blood Centre, England.
    Aurer, Igor
    University of Zagreb, Croatia.
    Avet-Loiseau, Herve
    Centre Hospital University of Toulouse, France.
    Aydinok, Yesim
    Ege University, Turkey.
    Bakchoul, Tamam
    University of Medical Greifswald, Germany.
    Balduini, Alessandra
    IRCCS Policlin San Matteo Fdn, Italy.
    Barcellini, Wilma
    Osped Maggiore Policlin, Italy.
    Baruch, Dominique
    University of Paris 05, France.
    Baruchel, Andre
    Hop University of Robert Dabre, France.
    Bayry, Jagadeesh
    Institute National Sante and Rech Med, France.
    Bento, Celeste
    Centre Hospital and University of Coimbra, Portugal.
    van den Berg, Anke
    University of Groningen, Netherlands.
    Bernardi, Rosa
    Ist Science San Raffaele, Italy.
    Bianchi, Paola
    Osped Maggiore Policlin, Italy.
    Bigas, Anna
    Institute Hospital del Mar Investgac Med, Spain.
    Biondi, Andrea
    University of Milano Bicocca, Italy.
    Bohonek, Milos
    Central Mil Hospital, Czech Republic.
    Bonnet, Dominique
    Francis Crick Institute, England.
    Borchmann, Peter
    University Hospital Cologne Int, Germany.
    Borregaard, Niels
    University of Copenhagen, Denmark.
    Braekkan, Sigrid
    University of Tromso, Norway.
    van den Brink, Marcel
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Brodin, Ellen
    University of Sykehuset Nordic Norge, Norway.
    Bullinger, Lars
    University of Klin Ulm, Germany.
    Buske, Christian
    University of Klinikum Ulm, Germany.
    Butzeck, Barbara
    European Federat Assoc Patients Haemochromatosis, France.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Campo, Elias
    University of Barcelona, Spain.
    Carbone, Antonino
    Centre Riferimento Oncol, Italy.
    Cervantes, Francisco
    University of Barcelona, Spain.
    Cesaro, Simone
    Policlin GB Rossi, Italy.
    Charbord, Pierre
    University of Paris 06, France.
    Claas, Frans
    Leids University, Netherlands.
    Cohen, Hannah
    Imperial Coll London, England.
    Conard, Jacqueline
    Hop Hotel Dieu, France.
    Coppo, Paul
    Hop St Antoine, France.
    Vives Corrons, Joan-Lluis
    University of Barcelona, Spain.
    da Costa, Lydie
    Hop Robert Debre, France.
    Davi, Frederic
    University of Paris 06, France.
    Delwel, Ruud
    Erasmus MC, Netherlands.
    Dianzani, Irma
    University of Turin, Italy.
    Domanovic, Dragoslav
    European Centre Disease Prevent and Control, Sweden.
    Donnelly, Peter
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Dovc Drnovsek, Tadeja
    Zavod RS Transfuzijsko Med, Slovenia.
    Dreyling, Martin
    University of Munich, Germany.
    Du, Ming-Qing
    University of Cambridge, England.
    Dufour, Carlo
    Ist Giannina Gaslini, Italy.
    Durand, Charles
    University of Paris 06, France.
    Efremov, Dimitar
    Int Centre Genet Engn and Biotechnol, Italy.
    Eleftheriou, Androulla
    Thalassaemia Int Fed, Cyprus.
    Elion, Jacques
    University of Paris Diderot, France.
    Emonts, Marieke
    Great North Childrens Hospital, England.
    Engelhardt, Monika
    University of Klinikum Freiburg, Germany.
    Ezine, Sophie
    University of Paris 05, France.
    Falkenburg, Fred
    Leids University, Netherlands.
    Favier, Remi
    Hop Enfants A Trousseau, France.
    Federico, Massimo
    University of Modena and Reggio Emilia, Italy.
    Fenaux, Pierre
    Hop St Louis, France.
    Fitzgibbon, Jude
    Queen Mary University of London, England.
    Flygare, Johan
    Lund University, Sweden.
    Foa, Robin
    University of Roma La Sapienza, Italy.
    Forrester, Lesley
    University of Edinburgh, Scotland.
    Galacteros, Frederic
    Hop University of Henri Mondor, France.
    Garagiola, Isabella
    University of Milan, Italy.
    Gardiner, Chris
    University of Oxford, England.
    Garraud, Olivier
    University of St Etienne, France.
    van Geet, Christel
    Katholieke University of Leuven, Belgium.
    Geiger, Hartmut
    University of Klinikum Ulm, Germany.
    Geissler, Jan
    CML Advocates Network, Switzerland.
    Germing, Ulrich
    University of Klinikum Dusseldorf, Germany.
    Ghevaert, Cedric
    University of Cambridge, England.
    Girelli, Domenico
    Institute Cochin, France.
    Godeau, Bertrand
    Hop University of Henri Mondor, France.
    Goekbuget, Nicola
    University of Klinikum Frankfurt, Germany.
    Goldschmidt, Hartmut
    University of Klinikum Heidelberg, Germany.
    Goodeve, Anne
    University of Sheffield, England.
    Graf, Thomas
    Centre Genom Regulat, Spain.
    Graziadei, Giovanna
    University of Milan, Italy.
    Griesshammer, Martin
    Muhlenkreisklin, Germany.
    Gruel, Yves
    Hop Trousseau, France.
    Guilhot, Francois
    University of Poitiers, France.
    von Gunten, Stephan
    University of Bern, Switzerland.
    Gyssens, Inge
    University of Hasselt, Belgium.
    Halter, Jorg
    University of Spital Basel, Switzerland.
    Harrison, Claire
    Guys and St Thomas, England.
    Harteveld, Cornelis
    Leids University, Netherlands.
    Hellstrom-Lindberg, Eva
    Karolinska Institute, Sweden.
    Hermine, Olivier
    University of Paris 05, France.
    Higgs, Douglas
    University of Oxford, England.
    Hillmen, Peter
    University of Leeds, England.
    Hirsch, Hans
    University of Basel, Switzerland.
    Hoskin, Peter
    Mt Vernon Hospital, England.
    Huls, Gerwin
    University of Groningen, Netherlands.
    Inati, Adlette
    Lebanese American University, Lebanon.
    Johnson, Peter
    University of Southampton, England.
    Kattamis, Antonis
    University of Athens, Greece.
    Kiefel, Volker
    University of Medical Rostock, Germany.
    Kleanthous, Marina
    Cyprus School Molecular Med, Cyprus.
    Klump, Hannes
    University of Klinikum Essen, Germany.
    Krause, Daniela
    Georg Speyer Haus Institute Tumorbiol and Expt Therapy, Germany.
    Kremer Hovinga, Johanna
    University of Bern, Switzerland.
    Lacaud, Georges
    University of Manchester, England.
    Lacroix-Desmazes, Sebastien
    Institute National Sante and Rech Med, France.
    Landman-Parker, Judith
    Hop Armand Trousseau, France.
    LeGouill, Steven
    University of Nantes, France.
    Lenz, Georg
    University of Klinikum Munster, Germany.
    von Lilienfeld-Toal, Marie
    University of Klinikum Jena, Germany.
    von Lindern, Marieke
    Sanquin Research, Netherlands.
    Lopez-Guillermo, Armando
    Hospital Clin Barcelona, Spain.
    Lopriore, Enrico
    Leiden University of Medical Centre, Netherlands.
    Lozano, Miguel
    University of Barcelona, Spain.
    MacIntyre, Elizabeth
    University of Paris 05, France.
    Makris, Michael
    Royal Hallamshire Hospital, England; University of Sheffield, England.
    Mannhalter, Christine
    Medical University of Wien, Austria.
    Martens, Joost
    Radboud University of Nijmegen, Netherlands.
    Mathas, Stephan
    Charite University of Medical Berlin, Germany.
    Matzdorff, Axel
    Caritasclin Saarbrucken, Germany.
    Medvinsky, Alexander
    University of Edinburgh, Scotland.
    Menendez, Pablo
    University of Barcelona, Spain.
    Rita Migliaccio, Anna
    Mt Sinai Hospital, NY 10029 USA.
    Miharada, Kenichi
    Lund University, Sweden.
    Mikulska, Malgorzata
    University of Genoa, Italy.
    Minard, Veronique
    Institute Gustave Roussy, France.
    Montalban, Carlos
    MD Anderson Cancer Centre Madrid, Spain.
    de Montalembert, Mariane
    Necker Enfants Malades University Hospital, France.
    Montserrat, Emili
    Hospital Clin Barcelona, Spain.
    Morange, Pierre-Emmanuel
    Aix Marseille University, France.
    Mountford, Joanne
    University of Glasgow, Scotland.
    Muckenthaler, Martina
    University of Klinikum Heidelberg, Germany.
    Mueller-Tidow, Carsten
    University of Klinikum Halle, Germany.
    Mumford, Andrew
    University of Bristol, England.
    Nadel, Bertrand
    University of Mediterranee, France.
    Navarro, Jose-Tomas
    Institute Catala Oncol, Spain.
    el Nemer, Wassim
    INSERM, France.
    Noizat-Pirenne, France
    Etab Francais Sang, France.
    OMahony, Brian
    European Haemophilia Consortium, Belgium.
    Oldenburg, Johannes
    University of Klinikum Bonn, Germany.
    Olsson, Martin
    Lund University, Sweden.
    Oostendorp, Robert
    Technical University of Munich, Germany.
    Palumbo, Antonio
    University of Turin, Italy.
    Passamonti, Francesco
    Osp Circolo and Fdn Macchi, Italy.
    Patient, Roger
    University of Oxford, England.
    Peffault de Latour, Regis
    NIH, MD 20892 USA.
    Pflumio, Francoise
    Institute Rech Radiobiol Cellulaire and Molecular IRCM, France.
    Pierelli, Luca
    University of Roma La Sapienza, Italy.
    Piga, Antonio
    University of Turin, Italy.
    Pollard, Debra
    Royal Free Hospital, England.
    Raaijmakers, Marc
    Erasmus MC, Netherlands.
    Radford, John
    University of Manchester, England.
    Rambach, Ralf
    DLH, Germany.
    Koneti Rao, A.
    Temple University of School Med, PA USA.
    Raslova, Hana
    University of Paris Sud, France.
    Rebulla, Paolo
    Ops Maggiore, Italy.
    Rees, David
    Kings Coll Hospital London, England.
    Ribrag, Vincent
    Institute Gustave Roussy, France.
    Rijneveld, Anita
    Erasmus MC, Netherlands.
    Rinalducci, Sara
    University of Tuscia, Italy.
    Robak, Tadeusz
    University of Medical Lodz, Poland.
    Roberts, Irene
    University of Oxford, England.
    Rodrigues, Charlene
    Great North Childrens Hospital, England.
    Rosendaal, Frits
    Leids University, Netherlands.
    Rosenwald, Andreas
    University of Wurzburg, Germany.
    Rule, Simon
    Derriford Hospital, England.
    Russo, Roberta
    University of Naples Federico II, Italy.
    Saglio, Guiseppe
    University of Turin, Italy.
    Sanchez, Mayka
    IJC, Spain.
    Scharf, Ruediger E.
    University of Dusseldorf, Germany.
    Schlenke, Peter
    Medical University of Graz, Austria.
    Semple, John
    St Michaels Hospital, Canada.
    Sierra, Jorge
    Hospital Santa Creu I Sant Pau, Spain.
    So-Osman, Cynthia
    Sanquin Research, Netherlands.
    Manuel Soria, Jose
    Hospital Santa Creu I Sant Pau, Spain.
    Stamatopoulos, Kostas
    Institute Appl Bioscience, Greece.
    Stegmayr, Bernd
    Umeå University, Sweden.
    Stunnenberg, Henk
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Swinkels, Dorine
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Pedro Taborda Barata, Joao
    University of Lisbon, Portugal.
    Taghon, Tom
    University of Ghent, Belgium.
    Taher, Ali
    Amer University of Beirut Medical Centre, Lebanon.
    Terpos, Evangelos
    National and Kapodistrian University of Athes, Greece.
    Daniel Tissot, Jean
    University of Lausanne, Switzerland.
    Touw, Ivo
    Erasmus MC, Netherlands.
    Toye, Ash
    University of Bristol, England.
    Trappe, Ralf
    Charite University of Medical Berlin, Germany.
    Unal, Sule
    Hacettepe University, Turkey.
    Vaulont, Sophie
    Institute Cochin, France.
    Viprakasit, Vip
    Mahidol University, Thailand.
    Vitolo, Umberto
    University of Turin, Italy.
    van Wijk, Richard
    University of Medical Centre Utrecht, Netherlands.
    Wojtowicz, Agnieszka
    CHU Vaudois, Switzerland.
    Zeerleder, Sacha
    Sanquin Research, Netherlands.
    Zieger, Barbara
    University of Klinikum Freiburg, Germany.
    The European Hematology Association Roadmap for European Hematology Research: a consensus document2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. 115-208Article in journal (Refereed)
    Abstract [en]

    The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

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  • 28.
    Engvall, Marie
    et al.
    Uppsala Univ, Sweden.
    Karlsson, Ylva
    Uppsala Univ, Sweden.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Jörnegren, Åsa
    Örebro Univ Hosp, Sweden.
    Mathot, Lucy
    Uppsala Univ, Sweden.
    Pandzic, Tatjana
    Uppsala Univ, Sweden.
    Palle, Josefine
    Uppsala Univ, Sweden.
    Ljungström, Viktor
    Uppsala Univ, Sweden.
    Cavelier, Lucia
    Uppsala Univ, Sweden.
    Lindberg, Eva Hellström
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Baliakas, Panagiotis
    Uppsala Univ, Sweden.
    Familial platelet disorder due to germline exonic deletions in RUNX1: a diagnostic challenge with distinct alterations of the transcript isoform equilibrium2022In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 63, no 10, p. 2311-2320Article in journal (Refereed)
    Abstract [en]

    Germline pathogenic variants in RUNX1 are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in RUNX1 accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline RUNX1 intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with LINC00160 resulting in a change in the 3 sequence of RUNX1. Expression analysis of the transcript isoform demonstrated altered RUNX1a/b/c ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic RUNX1 deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.

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  • 29.
    Eriksson, Mia
    et al.
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Peña-Martínez, Pablo
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Ramakrishnan, Ramprasad
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Chapellier, Marion
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Högberg, Carl
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Glowacki, Gabriella
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Orsmark-Pietras, Christina
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Velasco-Hernández, Talía
    Department of Molecular Hematology, Lund University, Lund, Sweden.
    Lazarevic, Vladimir Lj
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Juliusson, Gunnar
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Mulloy, James C
    Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
    Richter, Johan
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Fioretos, Thoas
    Department of Clinical Genetics, Lund, Sweden.
    Ebert, Benjamin L.
    Division of Hematology, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA.
    Järås, Marcus
    Department of Clinical Genetics, Lund, Sweden.
    Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NF?B-dependent differentiation of AML cells2017In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 1, no 23, p. 2046-2057Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NF?B-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NF?B, thus revealing a new putative strategy for therapeutically targeting AML cells.

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  • 30.
    Flygt, Hjalmar
    et al.
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Sandin, Fredrik
    Reg Canc Ctr, Sweden.
    Dahlen, Torsten
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lubking, Anna
    Skane Univ Hosp, Sweden.
    Markevarn, Berit
    Univ Hosp, Sweden.
    Myhr-Eriksson, Kristina
    Sunderby Hosp, Sweden.
    Olsson, Karin
    Reg Canc Ctr, Sweden.
    Olsson-Stromberg, Ulla
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Sjalander, Anders
    Umea Univ, Sweden.
    Soderlund, Stina
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Hoglund, Martin
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Successful tyrosine kinase inhibitor discontinuation outside clinical trials - data from the population-based Swedish chronic myeloid leukaemia registry2021In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 193, no 5, p. 915-921Article in journal (Refereed)
    Abstract [en]

    Clinical trials show that tyrosine kinase inhibitor (TKI) treatment can be discontinued in selected patients with chronic myeloid leukaemia (CML). Although updated CML guidelines support such procedure in clinical routine, data on TKI stopping outside clinical trials are limited. In this retrospective study utilising the Swedish CML registry, we examined TKI discontinuation in a population-based setting. Out of 584 patients diagnosed with chronic-phase CML (CML-CP) in 2007-2012, 548 had evaluable information on TKI discontinuation. With a median follow-up of nine years from diagnosis, 128 (23%) discontinued TKI therapy (&gt;= 1 month) due to achieving a DMR (deep molecular response) and 107 (20%) due to other causes (adverse events, allogeneic stem cell transplant, pregnancy, etc). Among those stopping in DMR, 49% re-initiated TKI treatment (median time to restart 4 center dot 8 months). In all, 38 patients stopped TKI within a clinical study and 90 outside a study. After 24 months 41 center dot 1% of patients discontinuing outside a study had re-initiated TKI treatment. TKI treatment duration pre-stop was longer and proportion treated with second-generation TKI slightly higher outside studies, conceivably affecting the clinical outcome. In summary we show that TKI discontinuation in CML in clinical practice is common and feasible and may be just as successful as when performed within a clinical trial.

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  • 31.
    Flygt, Hjalmar
    et al.
    Univ Uppsala Hosp, Sweden; Univ Uppsala Hosp, Sweden.
    Söderlund, Stina
    Univ Uppsala Hosp, Sweden; Univ Uppsala Hosp, Sweden.
    Stentoft, Jesper
    Aarhus Univ Hosp, Denmark.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Koskenvesa, Perttu
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Mustjoki, Satu
    Univ Helsinki, Finland; Univ Helsinki, Finland; Univ Helsinki, Finland; Univ Helsinki, Finland.
    Majeed, Waleed
    Stavanger Univ Hosp, Norway.
    Lubking, Anna
    Skane Univ Hosp, Sweden.
    Dreimane, Arta
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Markevarn, Berit
    Umea Univ Hosp, Sweden.
    Stenke, Leif
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Myhr Eriksson, Kristina
    Sunderby Hosp, Sweden.
    Gjertsen, Bjorn Tore
    Haukeland Hosp, Norway.
    Gedde-Dahl, Tobias
    Natl Hosp Norway, Norway.
    Dimitrijevic, Andreja
    Odense Univ Hosp, Denmark.
    Udby, Lene
    Zealand Univ Hosp, Denmark.
    Olsson-Strömberg, Ulla
    Univ Uppsala Hosp, Sweden; Univ Uppsala Hosp, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hosp Trondheim, Norway; Norwegian Univ Sci & Technol, Norway.
    Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study2021In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 107, no 6, p. 617-623Article in journal (Refereed)
    Abstract [en]

    Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-alpha in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-alpha (PegIFN-alpha) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 mu g/wk of PegIFN-alpha was added and increased to 25 mu g/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-alpha to DAS shows good long-term efficacy without increased toxicity.

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  • 32.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Fomichov, Victoria
    Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Juliusson, G.
    Lund University, Sweden; Lund University, Sweden.
    Börjeson, Sussanne
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health.
    Frequent and long-term follow-up of health-related quality of life following allogeneic haematopoietic stem cell transplantation2015In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 24, no 6, p. 898-910Article in journal (Refereed)
    Abstract [en]

    Health-related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n=18) or reduced intensity conditioning (RIC, n=76). HRQL was assessed with the EORTC QLQ C-30 during the inpatient period as well as during the following 3years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1year for HRQL to return to the baseline level. The only function that improved significantly 3years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease experienced reduced HRQL. These results provide a clinically useful overview of patients HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow-ups during the first year after HSCT to improve preventive or supportive interventions.

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  • 33.
    Gonzalez, Javier Martin
    et al.
    Univ Copenhagen, Denmark.
    Baudet, Aurelie
    Lund Univ, Sweden.
    Abelechian, Sahar
    Univ Copenhagen, Denmark.
    Bonderup, Kasper
    Univ Copenhagen, Denmark.
    dAltri, Teresa
    Univ Copenhagen, Denmark.
    Porse, Bo
    Univ Copenhagen, Denmark.
    Brakebusch, Cord
    Univ Copenhagen, Denmark.
    Juliusson, Gunnar
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Lund Univ, Sweden.
    A new genetic tool to improve immune-compromised mouse models: Derivation and CRISPR/Cas9-mediated targeting of NRG embryonic stem cell lines2018In: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 56, no 9, article id e23238Article in journal (Refereed)
    Abstract [en]

    Development of human hematopoietic stem cells and differentiation of embryonic stem (ES) cells/induced pluripotent stem (iPS) cells to hematopoietic stem cells are poorly understood. NOD (Non-obese diabetic)-derived mouse strains, such as NSG (NOD-Scid-il2Rg) or NRG (NOD-Rag1-il2Rg), are the best available models for studying the function of fetal and adult human hematopoietic cells as well as ES/iPS cell-derived hematopoietic stem cells. Unfortunately, engraftment of human hematopoietic stem cells is very variable in these models. Introduction of additional permissive mutations into these complex genetic backgrounds of the NRG/NSG mice by natural breeding is a very demanding task in terms of time and resources. Specifically, since the genetic elements defining the NSG/NRG phenotypes have not yet been fully characterized, intense backcrossing is required to ensure transmission of the full phenotype. Here we describe the derivation of embryonic stem cell (ESC) lines from NRG pre-implantation embryos generated by in vitro fertilization followed by the CRISPR/CAS9 targeting of the Gata-2 locus. After injection into morula stage embryos, cells from three tested lines gave rise to chimeric adult mice showing high contribution of the ESCs (70%-100%), assessed by coat color. Moreover, these lines have been successfully targeted using Cas9/CRISPR technology, and the mutant cells have been shown to remain germ line competent. Therefore, these new NRG ESC lines combined with genome editing nucleases bring a powerful genetic tool that facilitates the generation of new NOD-based mouse models with the aim to improve the existing xenograft models.

  • 34.
    Gunnarsson, N.
    et al.
    Umeå University, Sweden.
    Hoglund, M.
    University Hospital, Uppsala, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Sandin, F.
    Regional Cancer Centre, Uppsala, Sweden.
    Bjorkholm, M.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lambe, M.
    Regional Cancer Centre, Uppsala, Sweden; Karolinska Institute, Sweden.
    Markevarn, B.
    University Hospital, Umeå, Sweden.
    Olsson-Stromberg, U.
    University Hospital, Uppsala, Sweden; University Hospital, Uppsala, Sweden.
    Wadenvik, H.
    Sahlgrens University Hospital, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Sjalander, A.
    Umeå University, Sweden.
    No increased prevalence of malignancies among first-degree relatives of 800 patients with chronic myeloid leukemia: a population-based study in Sweden2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 8, p. 1825-1827Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 35.
    Gunnarsson, N.
    et al.
    Umeå University, Sweden.
    Höglund, M.
    University of Uppsala Hospital, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Wallberg-Jonsson, S.
    Umeå University, Sweden.
    Sandin, F.
    Regional Cancer Centre, Sweden.
    Björkholm, M.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lambe, M.
    Regional Cancer Centre, Sweden; Karolinska Institute, Sweden.
    Markevarn, B.
    University of Umeå Hospital, Sweden.
    Olsson-Stromberg, U.
    University of Uppsala Hospital, Sweden.
    Wadenvik, H.
    Sahlgrens University Hospital, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Sjalander, A.
    Umeå University, Sweden.
    Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 7, p. 1562-1567Article in journal (Refereed)
    Abstract [en]

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

  • 36.
    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, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    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 era2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 5, p. 683-688Article in journal (Refereed)
    Abstract [en]

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

  • 37.
    Hagglund, Hans
    et al.
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Yavuz, Akif Selim
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Dreimane, Arta
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Malm, Claes
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Sundin, Anders
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Sander, Birgitta
    Karolinska Inst, Sweden.
    Nilsson, Gunnar
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Graft-versus-mastocytosis effect after donor lymphocyte infusion: Proof of principle2021In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 106, no 2, p. 290-293Article in journal (Refereed)
    Abstract [en]

    Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patients report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect.

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  • 38.
    Hayden, Patrick J.
    et al.
    St James Hosp, Ireland.
    Iacobelli, Simona
    Tor Vergata Univ Rome, Italy.
    Antonio Perez-Simon, Jose
    Hosp Univ Virgen Rocio, Spain; Univ Seville, Spain.
    van Biezen, Anja
    Leiden EBMT Data Off, Netherlands.
    Minnema, Monique
    Univ Med Ctr Utrecht, Netherlands.
    Niittyvuopio, Riitta
    HUCH Comprehens Canc Ctr, Finland.
    Schoenland, Stefan
    Heidelberg Univ, Germany.
    Meijer, Ellen
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Blaise, Didier
    Marseille Inst Paoli Calmettes, France.
    Milpied, Noel
    CHU Bordeaux, France.
    Marquez-Malaver, Francisco J.
    Hosp Univ Virgen Rocio, Spain; Univ Seville, Spain.
    Veelken, Joan Hendrik
    Leiden Univ, Netherlands.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, France.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    NGuyen, Stephanie
    Hop La Pitie Salpetriere, France.
    Niederwieser, Dietger
    Univ Hosp Leipzig, Germany.
    Hunault-Berger, Mathilde
    CHRU Angers, France.
    Bourhis, Jean Henri
    Gustave Roussy Inst Cancerol, France.
    Passweg, Jakob
    Univ Hosp Basel, Switzerland.
    Bermudez, Arancha
    FEA Serv Hematol, Spain.
    Chalandon, Yves
    Hop Univ Geneve, Switzerland; Univ Geneva, Switzerland.
    Yakoub-Agha, Ibrahim
    Hop Claude Huriez, France.
    Garderet, Laurent
    Hosp St Antoine, France.
    Kroeger, Nicolaus
    Univ Hosp Eppendorf, Germany.
    Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWPIn: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609Article in journal (Refereed)
    Abstract [en]

    Objectives The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. Methods A retrospective analysis of the EBMT database (1991-2012) was performed. Results A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P amp;lt; .001) but not after 2002 (HR = 1.2, P = .276). Conclusion From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

  • 39.
    Hellström Lindberg, Eva
    et al.
    Karolinska institutet, Sverige; Karolinska universitetssjukhuset, Sverige.
    Cavelier, Lucia
    Uppsala universitet och Akademiska sjukhuset, Uppsala, Sverige.
    Cammenga, Jörg
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Andersson, Per-Ola
    Göteborgs universitet, Sverige; Södra Älvsborgs sjukhus, Borås, Sverige.
    Fioretos, Thoas
    Lunds universitet, Sverige; Skånes universitetsjukhus, Sverige.
    Rosenquist, Richard
    Karolinska institutet, Sverige; Karolinska universitetssjukhuset, Sverige.
    Precisionsmedicin standard vid flera hematologiska sjukdomar: Genpanelsekvensering viktig för diagnos och riktad behandling [Precision diagnostics and therapy in hematological malignancies]2021In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 118Article, review/survey (Refereed)
    Abstract [en]

    Precision diagnostics and therapy have been implemented rather early in clinical hematology due to the easy accessibility of blood and bone marrow, allowing not only for consecutive genetic analysis at diagnosis, remission and relapse, but also for culturing these cells and testing new drugs in vitro. One contributing factor has also been the relatively low number of »driver« mutations in hematologic malignancies and that some of them are gain of function mutations that are relatively easy to target by drugs. Examples of this development are ABL1-, JAK2-, and FLT3-inhibitors for the treatment of chronic myeloid leukemia, myeloproliferative neoplasms, and acute myeloid leukemia, respectively. More recently, gene panel sequencing has been introduced in clinical routine to identify genetic alterations with diagnostic, prognostic and predictive impact, and more sensitive techniques to monitor minimal residual disease are emerging. Whole genome and transcriptome sequencing are currently evaluated as the next diagnostic tool. Finally, a large number of targeted therapies are currently under development and/or undergoing clinical trials.

  • 40.
    Hjorth-Hansen, H.
    et al.
    St Olavs Hospital, Norway; Norwegian University of Science and Technology NTNU, Norway.
    Stentoft, J.
    Aarhus University Hospital, Denmark.
    Richter, J.
    Skåne University Hospital, Sweden.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Hoeglund, M.
    University of Uppsala Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Gjertsen, B. T.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Gruber, F. X.
    University Hospital North Norway, Norway.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Eriksson, K. M.
    Sunderbysjukhuset, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Lubking, A.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Vestergaard, H.
    Odense University Hospital, Denmark.
    Udby, L.
    Roskilde Hospital, Denmark.
    Bjerrum, O. W.
    University of Copenhagen Hospital, Denmark.
    Persson, I.
    Uppsala University, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden; University of Helsinki, Finland.
    Olsson-Stromberg, U.
    University of Uppsala Hospital, Sweden.
    Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 9, p. 1853-1860Article in journal (Refereed)
    Abstract [en]

    Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.

  • 41.
    Hjorth-Hansen, Henrik
    et al.
    St Olavs Hospital, Norway; Norwegian University of Science and Technology NTNU, Norway.
    Stenke, Leif
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Söderlund, Stina
    University of Uppsala Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Medical and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Ehrencrona, Hans
    Skåne University Hospital, Sweden.
    Gedde-Dahl, Tobias
    University of Oslo, Norway.
    Tore Gjertsen, Bjorn
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Hoglund, Martin
    University of Uppsala Hospital, Sweden.
    Koskenvesa, Perttu
    University of Helsinki, Finland; University of Helsinki, Finland.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Majeed, Waleed
    Stavanger University Hospital, Norway.
    Markevarn, Berit
    Umeå University Hospital, Sweden.
    Ohm, Lotta
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital, Sweden.
    Remes, Kari
    Turku University, Finland.
    Suominen, Merja
    Kanta Hame Central Hospital, Finland.
    Simonsson, Bengt
    University of Uppsala Hospital, Sweden.
    Porkka, Kimmo
    University of Helsinki, Finland; University of Helsinki, Finland.
    Mustjoki, Satu
    University of Helsinki, Finland; University of Helsinki, Finland.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006)2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 3, p. 243-250Article in journal (Refereed)
    Abstract [en]

    We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100mg QD or imatinib 400mg QD and report outcome as an intention-to-treat analysis with 36months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3months in 36% vs. 8% (P=0.02), at 12months in 81% vs. 46% (P=0.02) and at 18months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6months onwards, reaching 61% vs. 21% (Pless than0.05) at 36months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.

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  • 42.
    Hulegardh, Erik
    et al.
    Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Nilsson, Christer
    Karolinska University Hospital, Sweden.
    Lazarevic, Vladimir
    Swedish Acute Myeloid Leukemia Grp; Skåne University Hospital, Sweden; Skåne University Hospital, Sweden; Lund University, Sweden.
    Garelius, Hege
    Swedish Acute Myeloid Leukemia Grp; Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Antunovic, Petar
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Swedish Acute Myeloid Leukemia Grp.
    Rangert Derolf, Asa
    Swedish Acute Myeloid Leukemia Grp; Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Mollgard, Lars
    Swedish Acute Myeloid Leukemia Grp; Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Uggla, Bertil
    Swedish Acute Myeloid Leukemia Grp; Örebro University Hospital, Sweden.
    Wennstrom, Lovisa
    Swedish Acute Myeloid Leukemia Grp; Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Wahlin, Anders
    Swedish Acute Myeloid Leukemia Grp; Umeå University, Sweden; Norrland University Hospital, Sweden.
    Hoglund, Martin
    Swedish Acute Myeloid Leukemia Grp; Academic Hospital, Sweden; Academic Hospital, Sweden.
    Juliusson, Gunnar
    Skåne University Hospital, Sweden; Skåne University Hospital, Sweden; Lund University, Sweden;Swedish Acute Myeloid Leukemia Grp.
    Stockelberg, Dick
    Swedish Acute Myeloid Leukemia Grp; Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    Lehmann, Soren
    Swedish Acute Myeloid Leukemia Grp; Karolinska University Hospital, Sweden.
    Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: A report from the Swedish Acute Leukemia Registry2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 3, p. 208-214Article in journal (Refereed)
    Abstract [en]

    Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients.

  • 43.
    Hultcrantz, M.
    et al.
    Karolinska Inst, Sweden; Mem Sloan Kettering Canc Ctr, NY 10021 USA.
    Landtblom, A. Ravn
    Stockholm South Hosp, Sweden; Karolinska Inst, Sweden.
    Andreasson, B.
    NU Hosp Grp, Sweden.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Dickman, P. W.
    Karolinska Inst, Sweden.
    Kristinsson, S. Y.
    Univ Iceland, Iceland; Landspitali Natl Univ Hosp, Iceland.
    Bjorkholm, M.
    Karolinska Inst, Sweden.
    Andersson, T. M-L
    Karolinska Inst, Sweden.
    Incidence of myeloproliferative neoplasms - trends by subgroup and age in a population-based study in Sweden2020In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 287, no 4, p. 448-454Article in journal (Refereed)
    Abstract [en]

    Background The reported incidence of Philadelphia-negative myeloproliferative neoplasms (MPNs) differs substantially between previous reports, likely due to true regional differences in incidence and/or variations in the quality and coverage of the cancer registers. Objective We therefore assessed MPN incidence in Sweden during recent years using prospectively collected information captured in Swedish health registers. Methods Patients with MPNs were identified through the Swedish Cancer Register and Swedish Blood Cancer Register between 2000 and 2014. Information on the Swedish population was obtained from the Human Mortality Database. Crude and age-standardized incidence rates of MPNs with 95% confidence intervals (CIs) were calculated. Results A total of 6281 MPN cases were reported to the Swedish Cancer Register and Swedish Blood Cancer Register during 2000-2014. The age-standardized, to the Swedish population in 2000, incidence for all MPNs was 4.45 (95% confidence interval [CI] 4.34-4.56)/100 000 person-years. The age-standardized incidence for polycythemia vera was 1.48 (1.42-1.54), for essential thrombocythemia 1.60 (1.53-1.66) and for primary myelofibrosis 0.52 (0.48-0.56)/100 000 person-years, respectively. The incidence rate of MPNs was substantially higher in the older compared to the younger age groups. The incidence increased during the study period, likely to do better reporting and increasing age of the general population. Conclusion The reported MPN incidences in our study, which were in the higher interval of previously published studies, are likely more accurate compared to previous reports due to the population-based setting and high level of coverage in the Swedish Cancer and Blood Cancer Registers.

  • 44.
    Huuhtanen, Jani
    et al.
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland; Aalto Univ, Finland.
    Ilander, Mette
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Yadav, Bhagwan
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Dufva, Olli M. J.
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Lähteenmäki, Hanna
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Kasanen, Tiina
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Klievink, Jay
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Olsson-Strömberg, Ulla
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Stentoft, Jesper
    Aarhus Univ Hosp, Denmark.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Koskenvesa, Perttu
    Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Höglund, Martin
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Söderlund, Stina
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Dreimane, Arta
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Porkka, Kimmo
    Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland; ICAN Digital Precis Canc Med Flagship, Finland.
    Gedde-Dahl, Tobias
    Oslo Univ Hosp, Norway.
    Gjertsen, Björn T.
    Univ Bergen, Norway; Univ Bergen, Norway.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Myhr-Eriksson, Kristina
    Sunderby Hosp, Sweden.
    Markevärn, Berit
    Umea Univ Hosp, Sweden.
    Lübking, Anna
    Skane Univ Hosp, Sweden.
    Dimitrijevic, Andreja
    Odense Univ Hosp, Denmark.
    Udby, Lene
    Zealand Univ Hosp, Denmark.
    Bjerrum, Ole Weis
    Univ Hosp Copenhagen, Denmark.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Norway; Norwegian Univ Sci & Technol NTNU, Norway.
    Mustjoki, Satu
    Univ Helsinki, Finland; Univ Helsinki, Finland; Hematol Res Unit Helsinki, Finland; Helsinki Univ Hosp, Finland; ICAN Digital Precis Canc Med Flagship, Finland.
    IFN-a with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia2022In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 132, no 17, article id e152585Article in journal (Refereed)
    Abstract [en]

    In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.

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  • 45.
    Håkansson, Irene
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lundin, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Askmark, Håkan
    University of Uppsala Hospital, Sweden.
    Pirskanen, Ritva
    Karolinska Institute, Sweden.
    Carlson, Kristina
    University Hospital, Sweden.
    Piehl, Fredrik
    Karolinska Institute, Sweden.
    Hägglund, Hans
    University Hospital, Sweden.
    Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis - a case report2017In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 27, no 1, p. 90-93Article in journal (Refereed)
    Abstract [en]

    Myasthenia gravis (MG) is an autoimmune disease, with immune reactivity against the post-synaptic endplate of the neuromuscular junction. Apart from symptomatic treatment with choline esterase blockers, many patients also require immunomodulatory treatment. Despite existing treatment options, some patients are treatment refractory. We describe a patient with severe MG refractory to corticosteroids, four oral immunosuppressants, cyclophosphamide, rituximab and bortezomib who was treated with autologous haematopoietic stem cell transplantation. Two years after this, the patient has significantly improved in objective tests and in quality of life and leads an active life. Diplopia is her only remaining symptom and she is completely free of medication for MG. We believe that autologous haematopoietic stem cell transplantation can be an effective therapeutic option for carefully selected cases of severe, treatment refractory MG. (c) 2016 Elsevier B.V. All rights reserved.

  • 46.
    Ilander, M.
    et al.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Olsson-Stromberg, U.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden.
    Schlums, H.
    Karolinska Institute, Sweden.
    Guilhot, J.
    CHU Poitiers, France.
    Bruck, O.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Lahteenmaki, H.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Kasanen, T.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Soderlund, S.
    Uppsala University Hospital, Sweden.
    Hoglund, M.
    Uppsala University Hospital, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Sjalander, A.
    Umeå University, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Lubking, A.
    Skåne University Hospital, Sweden.
    Holm, E.
    Skåne University Hospital, Sweden.
    Bjoreman, M.
    University Hospital, Sweden.
    Lehmann, S.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden; Karolinska University Hospital, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden.
    Ohm, L.
    Karolinska University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Majeed, W.
    Stavanger University Hospital, Norway.
    Ehrencrona, H.
    Skåne University Hospital, Sweden.
    Koskela, S.
    Finnish Red Cross Blood Serv, Finland.
    Saussele, S.
    Heidelberg University, Germany.
    Mahon, F-X
    University of Bordeaux Segalen, France.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Hjorth-Hansen, H.
    St Olavs University Hospital, Norway.
    Bryceson, Y. T.
    Karolinska Institute, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, p. 1108-1116Article in journal (Refereed)
    Abstract [en]

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

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  • 47.
    Ingelsson, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Loitto, Vesa-Matti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Spyrou, Giannis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed)
    Abstract [en]

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

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  • 48.
    Jaako, P.
    et al.
    Lund University, Sweden.
    Ugale, A.
    Lund University, Sweden.
    Wahlestedt, M.
    Lund University, Sweden.
    Velasco-Hernandez, T.
    Lund University, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindström, M. S.
    Karolinska Institute, Sweden.
    Bryder, D.
    Lund University, Sweden.
    Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 1, p. 213-221Article in journal (Refereed)
    Abstract [en]

    Mutations resulting in constitutive activation of signaling pathways that regulate ribosome biogenesis are among the most common genetic events in acute myeloid leukemia (AML). However, whether ribosome biogenesis presents as a therapeutic target to treat AML remains unexplored. Perturbations in ribosome biogenesis trigger the 5S ribonucleoprotein particle (RNP)-Mdm2-p53 ribosomal stress pathway, and induction of this pathway has been shown to have therapeutic efficacy in Myc-driven lymphoma. In the current study we address the physiological and therapeutic role of the 5S RNP-Mdm2-p53 pathway in AML. By utilizing mice that have defective ribosome biogenesis due to downregulation of ribosomal protein S19 (Rps19), we demonstrate that induction of the 5S RNP-Mdm2-p53 pathway significantly delays the initiation of AML. However, even a severe Rps19 deficiency that normally results in acute bone marrow failure has no consistent efficacy on already established disease. Finally, by using mice that harbor a mutation in the Mdm2 gene disrupting its binding to 5S RNP, we show that loss of the 5S RNP-Mdm2-p53 pathway is dispensable for development of AML. Our study suggests that induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway holds limited potential as a single-agent therapy in the treatment of AML.

  • 49.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Lund, Johan
    Karolinska Institute, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Gruber, Astrid
    Karolinska Institute, Sweden.
    Alici, Evren
    Karolinska Institute, Sweden.
    Lauri, Birgitta
    Sunderby Hospital, Sweden.
    Blimark, Cecilie
    Sahlgrens University Hospital, Sweden.
    Mellqvist, Ulf-Henrik
    South Elvsborg Hospital, Sweden.
    Swedin, Agneta
    Skåne University Hospital, Sweden.
    Forsberg, Karin
    Norrland University Hospital, Sweden.
    Carlsson, Conny
    Hallands Hospital, Sweden.
    Hardling, Mats
    Uddevalla Central Hospital, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Nahi, Hareth
    Karolinska Institute, Sweden.
    Pharmacogenetic study of the impact of ABCB1 single-nucleotide polymorphisms on lenalidomide treatment outcomes in patients with multiple myeloma: results from a phase IV observational study and subsequent phase II clinical trial2018In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 81, no 1, p. 183-193Article in journal (Refereed)
    Abstract [en]

    Purpose Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs). Methods Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G amp;gt; A (Ser400Asn, rs2229109), 1236C amp;gt; T (silent, rs1128503), 2677G amp;gt; T/A (Ala893Ser, rs2032582), and 3435C amp;gt; T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated. Results No significant associations were found between genotype and either best response rates or hematological AEs, and 1236C amp;gt; T, 2677G amp;gt; T or 3435C amp;gt; T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics. Conclusions Our findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G amp;gt; A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.

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  • 50.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Chaireti, Roza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine. Karolinska University Hospital, Sweden.
    Lund, Johan
    Huddinge University Hospital, Sweden.
    Nahi, Hareth
    Huddinge University Hospital, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Green, Henrik
    National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 4, p. 355-362Article in journal (Refereed)
    Abstract [en]

    BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), 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. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (Pless than0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, Pless than0.001) and reduced OS (2 and 16months, respectively, Pless than0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) 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.

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