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  • 1.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Axdorph, Ulla
    Kalin, Mats
    Björkholm, Magnus
    Clinical experience of granulocyte transfusion in the management of neutropenic patients with haematological malignancies and severe infection2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 2, p. 112-116Article in journal (Refereed)
    Abstract [en]

    Background:

    Prolonged chemotherapy-induced neutropenia is a major risk factor for the development of severe bacterial and fungal infections. Infectious manifestations may progress despite adequate anti-infectious treatment and lead to a very high short-term mortality. Granulocyte transfusion (GT) therapy is often considered. However, its efficacy is not well documented.

    Methods:

    We retrospectively analyzed the clinical characteristics and outcome of a cohort of patients with haematological malignancies receiving GT during neutropenia and severe infection.

    Results:

    A total of 30 patients with a median age of 46 y (range 3-82 y) who had received 1 or more GT were included. Acute leukaemia (80%) and non-Hodgkin lymphoma (17%) predominated as the underlying malignancy. All patients had severe and prolonged (median 16 days) neutropenia. The major indications for GT were persistent fever and clinical deterioration despite broad anti-infectious therapy, in combination with progressive pneumonia (n = 16), neutropenic enterocolitis (n = 6), and soft tissue infections (n = 3). GTs were given for a median of 3 transfusions (range 1-14). The median time to fever defervescence after GT was 14 days (range 6-33 days). For 11 patients, the resolution of fever and all signs of infection could directly be related to GT, and 3 of these patients became long-term survivors. Mortality at 30 days post-GT was 40% and at 6 months post-GT was 72%. GT was well tolerated.

    Conclusions:

    A substantial proportion of severely ill neutropenic patients appeared to benefit from GT. The results further underline the need for well- designed, randomized, prospective trials to determine the efficacy of this intervention in patients with life-threatening infectious complications.

  • 2.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Adjuvanted influenza a (H1N1) 2009 vaccine in patients with hematological diseases: good safety and immunogenicity even in chemotherapy-treated patients2013In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 90, no 5, p. 413-419Article in journal (Refereed)
    Abstract [en]

    Background Patients with hematological malignancies are more susceptible to viral infections including influenza. In 2009, the World Health Organization classified the novel influenza A (H1N1) virus as pandemic. The potential impact of this pandemic for patients with hematological disorders was unknown. Institutional guidelines recommended two doses of AS03-adjuvanted influenza A (H1N1) 2009 pandemic vaccine for these patients. Objectives We aimed to determine the safety, immunogenicity, and clinical efficacy of this vaccine in patients with hematological diseases. Furthermore, we compared the immunological responses to that obtained by the non-adjuvanted trivalent seasonal influenza vaccine (TIV). Methods All included patients received adjuvanted pandemic vaccine and the majority received TIV. Serum for antibody analyses was collected at five time points. Results Thirty-one patients with different hematological diseases were included. After the second vaccine dose, a total of 25 (81%) reached both protective levels of antibodies and seroconversion response. Antibody titers1:40 persisted for 50% of responding patients at 1yr. Seroconversion was observed in 69% of 14 patients who had undergone hematopoietic stem cell transplantation and in all (9/9) patients with myeloma (five with ongoing treatment including high-dose corticosteroids). After vaccination with TIV, seroconversions against the three included strains were detected in 28%, 40%, and 20%. Response to the adjuvanted pandemic vaccine was superior (P<0.009). Conclusions A substantial proportion of patients with hematological malignancies including patients undergoing chemotherapy mounted a good response to the adjuvanted pandemic vaccine. This vaccine had superior immunogenicity as compared to the non-adjuvanted TIV.

  • 3.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Influenza A H1N1 2009 Vaccine in Patients with Hematological Diseases: Good Safety and Immunogenicity Even in Heavily Chemotherapy-Treated Patients2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21, p. 1054-Article in journal (Refereed)
  • 4.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Combination treatment with an erythropoiesis-stimulating agent and intravenous iron alleviates anaemia in patients with hereditary haemorrhagic telangiectasia2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 4, p. 350-353Article in journal (Refereed)
    Abstract [en]

    Background

    Patients with hereditary haemorrhagic telangiectasia (HHT) suffer from recurrent epistaxis and bleeding from gastrointestinal telangiectasias that occur despite otherwise normal haemostasis and result in iron deficiency anaemia with increasing severity. In advanced disease, anaemia may be severe, be irresponsive to iron supplementation, and may lead to red blood cell transfusion dependency.

    Methods

    We conducted a retrospective study at our Centre for Osler's Disease to evaluate the effectiveness of adding an erythropoiesis-stimulating agent (ESA) to intravenous iron supplementation in the management of anaemic HHT patients. Blood values and treatment parameters were collected for nine months before combination therapy (iron supplementation only) and 12 months during combination therapy (iron supplementation plus ESA).

    Results

    Four patients received intravenous iron and an ESA with mean weekly doses of 126 mg and 17,300 units (U), respectively. Mean haemoglobin improved significantly during combination therapy, from 106 g/L to 119 g/L (p < 0.001).

    Conclusion

    Anaemia can be alleviated in patients with HHT who are irresponsive to intravenous iron supplementation, by addition of an ESA. The proposed mechanism behind the iron irresponsiveness is that the anaemia is caused by a combination of recurrent haemorrhage and anaemia of chronic disease.

  • 5.
    Dickinson, M.
    et al.
    Peter MacCallum Canc Ctr, Haematol Dept, Melbourne, Vic, Australia..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Fenaux, P.
    Univ Paris 13, Hop Avicenne, Assistance Publ Hop Paris, Bobigny, France..
    Mittelman, M.
    Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel..
    Verma, A.
    Albert Einstein Coll Med, Dept Med, Div Med Oncol, New York, NY USA..
    Portella, M. S. O.
    Novartis Pharmaceut, Oncol Clin Dev, E Hanover, NJ USA..
    Burgess, P.
    Novartis Pharma AG, Global Drug Dev, Basel, Switzerland..
    Platzbecker, U.
    Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Internal Med 1, Dresden, Germany..
    Eltrombopag In Combination With Azacitidine For First-Line Treatment Of Mds Patients With Thrombocytopenia: The Randomized, Placebo-Controlled, Phase Iii, Support Study2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 55, p. S23-S24Article in journal (Other academic)
  • 6.
    Dickinson, Michael
    et al.
    Peter MacCallum Canc Ctr, Clin Haematol, Melbourne, Vic 3000, Australia;Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Fenaux, Pierre
    Univ Paris XIII, Hop Avicenne, AP HP, Bobigny, France.
    Mittelman, Moshe
    Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel.
    Verma, Amit
    Albert Einstein Coll Med, Dept Med, Div Med Oncol, New York, NY USA.
    Portella, Maria Socorro O.
    Novartis Pharmaceut, E Hanover, NJ USA.
    Burgess, Paul
    Novartis Pharma AG, Basel, Switzerland.
    Ramos, Pedro Marques
    Novartis Pharma AG, Basel, Switzerland.
    Choi, Jeea
    Novartis Pharmaceut, E Hanover, NJ USA.
    Platzbecker, Uwe
    Univ Leipzig, Univ Hosp Leipzig, Med Clin & Policlin 1, Leipzig, Germany.
    Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, no 25, p. 2629-2638Article in journal (Refereed)
    Abstract [en]

    Azacitidine treatment of myelodysplastic syndromes (MDSs) generally exacerbates thrombocytopenia during the first treatment cycles. A Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3, randomized, double-blind, placebo-controlled study, investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk MDS patients with baseline platelets <75 3 10(9)/L were randomized 1: 1 to eltrombopag (start, 200 mg/d [East Asians, 100 mg/d], maximum, 300 mg/d [East Asians, 150 mg/d]) or placebo, plus azacitidine (75 mg/m2 subcutaneously once daily for 7 days every 28 days). The primary end point was the proportion of patients platelet transfusion-free during cycles 1 through 4 of azacitidine therapy. Based on planned interim analyses, an independent data monitoring committee recommended stopping the study prematurely because efficacy outcomes crossed the predefined futility threshold and for safety reasons. At termination, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients met the primary end point. Overall response (International Working Group criteria; complete, marrow, or partial response) occurred in 20% and 35% of eltrombopag and placebo patients, respectively, by investigator assessment. There was no difference in hematologic improvement in any cell lineage between the 2 arms. There was no improvement in overall or progression-free survival. Adverse events with >= 10% occurrence in the eltrombopag vs placebo arm were febrile neutropenia and diarrhea. Compared with azacitidine alone, eltrombopag plus azacitidine worsened platelet recovery, with lower response rates and a trend toward increased progression to acute myeloid leukemia. This trial was registered at www.clinicaltrials.govas# NCT02158936.

  • 7.
    Ekstrand, C.
    et al.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Linder, M.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, H.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Bahmanyar, S.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Increased susceptibility to infections before the diagnosis of immune thrombocytopenia2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 4, p. 807-814Article in journal (Refereed)
    Abstract [en]

    Background Infections after diagnosis of primary chronic immune thrombocytopenia (cITP) have mostly been connected to the immunomodulation treatment. Infections may trigger autoimmune diseases and may be a complication of an already impaired immune system. Objectives To investigate the association of cITP with infection before diagnosis. We also estimated the incidence of cITP based on the new definition by the International ITP Working Group. Methods We identified 1087 adults with primary cITP between 2006 and 2012 using the Swedish Patient Register. Data on infections not already associated with secondary ITP were also retrieved from the register. The standardized incidence ratios (SIRs), using the rates from the general population, and 95% confidence intervals (CIs) were estimated as a measure of relative risk. We used data from the Prescribed Drug Register to estimate SIR for anti-infective treatment. Results The incidence of cITP was 2.30 per 100 000 person-years (95% CI, 2.15-2.45). cITP was associated with an increased risk of serious infections requiring inpatient or outpatient care within 5 years before cITP diagnosis (SIR = 8.74; 95% CI, 7.47-10.18). Higher magnitude SIRs were observed for candidiasis, viral infection at an unspecified site and acute upper respiratory infections. For anti-infective drugs the SIR was 1.37 (1.25-1.50) and the highest SIRs were observed for amoxicillin, macrolides, nitrofurantoin and antivirals. Conclusion Patients with cITP have increased risks of infection and anti-infective treatments before their cITP diagnosis, with a more marked risk for candidiasis and viral infections. The findings indicate that infection is not only related to the immunomodulation treatment but also to the disease itself.

  • 8.
    Ekstrand, Charlotta
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Characteristics of Patients at Initiation of Treatment for Primary Chronic Immune Thrombocytopenia2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 197-197, article id Abstr. 336Article in journal (Refereed)
  • 9.
    Ekstrand, Charlotta
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Increased Anti-infective Treatments Preceding a Diagnosis of Primary Immune Thrombocytopenia2015In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 24, p. 411-412Article in journal (Other academic)
  • 10.
    Ekstrand, Charlotta
    et al.
    Karolinska Inst, Ctr Pharmacoepidemiol, Dept Med, SE-17176 Stockholm, Sweden.
    Linder, Marie
    Karolinska Inst, Ctr Pharmacoepidemiol, Dept Med, SE-17176 Stockholm, Sweden.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Ctr Pharmacoepidemiol, Dept Med, SE-17176 Stockholm, Sweden;Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Bahmanyar, Shahram
    Karolinska Inst, Ctr Pharmacoepidemiol, Dept Med, SE-17176 Stockholm, Sweden.
    Patient characteristics when starting treatment and patterns of treatment in adults with chronic immune thrombocytopenia2019In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 30, no 7, p. 350-356Article in journal (Refereed)
    Abstract [en]

    Asymptomatic patients with primary chronic immune thrombocytopenia (ITP) are not recommended treatment if their platelet counts are above 30 x 10(9)/l. Factors such as age and comorbidities may influence clinical manifestations and should be considered for treatment decisions. The aim of this study was to determine the impact of clinical characteristics for initiation of ITP treatment, and the patterns of ITP treatment given. We performed an observational cohort study in Sweden with information from medical records and National Health Registers. Adults diagnosed with incident primary ITP between years 2009 and 2016 were included. Multinomial logistic regression was used to assess the impact of factors predicting treatment start. Out of 858 patients with chronic ITP from 71 hospitals we identified 585 (68%) with a first ITP treatment. For 537 (92%) corticosteroids were the first choice. The median platelet counts at start of treatment was 12 x 10(9)/l (interquartile range 5-27 x 10(9)/l). The variables predicting treatment start were platelet counts below 20 x 10(9)/l and treatment with antihypertensive drugs. Patients with diabetes were less likely to receive corticosteroids. Severe bleeding occurred in 75 (13%) of the patients. Platelet counts below 20 x 10(9)/l, antihypertensive treatment and bleedings were the strongest predictors of treatment start, diabetes yielded lower odds to start corticosteroid treatment. The majority of the patients had corticosteroids as first treatment while second treatment was diverse. Asymptomatic thrombocytopenia is not considered a reason as such for initiating treatment. In the latter years, splenectomy seemed to occur later in the course of treatment.

  • 11.
    Ekstrand, Charlotta
    et al.
    Karolinska Inst, Med, Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Med, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Med, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Med, Stockholm, Sweden..
    Susceptibility to Infection before Diagnosis of Primary Chronic Immune Thrombocytopenia2015In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 24, p. 519-519Article in journal (Other academic)
  • 12.
    Karlsson, Torbjörn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Effect of intravenous iron supplementation on iron stores in non-anemic iron-deficient patients with hereditary hemorrhagic telangiectasia2016In: Hematology Reports, ISSN 2038-8322, E-ISSN 2038-8330, Vol. 8, no 1, article id 6348Article in journal (Refereed)
    Abstract [en]

    In hemorrhagic telangiectasia (HHT), frequent episodes of nasal and gastrointestinal bleeding commonly lead to irondeficiency with or without anemia. In the retrospective study presented here we assessed the iron stores, as determined by analysis of plasma ferritin, during oral and intravenous iron supplementation, respectively, in a population of iron-deficient non-anemic HHT patients who were inadequately iron-repleted by oral supplementation. A switch from oral to intravenous iron supplementation was associated with a significant increase in ferritin in this patient population.

  • 13.
    Karlsson, Torbjörn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala Univ Hosp, Ctr Oslers Dis, Uppsala, Sweden;Vastmanlands Hosp, Dept Med, Vasteras, Sweden.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala Univ Hosp, Ctr Oslers Dis, Uppsala, Sweden.
    Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 3, p. 153-157Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT).

    Methods: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess.

    Results: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications.

    Conclusion: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.

  • 14. Kjellander, Christian
    et al.
    Bjorkholm, Magnus
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kalin, Mats
    Giske, Christian G.
    Hematological: Low all-cause mortality and low occurrence of antimicrobial resistance in hematological patients with bacteremia receiving no antibacterial prophylaxis: a single-center study2012In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 88, no 5, p. 422-430Article in journal (Refereed)
    Abstract [en]

    Background: Bacteremia is a major cause of morbidity and mortality in patients with hematological malignancies.

    Objectives: The aim of this study was to define temporal trends in species distribution, antimicrobial susceptibility, and all-cause mortality in bacteremic hospitalized patients receiving no antibacterial prophylaxis during chemotherapy-induced neutropenia.

    Methods: A total of 677 clinical episodes of bacteremia were identified in 463 patients during 2002-2008, and the results were compared with those published from the same institution during 1980-86 and 1988-2001. No major changes in patient selection were introduced during this period.

    Results: Between 2002 and 2008, the dominating pathogens were Escherichia coli (18%), coagulase-negative staphylococci (15%), viridans streptococci (14%), Klebsiella spp. (10%), and Enterococcus faecium (8%). The 7-d crude mortality rate was 5.2%. Polymicrobial bacteremia was seen in 25.7% of the patients who died within 7 d and in 13.1% of the survivors (P = 0.04). Acquired resistance was rarely observed, but a statistically significant increase in ciprofloxacin resistance in E. coli was observed. Comparing 2002-2008 with historical data from the same institution, the proportion of Gram-positive isolates remained stable at 53-55% from 1988.

    Conclusions: The avoidance of fluoroquinolone prophylaxis may have contributed to a stable proportion of Gram-positive bacteremia. The crude mortality was low in an international perspective. Acquired resistance was uncommon, but ciprofloxacin resistance in E. coli increased significantly. We believe that an indiscriminate use of antibacterial prophylaxis could be avoided in neutropenic patients without a negative impact on mortality.

  • 15. Lehmann, Sören
    et al.
    Bykov, Vladimir J N
    Ali, Dina
    Andrén, Ove
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Tidefelt, Ulf
    Uggla, Bertil
    Yachnin, Jeffrey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Juliusson, Gunnar
    Moshfegh, Ali
    Paul, Christer
    Wiman, Klas G
    Andersson, Per-Ola
    Targeting p53 in Vivo: a First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 29, p. 3633-3639Article in journal (Refereed)
    Abstract [en]

    PURPOSE

    APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.

    PATIENTS AND METHODS

    APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.

    RESULTS

    MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.

    CONCLUSION

    We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.

  • 16.
    Lofling, Lukas
    et al.
    Karolinska Inst, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Ekstrand, Charlotta
    Karolinska Inst, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    General Pharmacological Treatments Preceding A Primary Chronic Immune Thrombocytopenia Diagnosis2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 645-646, article id Abstr. 1110Article in journal (Refereed)
  • 17.
    Löfling, Lukas
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, SE-17176 Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, SE-17176 Stockholm, Sweden..
    Ekstrand, Charlotta
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, SE-17176 Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, SE-17176 Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, SE-17176 Stockholm, Sweden..
    Pharmacological agents preceding a diagnosis of immune thrombocytopenia in adult patients developing the chronic form: A Swedish national register study2017In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 160, p. 27-31Article in journal (Refereed)
    Abstract [en]

    Patients with primary chronic immune thrombocytopenia (cITP) have been reported to use more anti-infective medications, even before diagnosis of immune thrombocytopenia (ITP). The more common use of anti-infective medications may be due to general health problems, requiring medication in the early stages of cITP and before the diagnosis is set, rather than infections preceding the disease. Accordingly, cITP may not only be associated with use of anti-infective medications but also with medications for more general symptoms.

    Objective: To investigate use of medications for general symptoms, such as analgesics and vitamin supplements in patients with ITP developing the chronic form, the year preceding their first primary diagnosis in comparison with such use in the general population.

    Method: Swedish Health Registers were used to identify adult patients (n = 1087) with primary cITP during 2006-2012 and data on medications. Standardized Incidence Ratios (SIRs) and 95% confidence intervals (CI), were estimated as a measure of relative risk.

    Results: The association for overall studied medications was SIR = 1.36 (95% CI 1.32-1.41). A majority of the point estimates were above unity.

    Conclusion: In patients with cITP, prescription fills for medications used to treat pain conditions and vitamin deficiencies are more common in the year preceding their first diagnosis as compared with prescription fills in the general population. Our results suggest that patients later diagnosed with cITP receive treatment due to symptoms that could be signs of an early ITP. Accordingly, in investigations for unspecific pain symptoms and vitamin deficiencies, cITP should be considered as a differential diagnosis.

  • 18.
    Sohrabian, Donia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Linder, Marie
    Karolinska Inst, Med, Stockholm, Sweden..
    Ekstrand, Charlotta
    Karolinska Inst, Med, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Med, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Med, Stockholm, Sweden..
    Infection and Anti-Infective Treatment Preceding a Diagnosis of Primary Persisting Immune Thrombocytopenia2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 88-88, article id Abstr. 143Article in journal (Refereed)
  • 19.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Answer to "Letter to the Editor, Scandinavian Journal of Infectious Diseases"2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 9, p. 730-730Article in journal (Refereed)
  • 20.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Chowdhury, Onima
    Garelius, Hege
    Lorenz, Fryderyk
    Saft, Leonie
    Jacobsen, Sten-Eirik
    Hellström-Lindberg, Eva
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine2014In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 5, p. 439-445Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.

    PATIENTS AND METHODS:

    Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 109/L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.

    RESULTS:

    Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.

    CONCLUSION:

    The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

  • 21.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 7, p. 537-542Article in journal (Refereed)
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) and hypogammaglobulinemia who suffer from recurrent infections can be offered prophylactic intravenous immunoglobulin (Ig) substitution. Our aim was to assess the prevalence of pure IgG subclass deficiency (with normal Ig levels), its correlation to risk of infection, and the clinical value of routine measurement of serum IgG subclass levels in patients with CLL. Methods: Serum levels of Ig and IgG subclasses were determined in patients with CLL at Uppsala University Hospital. Clinical data were collected through patient records and questionnaires. Results: Hypogammaglobulinemia occurred in 52.3% out of 111 patients. These patients did not have a higher annual risk of infection than patients without hypogammaglobulinemia (79.5% vs 79.1%, p = 0.706 for all infections; 13.4% vs 11.2%, p = 0.394 for severe infection; and 1.7% vs 3.4%, p = 0.083 for sepsis). Pure subclass deficiency was uncommon and occurred in 6 patients (5.4%). The annual overall risk of infection, of severe infection, and of sepsis for these patients did not differ as compared to patients with no hypogammaglobulinemia and no subclass deficiency (70.8% vs 80.7%, p = 0.334; 11.8% vs 11.1%, p = 0.497; and 8.9% vs 2.3%, p = 0.067, respectively). Conclusions: Pure IgG subclass deficiency is rare in patients with CLL. In this heterogeneous cohort of patients, neither hypogammaglobulinemia nor pure IgG subclass deficiency were significant risk factors for infectious complications. Measurement of serum levels of Ig may be justified in patients with recurrent severe infections, but routine analysis of IgG subclass levels in patients with CLL is probably not warranted.

  • 22.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kättström, Magdalena
    Hammarlund, Ylva
    Roth, Daniel
    Andersson, Per-Ola
    Svensson, Magnus
    Nilsson, Ingmar
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kimby, Eva
    Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group2018In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 36, no 25, p. 3701-3707Article in journal (Refereed)
    Abstract [en]

    Aim: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent conjugated pneumococcal vaccine (PCV13), Prevenar13®, compared with a 23-valent capsular polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response.

     

    Background: Patients with CLL have an increased risk for infection and Streptococcus pneumoniae is one of the most common pathogens with high morbidity.  Patients with CLL are known to respond poorly to the traditionally used polysaccharide vaccines. Conjugation of polysaccharide to protein carriers renders a thymus-dependent, memory-inducing and more immunogenic vaccine. In patients with CLL, there is no consensus on a recommendation for pneumococcal vaccination, due to a lack of comparative studies.

     

    Methods: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n=63) or PPSV23 (n=65) after stratification by IgG levels and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, at one and at six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA).

     

    Results: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. The proportion of patients with good response (defined as response in 8 of 12 common serotypes according to predefined response criteria) was higher in PCV13 recipients than in PPSV23 recipients after one month (40% vs. 22%, p=0.034) as well as after six months (33% vs. 17%, p=0.041). Never did PPSV23 trigger a better immune response for any of the serotypes, than PCV13, regardless of analysis. For two of the serotypes, OPA GMTs were lower at the six months than at the one-month follow up. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated.

     

    Conclusions: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for many serotypes common for the two vaccines. PCV13 should be considered as a part in vaccination programs against Streptococcus pneumoniae for these patients and administered as early as possible during the course of the disease. 

  • 23.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lundström, Kristina Lamberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 56-60Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine the diagnostic yield of BAL in patients treated for hematological malignancies and how often it contributed to a modification of the anti-infectious therapy.

    METHODS: We reviewed records from 151 consecutive BAL procedures in 133 adult patients with hematological malignancies, treated at a tertiary hematology unit from 2004 to 2013. Extensive microbiological work-ups on BAL samples had been performed according to a standardized protocol.

    RESULTS: A microbiological finding causing the infectious episode could be identified in 59 (39%) cases. In 44 (29%) of the cases, results from BAL had an impact on clinical management either by contributing to a specific diagnosis (25%) or by leading to cessation of ongoing microbiological therapy. The most common diagnoses were invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). Diagnoses of IPA and PJP were based on results from BAL in 65% and 93% of cases, respectively. Several microbiological tests on BAL samples rendered no positive results. Complications were few and mainly mild.

    CONCLUSION: BAL is still important for either verifying or excluding some of the most important respiratory tract pathogens in patients with hematological malignancies, particularly IPA and PJP. Standardized procedures for BAL sampling should be continually revised to exclude unnecessary microbiological tests.

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