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  • 1. Andersen, Mette K.
    et al.
    Autio, Kirsi
    Barbany, Gisela
    Borgstroem, Georg
    Cavelier, Lucia
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johannsson, Johann H.
    Johansson, Bertil
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, nr 2, s. 235-243Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The translocation t(1;19)(q23;p13)/der(19) t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19) t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1.8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 x 10(9)/l, and the female/male ratio was 1.2. The predicted event-free survival (EFS) at 5 and 10 years was 0.79, whereas the predicted overall survival (OS) at 5 and 10 years was 0.85 and 0.82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19) t(1;19) (P = 0.004).

  • 2.
    Andersson, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Enblad, Gunilla
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala.
    Gustavsson, Anita
    Department of Oncology, Skåne University Hospital, Lund University, Lund .
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hagberg, Hans
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala .
    Molin, Daniel
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala .
    Tavelin, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Long term risk of infections in Hodgkin lymphoma long-term survivors2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 154, nr 5, s. 661-663Artikel i tidskrift (Refereegranskat)
  • 3. Bager, Ninna
    et al.
    Juul-Dam, Kristian L
    Sandahl, Julie D
    Abrahamsson, Jonas
    Beverloo, Berna
    de Bont, Eveline S J M
    Ha, Shau-Yin
    Jahnukainen, Kirsi
    Jónsson, Ólafur G
    Kaspers, Gertjan L
    Kovalova, Zhanna
    Lausen, Birgitte
    De Moerloose, Barbara
    Norén-Nyström, Ulrika
    Umeå University Hospital.
    Palle, Josefine
    Saks, Kadri
    Zeller, Bernward
    Kjeldsen, Eigil
    Hasle, Henrik
    Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia: A NOPHO-DBH-AML study2018Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, nr 4, s. 618-628Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.

  • 4. Berggren, Daniel Moreno
    et al.
    Folkvaljon, Yasin
    Engvall, Marie
    Sundberg, Johan
    Lambe, Mats
    Antunovic, Petar
    Garelius, Hege
    Lorenz, Fryderyk
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nilsson, Lars
    Rasmussen, Bengt
    Lehmann, Sören
    Hellström-Lindberg, Eva
    Jädersten, Martin
    Ejerblad, Elisabeth
    Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register2018Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, nr 5, s. 614-627Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). 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.

  • 5. Brandefors, Lena
    et al.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindh, Jack
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lundqvist, Kristina
    Kimby, Eva
    Prognostic factors and primary treatment for Waldenstrom macroglobulinemia: a Swedish Lymphoma Registry study2018Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, nr 4, s. 564-577Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present a nationwide prospective Swedish registry-based study of Waldenstrom macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11.5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86.1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin <= 115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin <= 115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.

  • 6.
    Brandefors, Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sander, Birgitta
    Department of Laboratory Medicine, Department of Pathology, Karolinska Institute, Stockholm, Sweden.
    Lundqvist, Kristina
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kimby, Eva
    Department of Haematology, Karolinska Institute, Stockholm, Sweden.
    Clinical characteristic and outcome of lymphoplasmacytic lymphoma of non-Waldenstrom macroglobulinemia type: A Swedish lymphoma registry study2022Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 196, nr 6, s. 1362-1368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lymphoplasmacytic lymphoma (LPL) not fulfilling the WHO diagnostic criteria (2017) for Waldenstrom’s macroglobulinemia (WM) (named non-WM LPL) is a rare disease and only a few systematic studies have been published. Here, we present a population-based study of non-WM LPL focusing on diagnostic difficulties, patient characteristics, and outcome. From 1511 patients included in the Swedish Lymphoma Registry 1 Jan 2000 – 31 Dec 2014 with a diagnosis of WM/LPL, we could confirm the diagnosis of non-WM LP in only 33 patients. The median age at diagnosis was 69 years. A paraprotein was found in most (IgG in 54%, IgA in 15%) and 12% of the cases were non-secretory. Compared with the WM patients, the non-WM LPL patients were younger, had more adverse prognostic factors such as elevated LDH, anaemia, and lymphocytosis at diagnosis. In addition, the non-WM LPL patients more often were symptomatic and received treatment at diagnosis. The overall survival (OS) did not significantly differ between the non-WM LPL and WM groups (P = 0.247), with a median survival time of 71 and 96 months, respectively. To conclude, we found differences in clinical features between WM and non-WM LPL, but no difference in survival.

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  • 7. Derolf, Asa
    et al.
    Juliusson, Gunnar
    Benson, Lina
    Floisand, Yngvar
    Lazarevic, Vladimir
    Antunovic, Petar
    Mollgard, Lars
    Lehmann, Soren
    Uggla, Bertil
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hoglund, Martin
    Deneberg, Stefan
    Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor2020Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, nr 1, s. 187-191Artikel i tidskrift (Refereegranskat)
  • 8.
    Edling, Charlotte E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Pedersen, Malin
    Experimental Clinical Chemistry, Lund University, Malmö University Hospital, Malmö.
    Carlsson, Leif
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Rönnstrand, Lars
    Experimental Clinical Chemistry, Lund University, Malmö University Hospital, Malmö.
    Palmer, Ruth H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå centrum för molekylär patogenes (UCMP).
    Hallberg, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haematopoietic progenitor cells utilise conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation2007Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 136, nr 2, s. 260-268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Receptor tyrosine kinase (RTK) c-Kit signalling is crucial for the proliferation, survival and differentiation of haematopoietic stem cells (HSCs). To further understand the mechanisms underlying these events we explored how the downstream mediators interact. The present study investigated the function of conventional protein kinase Cs (c-PKC) in c-Kit mediated signalling pathways in HSC-like cell lines. This analysis supported earlier findings, that steel factor (SF) activates c-PKC, extracellular signal-regulated kinase (Erk) and protein kinase B (PKB). The present results were consistent with an important role of c-PKC in the positive activation of Erk and for proliferation. Further, it was observed that c-PKC negatively regulated PKB activity upon SF stimulation, indicating that c-PKC acts as a suppressor of c-Kit signalling. Finally, these observations were extended to show that c-PKC mediated the phosphorylation of the endogenous c-Kit receptor on serine 746, resulting in decreased overall tyrosine phosphorylation of c-Kit upon SF stimulation. This report showed that this specific feedback mechanism of c-PKC mediated phosphorylation of the c-Kit receptor has consequences for both proliferation and survival of HSC-like cell lines.

  • 9.
    Enblom, Anneli
    et al.
    Department of Internal Medicine, Sunderby hospital, Luleå, Sweden.
    Girodon, Francois
    Service d'hématologie Biologique, CHU de Dijon, Dijon, France.
    Bak, Marie
    Department of Hematology, Roskilde hospital, Roskilde, Denmark.
    Hersby, Ditte
    Department of Hematology, Roskilde hospital, Roskilde, Denmark.
    Jooste, Valérie
    Registre Bourguignon des Cancers Digestifs, INSERM UMR 866 - CHU Dijon Bourgogne - Université Bourgogne Franche-Comté, Dijon, France.
    Hasselbalch, Hans
    Department of Hematology, Roskilde hospital, Roskilde, Denmark.
    Johansson, Peter
    Hematology and Coagulation section, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Andreasson, Björn
    NU hospital group, Uddevalla Hospital, Uddevalla, Sweden.
    A retrospective analysis of the impact of treatments and blood counts on survival and the risk of vascular events during the course of polycythaemia vera2017Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 177, nr 5, s. 800-805Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vascular and non-vascular complications are common in patients with polycythaemia vera. This retrospective study of 217 patients with polycythaemia vera aimed to determine whether blood counts with respect to different treatments influenced the complication rate and survival. We found that 78 (36%) patients suffered from at least one complication during follow-up. Older age and elevated lactate dehydrogenase at diagnosis were found to be risk factors for vascular complications. When the vascular complication occurred, 41% of the patients with a complication had elevated white blood cells (WBC) compared with 20% of patients without a complication (P = 0·042). Patients treated with hydroxycarbamide (HC; also termed hydroxyurea) experienced significantly fewer vascular complications (11%) than patients treated with phlebotomy only (27%) (P = 0·013). We also found a survival advantage for patients treated with HC, when adjusted for age, gender and time period of diagnosis (Hazard ratio for phlebotomy-treated patients compared to HC-treated patients at 5 years was 2·42, 95% confidence interval 1·03-5·72, P = 0·043). Concerning survival and vascular complications, HC-treated patients who needed at least one phlebotomy per year were not significantly different from HC-treated patients with a low phlebotomy requirement. We conclude that complementary phlebotomy in HC-treated patients in order to maintain the haematocrit, is safe.

  • 10.
    Enblom-Larsson, Anneli
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Renlund, Henrik
    Uppsala Clinical Research Centre Uppsala University, Uppsala, Sweden.
    Andréasson, Björn
    NU Hospital Group, Uddevalla, Sweden.
    Holmberg, Henrik
    Umeå universitet, Medicinska fakulteten, Institutionen för epidemiologi och global hälsa.
    Liljeholm, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Thromboembolic events, major bleeding and mortality in essential thrombocythaemia and polycythaemia vera: a matched nationwide population-based study2024Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thromboembolic events and bleeding are known complications in essential thrombocythaemia (ET) and polycythaemia vera (PV). Using multiple Swedish health care registers, we assessed the rate of arterial and venous events, major bleeding, all-cause stroke and all-cause mortality in ET and PV compared to matched controls. For each patient with ET (n = 3141) and PV (n = 2604), five matched controls were randomly selected. In total, 327 and 405 arterial or venous events were seen in the group of ET and PV patients respectively. Compared to corresponding controls, the rate of venous thromboembolism, major bleeding and all-cause mortality per 100 treatment years was significantly increased among both ET (0.63, 0.79 and 3.70) and PV patients (0.94, 1.20 and 4.80). The PV patients also displayed a significantly higher rate of arterial events and all-cause stroke compared to controls. When dividing the cohort into age groups, we found a significantly higher rate of arterial and venous events in all age groups of PV patients, and the rate of all-cause mortality was significantly higher in both ET and PV patients in all ages above the age of 50. This study confirms that PV and ET are diseases truly marked by thromboembolic complications and bleeding.

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  • 11.
    Etekal, Tommy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Koehn, Kelly
    Division of Hematological Malignancies and Cellular Therapeutics, University of Kansas, KS, Lawrence, United States.
    Sborov, Douglas W.
    Division of Hematology and Hematological Malignancies, University of Utah, UT, Salt Lake City, United States.
    McClune, Brian
    Division of Hematology and Hematological Malignancies, University of Utah, UT, Salt Lake City, United States.
    Prasad, Vinay
    Division of Hematology/Oncology, University of California San Francisco, CA, San Francisco, United States.
    Haslam, Alyson
    Department of Epidemiology/Biostatistics, University of California San Francisco, CA, San Francisco, United States.
    Berger, Katherine
    Patient Advocate, University of Hartford, CT, West Hartford, United States.
    Booth, Christopher
    Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, ON, Kingston, Canada.
    Al Hadidi, Samer
    Myeloma Institute, The University of Arkansas for Medical Sciences, AR, Little Rock, United States.
    Abdallah, Al-Ola
    Division of Hematological Malignancies and Cellular Therapeutics, University of Kansas, KS, Lawrence, United States.
    Goodman, Aaron
    Division of Blood and Marrow Transplantation, University of California San Diego, CA, La Jolla, United States.
    Mohyuddin, Ghulam Rehman
    Division of Hematology and Hematological Malignancies, University of Utah, UT, Salt Lake City, United States.
    Time-to-event surrogate end-points in multiple myeloma randomised trials from 2005 to 2019: a surrogacy analysis2023Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 200, nr 5, s. 587-594Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Use of surrogate end-points such as progression-free survival (PFS) and other time-to-event (TTE) end-points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end-points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co-primary end-point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38–0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30–0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42–0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.

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  • 12.
    Flygt, Hjalmar
    et al.
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Sandin, Fredrik
    Regional Cancer Centre, Uppsala-Örebro, Sweden.
    Dahlén, Torsten
    Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Dremaine, Arta
    Department of Hematology, University Hospital, Linköping, Sweden.
    Lübking, Anna
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Markevärn, Berit
    Department of Hematology, University Hospital, Umeå, Sweden.
    Myhr-Eriksson, Kristina
    Department of Hematology, Sunderby Hospital, Luleå, Sweden.
    Olsson, Karin
    Regional Cancer Centre, Uppsala-Örebro, Sweden.
    Olsson-Strömberg, Ulla
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Söderlund, Stina
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Wennström, Lovisa
    Department of Hematology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Wadenvik, Hans
    Department of Hematology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Stenke, Leif
    Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Höglund, Martin
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Richter, Johan
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Successful tyrosine kinase inhibitor discontinuation outside clinical trials: data from the population-based Swedish chronic myeloid leukaemia registry2021Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 193, nr 5, s. 915-921Artikel i tidskrift (Refereegranskat)
    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 (≥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 4·8 months). In all, 38 patients stopped TKI within a clinical study and 90 outside a study. After 24 months 41·1% 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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  • 13. Grövdal, Michael
    et al.
    Karimi, Mohsen
    Khan, Rasheed
    Aggerholm, Anni
    Antunovic, Petar
    Astermark, Jan
    Bernell, Per
    Engström, Lena-Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kjeldsen, Lars
    Linder, Olle
    Nilsson, Lars
    Olsson, Anna
    Holm, Mette S
    Tangen, Jon M
    Wallvik, Jonas
    Oberg, Gunnar
    Hokland, Peter
    Jacobsen, Sten E
    Porwit, Anna
    Hellström-Lindberg, Eva
    Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy2010Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 150, nr 3, s. 293-302Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.

  • 14.
    Gunnarsson, Niklas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Stenke, Leif
    Höglund, Martin
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Department of Haematology, University Hospital, Umeå.
    Olsson-Strömberg, Ulla
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, nr 5, s. 683-688Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3·7 (range 0-9·9) years, 65 (7·5%) 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 1·52 (95% CI 1·13-1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, 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.

  • 15.
    Hedenus, Michael
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper.
    Adriansson, Magnus
    Watson, David
    Matcham, James
    Rossi, Gregory
    Littlewood, Timothy J
    San Miguel, Jesus
    Kramer, Mark H H
    Schipperus, Martin R
    Juvonen, Eeva
    Taylor, Kerry
    Belch, Andrew
    Altés, Albert
    Martinelli, Giovanni
    Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study2003Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 122, nr 3, s. 394-403Artikel i tidskrift (Refereegranskat)
  • 16.
    Hedenus, Michael
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper.
    Hansen, Sören
    Taylor, Kerry
    Arthur, Chris
    Emmerich, Berthold
    Dewey, Claire
    Watson, David
    Rossi, Gregory
    Österborg, Anders
    Randomized dose-finding study of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies2002Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 119, nr 1, s. 79-86Artikel i tidskrift (Refereegranskat)
  • 17.
    Karlsson, Lene
    et al.
    Department of Pediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Cheuk, Daniel
    Department of Pediatrics and Adolescent Medicine, Hong Kong Children's Hospital and Hong Kong Pediatric Hematology and Oncology Study Group (HKPHOSG), Hong Kong.
    De Moerloose, Barbara
    Department of Pediatric Hematology-Oncology, Ghent University Hospital, Ghent, Belgium.
    Hasle, Henrik
    Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Jahnukainen, Kirsi
    New Children's hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Juul-Dam, Kristian Løvvik
    Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Kaspers, Gertjan
    Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands; Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Amsterdam, Netherlands.
    Kovalova, Zanna
    Department of Paediatric Oncology/Haematology, Children's Clinical University Hospital, Riga, Latvia.
    Lausen, Birgitte
    Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Palle, Josefine
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Pronk, Cornelis Jan
    Childhood Cancer Center, Skåne University Hospital, Lund, Sweden.
    Saks, Kadri
    Department of Paediatrics, SA Tallinna Lastehaigla, Tallinn, Estonia.
    Tierens, Anne
    Department of Pathobiology and Laboratory Medicine, University Health Network, Toronto General Hospital, ON, Toronto, Canada.
    Zeller, Bernward
    Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
    Abrahamsson, Jonas
    Department of Pediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia2023Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 201, nr 4, s. 757-765Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 × 109/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%–52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (= 37) achieved complete remission (CR) with OS 57% (95% CI: 42%–75%) compared to 12% (95% CI: 4%–35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%–66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%–77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.

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  • 18. Karlsson, Lene
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Nyström, Ulrika Noren
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Palle, Josefine
    Tierens, Anne
    Zeller, Bernward
    Abrahamsson, Jonas
    Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia2017Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, nr 4, s. 592-602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y) was 39 +/- 4% for the whole group and 43 +/- 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) +/- anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse >= 1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 +/- 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.

  • 19. Karrman, Kristina
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Andersen, Mette K
    Autio, Kirsi
    Borgström, Georg
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Kerndrup, Gitte
    Johansson, Bertil
    High incidence of the ETV6/RUNX1 fusion gene in paediatric precursor B-cell acute lymphoblastic leukaemias with trisomy 21 as the sole cytogenetic change: a Nordic series of cases diagnosed 1989-2005.2006Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 135, nr 3, s. 352-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Trisomy 21 is common in ETV6/RUNX1-positive acute lymphoblastic leukaemia (ALL); both these aberrations are associated with a favourable outcome. The prognostic impact of +21 as a sole cytogenetic change could be due to a cryptic t(12;21)(p13;q22). The occurrence of ETV6/RUNX1 was determined in 66 childhood ALLs with an acquired +21 and a chromosome number <51. ETV6/RUNX1 was found in 45% of cases and in the majority (10/18; 56%) of ALLs with sole +21. Event-free survival did not differ between the t(12;21)-positive and -negative cases. Thus, the prognostic impact of +21 is not attributable to cryptic ETV6/RUNX1.

  • 20.
    Kuchinskaya, Ekaterina
    et al.
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Heyman, Mats
    Astrid Lindgren’s Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Nordgren, Ann
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Söderhäll, Stefan
    Astrid Lindgren’s Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Wehner, Peder
    Paediatric Oncology Department, University Hospital, Odense, Denmark.
    Vettenranta, Kim
    Paediatric Oncology Department, University Hospital, Tampere, Finland.
    Jonsson, Olafur
    Childrens Hospital, Hringsins, Landspitali, Hringbraut, Reykjavik, Iceland.
    Wesenberg, Finn
    Barneklinikken, Rikshospitalet, Oslo, Norway.
    Sahlén, Sigrid
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Magnus
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Blennow, Elisabeth
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 152, nr 5, s. 615-622Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) - 2000 treatment protocol. Among the patients, 452 were diagnosed with B-cell precursor (BCP)-ALL and 66 with T-ALL. A higher incidence of 9p21 deletions was found in T-ALL (38%) compared to BCP-ALL (15·7%). Homozygous deletions were found in 19·7% of T-ALL and 4·0% of BCP-ALL; hemizygous deletions were found in 18·2% and 11·7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi- or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement.

  • 21. Lagerlöf, Ingemar
    et al.
    Holte, Harald
    Glimelius, Ingrid
    Björkholm, Magnus
    Enblad, Gunilla
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Fluge, Oystein
    Fohlin, Helena
    Fosså, Alexander
    Goldkuhl, Christina
    Gustavsson, Anita
    Johansson, Ann Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Linderoth, Johan
    Nome, Ole
    Palma, Marzia
    Åkesson, Lisa
    Ostenstad, Bjorn
    Raud, Cecilia
    Glimelius, Bengt
    Molin, Daniel
    No excess long-term mortality in stage I-IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy2020Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, nr 5, s. 685-691Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.

  • 22.
    Lahtinen, Atte K.
    et al.
    Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Funke, Miriam
    Centre of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Biology, University Münster, Munster, Germany.
    Krallmann, Claudia
    Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Munster, Germany.
    Wyrwoll, Margot J.
    Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Munster, Germany.
    Jarisch, Andrea
    Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescent Medicine, University Hospital Frankfurt, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
    Yang, Yifan
    NORDFERTIL Research Lab Stockholm, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Bjarnason, Ragnar
    Children's Medical Center, Landspítali University Hospital, Reykjavik, Iceland; Department of Paediatrics, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Romerius, Patrik
    Department of Paediatric Oncology and Haematology, Clinical Sciences, Lund University, Barn-Och Ungdomssjukhuset Lund, Skånes Universitetssjukhus, Lund, Sweden.
    Sundin, Mikael
    Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Section of Paediatric Haematology, Immunology and HCT, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Langenskiöld, Cecilia
    Department of Paediatric Oncology, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Cremers, Jann-Frederik
    Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Munster, Germany.
    Kliesch, Sabine
    Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Munster, Germany.
    Stukenborg, Jan-Bernd
    NORDFERTIL Research Lab Stockholm, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Neuhaus, Nina
    Centre of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Biology, University Münster, Munster, Germany.
    Jahnukainen, Kirsi
    NORDFERTIL Research Lab Stockholm, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Decreased spermatogonial numbers in boys with severe haematological diseases2024Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study examines spermatogonial numbers in testicular samples from 43 prepubertal patients undergoing haematopoietic stem cell transplantation (HSCT). High-dose chemotherapy and/or radiation during HSCT can impact spermatogenesis requiring fertility preservation. Results show that 49% of patients have decreased and 19% severely depleted spermatogonial pool prior to HSCT. Patients with Fanconi anaemia exhibit significantly reduced spermatogonial numbers. Patients with immunodeficiency or aplastic anaemia generally present within the normal range, while results in patients with myelodysplastic syndrome or myeloproliferative neoplasm vary. The study emphasizes the importance of assessing spermatogonial numbers in patients with severe haematological diseases for informed fertility preservation decisions.

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  • 23.
    Li, Aihong
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Goldwasser, Meredith A
    Zhou, Jianbiao
    Armstrong, Scott A
    Wang, Hongjun
    Dalton, Virginia
    Fletcher, Jonathan A
    Sallan, Stephen E
    Silverman, Lewis B
    Gribben, John G
    Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias.2005Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 131, nr 2, s. 185-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Infant acute lymphoblastic leukaemia (ALL) represents a rare but unique subset with poor prognosis. We analysed mixed-lineage leukaemia (MLL) gene rearrangements and the sequences of complete and incomplete immunoglobulin heavy chain gene rearrangements (IGH) in 14 infants (age < or = 12 months at diagnosis) enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. The dynamics of the leukaemic clone were followed during the course of the disease by quantitative real-time polymerase chain reaction of IGH rearrangements. Sixteen sequences were obtained from 13 (93%) of these infants. There was marked over usage of the V(H)6.1 gene segment (64%) in infants compared with older children with ALL (8%), (P < 0.001) and overusage of D(H)6 (P = 0.004) and J(H)1 (P = 0.004). Poor outcome was associated with MLL gene rearrangements rather than any specific V(H)D(H)J(H) gene usage patterns. Levels of minimal residual disease (MRD) at the end of induction appeared to be high in infants with ALL compared with older children, and although the number of infant cases studied was small, there were no differences in MRD levels after induction therapy in infant ALL with or without MLL gene rearrangements (P = 0.41) and quantitative MRD assessment at the early time points may not be predictive of outcome. Novel treatment strategies are required to improve the outcome in this poor prognosis subset of children with ALL.

  • 24. Linderoth, Johan
    et al.
    Edén, Patrik
    Ehinger, Mats
    Valcich, Jeanette
    Jerkeman, Mats
    Bendahl, Pär-Ola
    Berglund, Mattias
    Enblad, Gunilla
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Cavallin-Ståhl, Eva
    Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma2008Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 141, nr 4, s. 423-432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.

  • 25. Liwing, Johan
    et al.
    Uttervall, Katarina
    Lund, Johan
    Aldrin, Anders
    Blimark, Cecilie
    Carlson, Kristina
    Enestig, Jon
    Flogegård, Max
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gruber, Astrid
    Kviele, Helene Haglöf
    Johansson, Peter
    Lauri, Birgitta
    Mellqvist, Ulf-Henrik
    Swedin, Agneta
    Svensson, Magnus
    Näsman, Per
    Alici, Evren
    Gahrton, Gösta
    Aschan, Johan
    Nahi, Hareth
    Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population2014Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 164, nr 5, s. 684-693Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2.8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4.9 years) compared to conventional treatment (2.3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6.9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

  • 26.
    Mauerer, Katja
    et al.
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Zahrieh, David
    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Gorgun, Gullu
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Li, Aihong
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Zhou, Jianbiao
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Ansén, Sascha
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Rassenti, Laura Z
    CLL Research Consortium, University of California San Diego, CA, USA.
    Gribben, John G
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Immunoglobulin gene segment usage, location and immunogenicity in mutated and unmutated chronic lymphocytic leukaemia2005Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 129, nr 4, s. 499-510Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mutational status of the variable region of the immunoglobulin heavy chain gene (IgV(H)) is an important prognostic marker in B-cell chronic lymphocytic leukaemia (B-CLL), with mutated patients having improved outcome. To examine the impact of mutational status on V(H), D(H), and J(H) gene segment location and immunogenicity, we analysed 375 IgH sequences from 356 patients with B-CLL. Although V(H) and D(H) gene usage was different in mutated compared to unmutated patients, there was no impact of gene location on frequency of use or clinical outcome. Surprisingly, somatic mutations did not increase the immunogenicity of the Ig, as assessed by predicted binding affinity of Ig-derived peptides to major histocompatibility Class I and Class II molecules. Even excluding patients using V(H)1-69, cases using the V(H)1 gene family had a poor outcome. Both mutated and unmutated CLL patients demonstrated evidence of antigen selection. The worst outcome was seen in the subset of 14 unmutated patients with similar HCDR3 amino acid sequence using V(H)1-69, D(H)3-3 and J(H)6, suggesting an antigen-driven process modulating the clinical course.

  • 27. Menter, Thomas
    et al.
    Tzankov, Alexandar
    Zucca, Emanuele
    Kimby, Eva
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Sundstrom, Christer
    Beiske, Klaus
    Cogliatti, Sergio
    Banz, Yara
    Cathomas, Gieri
    Katjalainen-Lindsberg, Marja-Liisa
    Grobholz, Rainer
    Mazzucchelli, Luca
    Sander, Birgitta
    Hawle, Hanne
    Hayoz, Stefanie
    Dirnhofer, Stefan
    Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy2020Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 189, nr 4, s. 707-717Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT00544219) of 154 treatment-naive FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid (R) A high ratio of CD4- to CD8-positive T cells (P = 0 center dot 009) and increased amounts of PD1(+) tumour-infiltrating T cells (P = 0 center dot 007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1(+) T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R-2. In the latter group, high amounts of GATA3(+) T helper (Th2) equivalents were associated with better progression-free survival (P < 0 center dot 001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4(+) and, particularly, PD1(+) T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents.

  • 28. Merup, Mats
    et al.
    Lazarevic, Vladimir
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Medicin.
    Nahi, Hareth
    Andreasson, Björn
    Malm, Claes
    Nilsson, Lars
    Brune, Mats
    LeBlanc, Katarina
    Kutti, Jack
    Birgegård, Gunnar
    Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens.2006Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 135, nr 3, s. 367-373Artikel i tidskrift (Refereegranskat)
  • 29. Moreno Berggren, Daniel
    et al.
    Kjellander, Matilda
    Backlund, Ellen
    Engvall, Marie
    Garelius, Hege
    Lorenz, Fryderyk
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nilsson, Lars
    Rasmussen, Bengt
    Lehmann, Sören
    Hellström-Lindberg, Eva
    Jädersten, Martin
    Ungerstedt, Johanna
    Ejerblad, Elisabeth
    Prognostic scoring systems and comorbidities in chronic myelomonocytic leukaemia: a nationwide population-based study2021Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 192, nr 3, s. 474-483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Outcomes in chronic myelomonocytic leukaemia (CMML) are highly variable and may be affected by comorbidity. Therefore, prognostic models and comorbidity indices are important tools to estimate survival and to guide clinicians in individualising treatment. In this nationwide population-based study, we assess comorbidities and for the first time validate comorbidity indices in CMML. We also compare the prognostic power of: the revised International Prognostic Scoring System (IPSS-R), CMML-specific prognostic scoring system (CPSS), MD Anderson Prognostic Scoring System (MDAPS) and Mayo score. In this cohort of 337 patients with CMML, diagnosed between 2009 and 2015, the median overall survival was 21 center dot 3 months. Autoimmune conditions were present in 25% of the patients, with polymyalgia rheumatica and Hashimoto's thyroiditis being most common. Of the tested comorbidity indices: the Charlson Comorbidity Index (CCI), Haematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) and Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI), CCI had the highest C-index (0 center dot 62) and was the only comorbidity index independently associated with survival in multivariable analyses. When comparing the prognostic power of the scoring systems, the CPSS had the highest C-index (0 center dot 69). In conclusion, using 'real-world' data we found that the CCI and CPSS have the best prognostic power and that autoimmune conditions are overrepresented in CMML.

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  • 30.
    Norén-Nyström, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Heyman, Mats
    Frisk, Per
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sundström, Christer
    Porwit, Anna
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Vascular density in childhood acute lymphoblastic leukaemia correlates to biological factors and outcome2009Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 146, nr 5, s. 521-530Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The issue of angiogenesis and its clinical relevance in childhood acute lymphoblastic leukaemia (ALL) is controversial. In the present study, microvessel density (MVD), analysed in 185 diagnostic bone marrow biopsies, was higher in T-cell ALL compared to B-cell precursor (BCP)-ALL (P = 0·013). In the BCP group, cases with t(12;21) were characterized by a low MVD while patients with high-hyperdiploid leukaemia (HeH, 51–61 chromosomes) showed a high MVD compared to other BCP patients (P = 0·001 and 0·002 respectively). There was a correlation between MVD and white blood cell (WBC) count in high-risk BCP patients (P = 0·021). In addition, BCP patients with a high marrow reticulin fibre density and high MVD had an unfavourable outcome compared to the other BCP patients (P = 0·002). The fraction of vessels in which lumina were filled with blasts (blast congested vessel fraction) correlated strongly with WBC count (P < 0·001). These findings indicate that the angiogenic process interacts with other stroma-factors, such as reticulin fibre density, in its effect on outcome, and is coupled to both the ALL genotype and phenotype. One possible implication is that different subtypes of childhood ALL may respond differently to anti-angiogenic drugs as a supplement in first-line treatment.

  • 31. Olsson, Linda
    et al.
    Oefverholm, Ingegerd Ivanov
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Zachariadis, Vasilios
    Nordlund, Jessica
    Sjoegren, Helene
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nordgren, Ann
    Paulsson, Kajsa
    Heyman, Mats
    Barbany, Gisela
    Johansson, Bertil
    The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 20132015Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 170, nr 6, s. 847-858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N=218) or multiplex ligation-dependent probe amplification (N=116) analyses. IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P<0001) and overall survival (pOS; 73% vs. 89%; P=0001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, IKZF1 was the strongest independent factor for relapse and death. IKZF1 was present in 27% of cases with non-informative cytogenetics (BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P<0001). Importantly, neither MRD nor WBC count predicted events in the IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and IKZF1 increased the risk of relapse (75% vs. 30% for cases with only IKZF1; P=0045), indicating that BCP-other ALL with both P2RY8-CRLF2 and IKZF1 constitutes a particularly high-risk group.

  • 32. Olsson, Linda
    et al.
    Zettermark, Sofia
    Biloglav, Andrea
    Castor, Anders
    Behrendtz, Mikael
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Paulsson, Kajsa
    Johansson, Bertil
    The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes2016Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, nr 2, s. 292-301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 33. Olsson-Arvidsson, Linda
    et al.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sjögren, Helene
    Johansson, Bertil
    Frequent false-negative FIP1L1-PDGFRA FISH analyses of bone marrow samples from clonal eosinophilia at diagnosis2020Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, nr 5, s. e64-e79Artikel i tidskrift (Refereegranskat)
  • 34. Palle, J
    et al.
    Frost, B M
    Forestier, E
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Gustafsson, G
    Nygren, P
    Hellebostad, M
    Jonsson, O G
    Kanerva, J
    Schmiegelow, K
    Larsson, R
    Lönnerholm, G
    Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.2005Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 129, nr 2, s. 189-98Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.

  • 35.
    Salomao, Norman
    et al.
    Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France.
    Maslah, Nabih
    Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France.
    Giulianelli, Anouk
    Service d'Hématologie Senior—Hôpital Saint-Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university, Paris, France.
    Drevon, Louis
    Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France; Service d'Hématologie Senior—Hôpital Saint-Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university, Paris, France.
    Aguinaga, Lorea
    Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France; Service d'Hématologie Senior—Hôpital Saint-Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university, Paris, France.
    Gu, Xiaolian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Cassinat, Bruno
    Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France; Service d'Hématologie Senior—Hôpital Saint-Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university, Paris, France.
    Giraudier, Stephane
    Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France; Service d'Hématologie Senior—Hôpital Saint-Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university, Paris, France.
    Fenaux, Pierre
    Service d'Hématologie Senior—Hôpital Saint-Louis—Assistance Publique Hôpitaux de Paris, and Paris Cité university, Paris, France.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Inserm UMRS1131, Institut de Recherche Saint-Louis, Institut de Génétique Moléculaire, Université de Paris-Cité, Hôpital St. Louis, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia2023Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 201, nr 2, s. 234-248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+/CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.

  • 36.
    Sandström, Herbert
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wahlin, A
    Eriksson, M
    Bergström, I
    Serum thymidine kinase in congenital dyserythropoietic anaemia type III.1994Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 87, nr 3, s. 653-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Serum thymidine kinase (TK) was determined in a family with congenital dyserythropoietic anaemia type III (CDA, type III). 20 patients and 10 of their healthy siblings were investigated. Elevated TK was found in all 20 patients (median 56.2 U) but their healthy siblings had normal values (median 2.65 U). We suggest that determination of TK should be used for discrimination between healthy siblings and individuals affected by CDA type III when bone marrow examination is not suitable.

  • 37.
    Sandström, Herbert
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wahlin, A
    Eriksson, M
    Holmgren, G
    Lind, L
    Sandgren, O
    Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III).1997Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 98, nr 4, s. 845-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22. In this paper we report the observation of visual disturbances with macular degeneration and angioid streaks in six patients with CDA III and discuss the apparent association between CDA III, angioid streaks and monoclonal gammopathy. We suggest that this triad forms a previously unreported syndrome.

  • 38. Thörn, Ingrid
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Botling, Johan
    Thuresson, Britt
    Wasslavik, Carina
    Björklund, Elisabet
    Li, Aihong
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lindström-Eriksson, Eleonor
    Malec, Maria
    Grönlund, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Torikka, Kerstin
    Heldrup, Jesper
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Söderhäll, Stefan
    Jacobsson, Stefan
    Olofsson, Tor
    Porwit, Anna
    Lönnerholm, Gudmar
    Rosenquist, Richard
    Sundström, Christer
    Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 152, nr 6, s. 743-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.

  • 39. Tierens, Anne
    et al.
    Bjørklund, Elizabeth
    Siitonen, Sanna
    Marquart, Hanne Vibeke
    Wulff-Juergensen, Gitte
    Pelliniemi, Tarja-Terttu
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Lausen, Birgitte
    Jonsson, Olafur G.
    Palle, Josefine
    Zeller, Bem
    Fogelstrand, Linda
    Abrahamsson, Jonas
    Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study2016Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, nr 4, s. 600-609Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0.1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65.7% and 22.7%, respectively (P < 0.001) and an OS of 77.6% (P = 0.025) and 51.8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57.7% and 11.7%, respectively (P < 0001) and an OS of 786% and 2811%) (P < 0001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR): 5.0; 95% confidence interval (CI): 1.9-133] and OS (HR: 7.0; 95% CI: 20-245). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.

  • 40.
    Wahlin, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Markevärn, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Golovleva, I
    Nilsson, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia.2001Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 115, nr 1, s. 25-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prognostic factors were studied in a series of 211 acute myeloid leukaemia (AML) patients over 60 years of age, treated at a single centre. The patients were allocated into three risk groups based on cytogenetics, occurrence of antecedent haematological disorder and leucocyte count. Only 3% had low-risk features, 39% had intermediate- and 58% had adverse-risk features. Complete remission (CR) was achieved in 43% of all patients. In multivariate analyses, the number of cycles needed to achieve CR and the risk group were significantly associated with the duration of CR. Median survival time for the entire cohort of patients was only 107 d. Advanced age, low induction treatment intensity, treatment during earlier years and adverse-risk group were associated with shorter overall survival times. Risk group classification may help selection of elderly patients with a good chance of benefiting from intensive treatment to actually receive such treatment, while sparing others with a low probability of survival benefit from toxic treatment. Low intensity induction treatment reduces the chance of obtaining complete remission, produces inferior survival times and should consequently be avoided when the aim is to obtain complete remission. In elderly AML patients, introducing age and re-evaluation of intermediate and good prognosis patients regarding response to induction treatment may improve the risk group classification.

  • 41. Zachariadis, Vasilios
    et al.
    Schoumans, Jacqueline
    Barbany, Gisela
    Heyman, Mats
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Johansson, Bertil
    Nordenskjöld, Magnus
    Nordgren, Ann
    Homozygous deletions of CDKN2A are present in all dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukaemias and may be important for leukaemic transformation2012Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 159, nr 4, s. 488-491Artikel i tidskrift (Refereegranskat)
  • 42. Zdebska, E
    et al.
    Gołaszewska, E
    Fabijańska-Mitek, J
    Schachter, H
    Shalev, H
    Tamary, H
    Sandström, Herbert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wahlin, A
    Kościelak, J
    Glycoconjugate abnormalities in patients with congenital dyserythropoietic anaemia type I, II and III.2001Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 114, nr 4, s. 907-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Congenital dyserythropoietic anaemia type II (CDA II) is well known for glycosylation abnormalities affecting erythrocyte membrane glycoconjugates that encompass hypoglycosylation of band 3 glycoprotein and accumulation of glycosphingolipids: lactotriaosylceramides, neolactotriaosylceramide and polyglycosylceramides. These abnormalities were not observed in erythrocytes from patients with CDA of either type I or III. Recently, however, we have described a CDA type I patient in Poland with identical, though less pronounced, glycoconjugate abnormalities to those observed in patients with CDA type II. The abnormalities included partial unglycosylation of O-linked glycosylation sites in glycophorin A. These abnormalities are now reported in three Bedouin patients from Israel with CDA type I. In addition, the erythrocyte membranes of these patients exhibited highly increased globotetraosylceramide content. Glycoconjugate abnormalities were also present in erythrocyte membranes from three patients from Northern Sweden with CDA type III but they almost exclusively affected glycosphingolipids. In erythrocytes of all patients examined including one with CDA type II, polyglycosylceramides were significantly hypoglycosylated although, on a molar basis, their contents in erythrocyte membranes were increased. Thus, glycoconjugate abnormalities of varying intensity occur in erythrocyte membranes from all patients with CDA that were investigated.

  • 43. Zeller, Bernward
    et al.
    Glosli, Heidi
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ha, Shau-Yin
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Hasle, Henrik
    Abrahamsson, Jonas
    Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 x 10(9)/l. The NOPHO experience 1984-20142017Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, nr 3, s. 448-456Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC > 200 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 10(9)/l and 57 (6%) had WBC >= 200 x 10(9)/l. Patients with WBC >= 200 x 10(9)/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 x 10(9)/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.

  • 44.
    Öfverholm, Ingegerd
    et al.
    Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Rezayee, Fatemah
    Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Heyman, Mats
    Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
    Harila, Arja
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Arvidsson, Linda
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Schmiegelow, Kjeld
    Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark; Faculty of Medicine, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Barbany, Gisela
    Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    The prognostic impact of IKZF1 deletions and UKALL genetic classifiers in paediatric B-cell precursor acute lymphoblastic leukaemia treated according to NOPHO 2008 protocols2023Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 202, nr 2, s. 384-392Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigated 390 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients treated according to NOPHO ALL 2008, regarding copy number alterations (CNA) of eight loci associated with adverse prognosis, including IKZF1. The impact on outcome was investigated for each locus individually, combined as CNA profiles and together with cytogenetic information. The presence of IKZF1 deletion or a poor-risk CNA profile was associated with poor outcome in the whole cohort. In the standard-risk group, IKZF1-deleted cases had an inferior probability of relapse-free survival (pRFS) (p ≤ 0.001) and overall survival (pOS) (p ≤ 0.001). Additionally, among B-other patients, IKZF1 deletion correlated with poor pRFS (60% vs. 90%) and pOS (65% vs. 89%). Both IKZF1 deletion and a poor-risk CNA profile were independent factors for relapse and death in multivariable analyses adjusting for known risk factors including measurable residual disease. Our data indicate that BCP-ALL patients with high-risk CNA or IKZF1 deletion have worse prognosis despite otherwise low-risk features. Conversely, patients with both a good CNA and cytogenetic profile had a superior relapse-free (p ≤ 0.001) and overall survival (p ≤ 0.001) in the cohort, across all risk groups. Taken together, our findings highlight the potential of CNA assessment to refine stratification in ALL.

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  • 45. Österroos, Albin
    et al.
    Eriksson, Anna
    Antunovic, Petar
    Cammenga, Jorg
    Deneberg, Stefan
    Lazarevic, Vladimir
    Lorenz, Fryderyk
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Möllgård, Lars
    Derolf, Asa R.
    Uggla, Bertil
    Wennström, Lovisa
    Ölander, Emma
    Hoglund, Martin
    Juliusson, Gunnar
    Lehmann, Sören
    Real-world data on treatment patterns and outcomes of hypomethylating therapy in patients with newly diagnosed acute myeloid leukaemia aged >= 60 years2020Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 189, nr 1, s. e13-e16Artikel i tidskrift (Refereegranskat)
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