Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Infectious and bleeding complications in patients with hematological malignancies: Studies on diagnosis and prevention
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS).

Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted.

There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL.

Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests.

Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1304
Keyword [en]
Chronic lymphocytic leukemia, Immunodeficiency, Hypogammaglobulinemia, IgG subclass, Pneumococci, Pneumococcal vaccine, Polysaccharide vaccine, Protein-conjugate vaccine, Aspergillosis, Bronchoalveolar lavage, Invasive fungal disease, Pneumocystis jirovecii pneumonia, Myelodysplastic syndrome, Azacitidine, Eltrombopag, Thrombocytopenia, Thrombopoietin receptor
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-316461ISBN: 978-91-554-9830-6 (print)OAI: oai:DiVA.org:uu-316461DiVA: diva2:1077889
Public defence
2017-04-24, Rosénsalen, Akademiska sjukhuset, Ingång 95/96 nbv, Sjukhusvägen, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2017-04-03 Created: 2017-03-01 Last updated: 2017-04-18
List of papers
1. Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia
Open this publication in new window or tab >>Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia
2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 7, 537-542 p.Article in journal (Refereed) Published
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.

Keyword
Hypogammaglobulinemia, IgG subclass, chronic lymphocytic leukemia, immunodeficiency
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203524 (URN)10.3109/00365548.2013.769279 (DOI)000320380900007 ()
Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-03-01Bibliographically approved
2. 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 group
Open this publication in new window or tab >>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 group
Show others...
(English)Manuscript (preprint) (Other academic)
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. 

Keyword
Chronic lymphocytic leukemia (CLL), vaccine, Pneumococci, Pneumococcal vaccine, Polysaccharide vaccine, protein-conjugate vaccine, immunogenicity
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-316457 (URN)
Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-03-01
3. Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?
Open this publication in new window or tab >>Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?
2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, 56-60 p.Article in journal (Refereed) Published
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.

Keyword
Aspergillosis, bronchoalveolar lavage, hematological malignancies, immunodeficiency, invasive fungal disease, neutropenia, Pneumocystis jirovecii pneumonia, pulmonary infiltrates
National Category
Family Medicine Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-310816 (URN)10.1080/03009734.2016.1237595 (DOI)000396476600008 ()27739337 (PubMedID)
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2017-04-12Bibliographically approved
4. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
Open this publication in new window or tab >>A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
Show others...
2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 5, 439-445 p.Article in journal (Refereed) Published
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.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-233787 (URN)10.1111/ejh.12383 (DOI)000343970700011 ()24853277 (PubMedID)
Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-03-01Bibliographically approved

Open Access in DiVA

fulltext(2471 kB)140 downloads
File information
File name FULLTEXT01.pdfFile size 2471 kBChecksum SHA-512
73f53ec71371bc6bfcab185acb78d9d194b3f73c54716a323fad4dbfaeab005d2081185898c01352b1c6eed200eb0fdeaf32dd33ab64d027174b823bc1c924e5
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Svensson, Tobias
By organisation
Haematology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 140 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 713 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf