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  • 51.
    Robin, Marie
    et al.
    Hop St Louis, France.
    Chevret, Sylvie
    Univ Paris 07, France.
    Koster, Linda
    EBMT Data Off Leiden, Netherlands.
    Wolschke, Christine
    Univ Hosp Eppendorf, Germany.
    Yakoub-Agha, Ibrahim
    Univ Lille, France.
    Bourhis, Jean Henri
    Univ Paris Saclay, France.
    Chevallier, Patrice
    CHU Nantes, France.
    Cornelissen, Jan J.
    Erasmus Univ, Netherlands.
    Remenyi, Peter
    St Istvan and St Laszlo Hosp, Hungary.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Poire, Xavier
    Clin Univ St Luc, Belgium.
    Craddock, Charles
    Queen Elizabeth Hosp, England.
    Socie, Gerard
    Hop St Louis, France.
    Itala-Remes, Maija
    HUCH Comprehens Canc Ctr, Finland.
    Schouten, Harry C.
    Univ Hosp Maastricht, Netherlands.
    Marchand, Tony
    CHU Rennes, France.
    Passweg, Jakob
    Univ Hosp, Switzerland.
    Blaise, Didier
    Aix Marseille Univ, France.
    Damaj, Gandhi
    CHU Caen, France.
    Ozkurt, Zubeyde Nur
    Gazi Univ, Turkey.
    Zuckerman, Tsila
    Rambam Med Ctr, Israel.
    Cluzeau, Thomas
    Univ Cote Azur, France.
    Labussiere-Wallet, Helene
    Ctr Hosp Lyon Sud, France.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    McLornan, Donal
    Kings Coll London, England.
    Chalandon, Yves
    Univ Geneva, Switzerland; Univ Geneva, Switzerland.
    Kroger, Nicolaus
    EBMT Data Off Leiden, Netherlands.
    Antilymphocyte globulin for matched sibling donor transplantation in patients with myelofibrosis2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 6, p. 1230-1236Article in journal (Refereed)
    Abstract [en]

    The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n= 287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P= 0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versushost disease without increasing the risk of relapse.

  • 52.
    Rosengren, S.
    et al.
    University of Uppsala Hospital, Sweden.
    Mellqvist, U-H
    South Elvsborg Hospital, Sweden.
    Nahi, H.
    Karolinska Institute, Sweden.
    Forsberg, K.
    Norrlands University Hospital, Sweden.
    Lenhoff, S.
    Skåne University Hospital, Sweden.
    Strömberg, O.
    Karolinska Institute, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Linder, O.
    Örebro University Hospital, Sweden.
    Carlson, K.
    University of Uppsala Hospital, Sweden.
    Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation in Sweden, long-term results from all patients treated in 1994-20092016In: BONE MARROW TRANSPLANTATION, ISSN 0268-3369, Vol. 51, no 12, p. 1569-1572Article in journal (Refereed)
    Abstract [en]

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

  • 53.
    Schober, Sebastian J
    et al.
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.
    von Luettichau, Irene
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.
    Wawer, Angela
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.
    Steinhauser, Maximilian
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.
    Salat, Christoph
    Medical Center for Hematology and Oncology Munich MVZ, 80639 Munich, Germany.
    Schwinger, Wolfgang
    Department of Pediatrics, Medical University of Graz, A-8036 Graz, Austria.
    Ussowicz, Marek
    Department of Pediatric Oncology, Hematology and Bone Marrow Transplantation, Wroclaw Medical University, 50-368 Wroclaw, Poland.
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Region Östergötland, Center for Business support and Development, Regional Cancer Center.
    Castagna, Luca
    Department of Oncology and Hematology, IRCCS Humanitas Cancer Center, Humanitas University, 20089, Milan, Italy.
    Kolb, Hans-Jochem
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.
    Burdach, Stefan E G
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany; CCC München-Comprehensive Cancer Center, DKTK German Cancer Consortium Munich, 80336 Munich, Germany.
    Thiel, Uwe
    Department of Pediatrics and Childrens Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.
    Donor lymphocyte infusions in adolescents and young adults for control of advanced pediatric sarcoma2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 32, p. 22741-22748Article in journal (Refereed)
    Abstract [en]

    Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a graft-versus-tumor effect in pediatric sarcoma patients. Here, we describe general feasibility, toxicity and efficacy of DLI after allo-SCT.

  • 54.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala University, Sweden.
    Bergquist, Jonas
    Uppsala University, Sweden.
    Aluthgedara, Warunika
    Uppsala University, Sweden.
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Sweden.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Svedberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Söderlund, Stina
    Uppsala University, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Johnsson, Anders
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Aagesen, Jesper
    Ryhov County Hospital, Sweden.
    Alsenhed, Jonas
    Vastervik Hosp, Dept Internal Med, Västervik, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia2016In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed)
    Abstract [en]

    Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

  • 55.
    Staffas, A.
    et al.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Arabanian, L. S.
    University of Gothenburg, Sweden.
    Wei, S. Y.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Jansson, A.
    Sahlgrens University Hospital, Sweden.
    Stahlman, S.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Johansson, P.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Fogelstrand, L.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Kuchenbauer, F.
    University Hospital Ulm, Germany.
    Palmqvist, L.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice2017In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, no 11, p. 1516-1524Article in journal (Refereed)
    Abstract [en]

    HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL -/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL -/- mice as rapid as in wild-type mice. However, FL -/- mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3 dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1.

  • 56.
    Söderlund, Stina
    et al.
    Uppsala University, Sweden; University of Uppsala Hospital, Sweden.
    Dahlen, Torsten
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Sandin, Fredrik
    Regional Cancer Centre Uppsala Örebro, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala University, Sweden; University of Uppsala Hospital, Sweden.
    Creignou, Maria
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Lubking, Anna
    Skåne University Hospital, Sweden.
    Markevarn, Berit
    Umeå University Hospital, Sweden.
    Sjalander, Anders
    Umeå University, Sweden.
    Wadenvik, Hans
    Sahlgrens University Hospital, Sweden.
    Stenke, Leif
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Hoglund, Martin
    Uppsala University, Sweden; University of Uppsala Hospital, Sweden.
    Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era - a report from the Swedish CML register2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 57-66Article in journal (Refereed)
    Abstract [en]

    Objectives: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment. Methods: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment. Results: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively. Conclusion: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

  • 57.
    Terpos, Evangelos
    et al.
    Univ Athens, Greece.
    Katodritou, Eirini
    Theagen Canc Ctr, Greece.
    de la Rubia, Javier
    Univ Catolica Valencia, Spain.
    Hungria, Vania
    Theagen Canc Ctr, Greece; Ctr Estudos Hemoctr Santa Casa Sao Paolo, Brazil.
    Hulin, Cyrille
    CHU Bordeaux, France.
    Roussou, Maria
    Univ Athens, Greece.
    Delforge, Michel
    Univ Hosp Leuven, Belgium.
    Bries, Greet
    AZ Turnhout, Belgium.
    Stoppa, Anne-Marie
    Inst Paoli Calmettes, France.
    Aagesen, Jesper
    Ryhov Cty Hosp, Sweden.
    Sargin, Deniz
    Istanbul Univ, Turkey.
    Belch, Andrew
    Cross Canc Inst, Canada.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Diels, Joris
    Janssen Res and Dev, Belgium.
    Olie, Robert A.
    Janssen Cilag AG, Switzerland.
    Robinson, Don Jr.
    Janssen Global Serv, NJ USA.
    Spencer, Mike
    Janssen Cilag UK, England.
    Potamianou, Anna
    Janssen Cilag Pharmaceut SACI, Greece.
    van de Velde, Helgi
    Janssen Res and Dev, Belgium; Millennium Pharmaceut Inc, MA USA.
    Dimopoulos, Meletios A.
    Univ Athens, Greece.
    Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 101, no 4, p. 556-565Article in journal (Refereed)
    Abstract [en]

    Objective: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE (R) OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice. Method: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment-free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. Results: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (amp;gt;= partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months median follow-up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. Conclusion: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population.

  • 58.
    Tesi, Bianca
    et al.
    Karolinska University Hospital Huddinge, Sweden; Karolinska Institute, Sweden.
    Davidsson, Josef
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Voss, Matthias
    Karolinska University Hospital Huddinge, Sweden.
    Rahikkala, Elisa
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Holmes, Tim D.
    Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway.
    Chiang, Samuel C. C.
    Karolinska University Hospital Huddinge, Sweden.
    Komulainen-Ebrahim, Jonna
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Gorcenco, Sorina
    Lund University, Sweden.
    Rundberg Nilsson, Alexandra
    Lund University, Sweden.
    Ripperger, Tim
    Hannover Medical Sch, Germany.
    Kokkonen, Hannaleena
    Oulu University Hospital, Finland.
    Bryder, David
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden.
    Henter, Jan-Inge
    Karolinska Institute, Sweden.
    Mottonen, Merja
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Niinimaki, Riitta
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Nilsson, Lars
    Skåne University Hospital, Sweden.
    Pronk, Cornelis Jan
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Puschmann, Andreas
    Lund University, Sweden.
    Qian, Hong
    Karolinska University Hospital Huddinge, Sweden.
    Uusimaa, Johanna
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Moilanen, Jukka
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Tedgard, Ulf
    Skåne University Hospital, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Lund University, Sweden.
    Bryceson, Yenan T.
    Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway.
    Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 16, p. 2266-2279Article in journal (Refereed)
    Abstract [en]

    Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cis SAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 1 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-alpha or IFN-gamma induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with 27/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.

  • 59.
    Tunströmer, Kjersti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Quantification of Platelet Contractile Movements during Thrombus Formation2018In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 118, no 09, p. 1600-1611Article in journal (Refereed)
    Abstract [en]

    Imaging methods based on time-lapse microscopy are important tools for studying the dynamic events that shape thrombus formation upon vascular injury. However, there is a lack of methods to translate the vast amount of visual data generated in such experiments into quantitative variables describing platelet movements that can be subjected to systematic analysis. In this study, we developed experimental and computational protocols allowing for a detailed mathematical analysis of platelet movements within a developing thrombus. We used a flow chamber-based model of thrombosis wherein a collagen strip was used to initiate platelet adhesion and activation. Combining the use of a platelet staining protocol, designed to enable identification of individual platelets, and image processing, we tracked the movements of a large number of individual platelets during thrombus formation and consolidation. These data were then processed to generate aggregate measures describing the heterogeneous movements of platelets in different areas of the thrombus and at different time points. Applying this model and its potential, to a comparative analysis on a panel of platelet inhibitors, we found that total platelet intra-thrombus movements are only slightly reduced by blocking the interactions between glycoproteins IIb/IIIa and Ib and their ligands or by inhibiting thromboxane synthesis or P2Y12 signalling. In contrast, whereas 30 to 40% of the platelets movements (for the CD42a-labelled platelets) and 20% (for the pro-coagulant platelets), within a thrombus, are contractile, i.e., towards the centre of the thrombus, this contractile component is almost totally abolished in the presence of agents inhibiting these pathways.

  • 60.
    Tynngård, Nahreen
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regional Board, Research and Development Unit.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Trinks, Marie
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Berlin, Gösta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Storage-induced change in platelet transfusion response evaluated by serial transfusions from one donor to one patient2019In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 59, no 2, p. 723-728Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Storage of platelet concentrates (PCs) results in storage lesions with possible detrimental effects on platelet recovery after transfusion, which might affect their ability to prevent or arrest bleeding. The aim of this study was to compare the quality of PCs stored for 1 to 3 or 5 to 7 days by assessing the corrected count increment (CCI) after transfusion. To isolate the effects of storage time, we studied serial transfusions of PCs obtained from one donor and one donation, and transfused to one single recipient after storage for 1 to 3 days and 5 to 7 days.

    STUDY DESIGN AND METHODS

    Platelets were obtained from one donor by apheresis, divided into two units (>240 × 109platelets/unit) and stored for 1 to 3 and 5 to 7 days, respectively, before transfusion. The PCs were transfused on normal indications to patients undergoing treatment at the hematology ward. Platelet count was measured before and after transfusion.

    RESULTS

    Thirty patients concluded the study according to the protocol. The mean storage time was 2.4 ± 0.7 and 5.7 ± 0.8 days for platelets transfused on Days 1 to 3 and 5 to 7, respectively. Storage for 5 to 7 days decreased the 1‐hour transfusion response as compared to platelets stored 1 to 3 days, from a CCI of 17 ± 7 to 13 ± 5. Despite this decrease, 86% of the 5 to 7 days stored PCs resulted in a CCI above the cutoff value for a successful transfusion of 7.5, which was not significantly different to PCs stored for 1 to 3 days.

    CONCLUSION

    Storage of PCs for 5 to 7 days only slightly altered the transfusion response.

  • 61.
    Vaht, Krista
    et al.
    Sahlgrens Univ Hosp, Sweden; Gothenburg Univ, Sweden.
    Goransson, Magnus
    Sahlgrens Univ Hosp, Sweden.
    Carlson, Kristina
    Uppsala Univ Hosp, Sweden.
    Isaksson, Cecilia
    Univ Hosp, Sweden.
    Lenhoff, Stig
    Lund Univ, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Uggla, Bertil
    Orebro Univ, Sweden.
    Winiarski, Jacek
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Ljungman, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Andersson, Per-Ola
    Gothenburg Univ, Sweden; Sodra Alvsborg Hosp Boras, Sweden.
    Brune, Mats
    Sahlgrens Univ Hosp, Sweden; Gothenburg Univ, Sweden.
    High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study2019In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 25, no 10, p. 1970-1974Article in journal (Refereed)
    Abstract [en]

    Allogeneic stem cell transplantation (SCT) as primary treatment for aplastic anemia (AA) is being increasingly used. Yet, age, stem cell source, and donor type are important outcome factors. We have recently performed a nationwide cohort study of all patients with AA in Sweden diagnosed from 2000 to 2011 and now present outcome data on SCT patients. In total, 68 patients underwent SCT, and 63% of them had failed immunosuppressive therapy. We found that, with a median follow-up of 109 months (range, 35 to 192 months), 5-year overall survival (OS) for all patients was 86.8%, whereas graft-versus-host disease-free, relapse/rejection-free survival (GRFS) at 5 years was 69.1%. There was no survival impact regarding the donor type or stem cell source. Patients aged amp;gt;= 40 years had a higher transplant-related mortality (29.4% versus 7.8%; P= .023), which translated into a lower 5-year OS: 70.6% versus 92.2% (A=.022) and a trend of lower GRFS (52.9% versus 74.5%; P = .069). In conclusion, we found in this real-world setting that both OS and GRFS were high, but SCT for patients with AA aged amp;gt;= 40 years is problematic, and clinical trials addressing this issue are warranted. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

  • 62.
    Vaht, Krista
    et al.
    Sahlgrens University Hospital, Sweden; Gothenburg University, Sweden.
    Goransson, Magnus
    Sahlgrens University Hospital, Sweden.
    Carlson, Kristina
    Uppsala University Hospital, Sweden.
    Isaksson, Cecilia
    University Hospital, Sweden.
    Lenhoff, Stig
    Lund University, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Uggla, Bertil
    Örebro University, Sweden.
    Winiarski, Jacek
    Karolinska University Hospital, Sweden.
    Ljungman, Per
    Karolinska University Hospital Huddinge, Sweden.
    Brune, Mats
    Sahlgrens University Hospital, Sweden; Gothenburg University, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hospital Boras, Sweden; Gothenburg University, Sweden.
    Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000-20112017In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no 10, p. 1683-1690Article in journal (Refereed)
    Abstract [en]

    A plastic anemia is a rare life-threatening disease. However, since the introduction of immunosuppressive therapy and allogeneic stem cell transplantation, the outcome has improved considerably, and the 5-year survival is reported to be 70-80% in selected patient cohorts. Yet, contemporary population-based data on incidence and survival are lacking. We performed a national retrospective study to determine the incidence, treatment, and survival of patients with aplastic anemia diagnosed in Sweden from 2000-2011. Patients were included via the National Patient Registry, and diagnosed according to the Camitta criteria. In total, 257 confirmed cases were identified, with an overall incidence of 2.35 (95% CI: 2.06-2.64) cases per million inhabitants per year. Median age was 60 years (range: 2-92), and median follow up was 76 (0-193) months. Primary treatments included immunosuppressive therapy (63%), allogenic stem cell transplantation (10%), or single-agent cyclosporine/no specific therapy (27%). The 5-year survival was 90.7% in patients aged 0-18 years, 90.5% in patients aged 19-39 years, 70.7% in patients aged 40-59 years, and 38.1% in patients aged amp;gt;= 60 years. Multivariate analysis showed that age (both 40-59 and amp;gt;= 60 age groups), very severe aplastic anemia and single-agent cyclosporine/no specific therapy were independent risk factors for inferior survival. In conclusion, younger aplastic anemia patients experience a very good long-term survival, while that of patients amp;gt;= 60 years in particular remains poor. Apparently, the challenge today is to improve the management of older aplastic anemia patients, and prospective studies to address this medical need are warranted.

  • 63.
    Vaht, Krista
    et al.
    Sahlgrens Univ Hosp, Sweden; Gothenburg Univ, Sweden.
    Goransson, Magnus
    Sahlgrens Univ Hosp, Sweden.
    Carlson, Kristina
    Uppsala Univ Hosp, Sweden.
    Isaksson, Cecilia
    Univ Hosp, Sweden.
    Lenhoff, Stig
    Lund Univ, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Uggla, Bertil
    Orebro Univ, Sweden.
    Winiarski, Jacek
    Karolinska Inst, Sweden; CLINTEC, Sweden.
    Ljungman, Per
    Karolinska Inst, Sweden.
    Brune, Mats
    Sahlgrens Univ Hosp, Sweden; Gothenburg Univ, Sweden.
    Andersson, Per-Ola
    Gothenburg Univ, Sweden; Sodra Alvsborg Hosp Boras, Sweden.
    Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia A Swedish nationwide cohort study2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 6, p. 613-620Article in journal (Refereed)
    Abstract [en]

    ObjectivesAntithymocyte globulin (ATG)-based immunosuppression remains a cornerstone in aplastic anaemia (AA) treatment. However, most ATG studies are not population-based and knowledge about real-world results concerning response and outcome could offer important information for treating physicians. MethodsWe have recently performed a nationwide retrospective cohort study on all AA patients diagnosed in Sweden in 2000-2011 and now present treatment and outcome data on patients receiving first-line ATG. In total, 158 patients showed a 47.0% response rate which was similar in all age groups (range 41.5%-51.7%) with no difference regarding ATG formulation. The response was significantly associated with severity gradeespecially at time of treatment initiation: very severe (VSAA) 22.7%; severe (SAA) 54.5% (Pamp;lt;.001); and non-severe 88.5% (Pamp;lt;.001). A logistic regression-based predictive model indicated that VSAA patients with an absolute reticulocyte count amp;lt;25x10(9)/L had only a 19% probability of response. In a multivariable analysis, age and VSAA at the time of treatment were the independent factors for inferior survival. ConclusionsReal-world VSAA patients respond poorly to ATG which indicates the need for a different treatment approach. Our findings suggest that age alone should not be a discriminating factor for administering ATG treatment.

  • 64.
    Velasco-Hernandez, T.
    et al.
    Lund University, Sweden.
    Tornero, D.
    Skånes University Hospital, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Lund University, Sweden; Skånes University Hospital, Sweden.
    Loss of HIF-1 alpha accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 12, p. 2366-2374Article in journal (Refereed)
    Abstract [en]

    Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1 alpha loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1 alpha leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1 alpha loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1 alpha deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1 alpha. Some of our findings are in contrary to what has been previously described for the role of HIF-1 alpha in other myeloid hematologic malignancies and question the potential of HIF-1 alpha as a therapeutic target.

  • 65.
    Velasco-Hernandez, Talia
    et al.
    Lund University, Sweden; Lund University, Sweden.
    Sawen, Petter
    Lund University, Sweden.
    Bryder, David
    Lund University, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Lund University, Sweden; Lund University, Sweden; Skånes University Hospital, Sweden.
    Potential Pitfalls of the Mx1-Cre System: Implications for Experimental Modeling of Normal and Malignant Hematopoiesis2016In: Stem Cell Reports, ISSN 2213-6711, Vol. 7, no 1, p. 21-28Article in journal (Refereed)
    Abstract [en]

    Conditional knockout mice are commonly used to study the function of specific genes in hematopoiesis. Different promoters that drive Cre expression have been utilized, with the interferon-inducible Mx1-Cre still being the most commonly used "deleter strain in experimental hematology. However, different pitfalls associated with this system could lead to misinterpretation in functional studies. We present here two of these issues related to the use of Mx1-Cre: first, a high spontaneous recombination rate when applying commonly used techniques in experimental hematology, and second, undesired short-term consequences of the use of polyinosinic: polycytidylic acid, including changes in cellular phenotypes that, however, resolve within days. Our studies emphasize therefore that proper controls are crucial when modeling gene deletion using the Mx1-Cre transgene.

  • 66.
    Velasco-Hernandez, Talia
    et al.
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Hidalgo, Isabel
    Lund Univ, Sweden.
    Erlandsson, Eva
    Lund Univ, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Bryder, David
    Lund Univ, Sweden; Gothenburg Univ, Sweden.
    Hif-1 alpha Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML2019In: Stem Cell Reports, ISSN 2213-6711, Vol. 12, no 1, p. 112-121Article in journal (Refereed)
    Abstract [en]

    Relapse of acute myeloid leukemia (AML) remains a significant clinical challenge due to limited therapeutic options and poor prognosis. Leukemic stem cells (LSCs) are the cellular units responsible for relapse in AML, and strategies that target LSCs are thus critical. One proposed potential strategy to this end is to break the quiescent state of LSCs, thereby sensitizing LSCs to conventional cytostatics. The hypoxia-inducible factor (HIF) pathway is a main driver of cellular quiescence and a potential therapeutic target, with precedence from both solid cancers and leukemias. Here, we used a conditional knockout Hif-1 alpha mouse model together with a standard chemotherapy regimen to evaluate LSC targeting in AML. Contrary to expectation, our studies revealed that Hif-1 alpha-deleted-leukemias displayed a faster disease progression after chemotherapy. Our studies thereby challenge the general notion of cancer stem cell sensitization by inhibition of the HIF pathway, and warrant caution when applying HIF inhibition in combination with chemotherapy in AML.

  • 67.
    Winqvist, Maria
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Andersson, Per-Ola
    Boras Hosp, Sweden.
    Asklid, Anna
    Karolinska Inst, Sweden.
    Karlsson, Karin
    Lund Univ Hosp, Sweden.
    Karlsson, Claes
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Lauri, Birgitta
    Sunderby Hosp, Sweden.
    Lundin, Jeanette
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Mattsson, Mattias
    Uppsala Univ Hosp, Sweden.
    Norin, Stefan
    Karolinska Inst, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Rosenquist, Richard
    Karolinska Inst, Sweden.
    Spath, Florentin
    Umea Univ, Sweden.
    Hansson, Lotta
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Osterborg, Anders
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 5, p. E208-E210Article in journal (Other academic)
    Abstract [en]

    n/a

  • 68.
    Winqvist, Maria
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Asklid, Anna
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Andersson, P. O.
    South Älvsborg Hospital, Sweden.
    Karlsson, Karin
    Skåne University Hospital, Sweden.
    Karlsson, Claes
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Lauri, Birgitta
    Sunderby Hospital, Sweden.
    Lundin, Jeanette
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Mattsson, Mattias
    University of Uppsala Hospital, Sweden.
    Norin, Stefan
    Karolinska University Hospital, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Hansson, Lotta
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Osterborg, Anders
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 12, p. 1573-1580Article in journal (Refereed)
    Abstract [en]

    Ibrutinib, a Brutons tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine healthcare are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy amp;gt;= 10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richters transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia.

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