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A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
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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.

Place, publisher, year, edition, pages
2014. Vol. 93, no 5, 439-445 p.
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-233787DOI: 10.1111/ejh.12383ISI: 000343970700011PubMedID: 24853277OAI: oai:DiVA.org:uu-233787DiVA: diva2:754292
Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Infectious and bleeding complications in patients with hematological malignancies: Studies on diagnosis and prevention
Open this publication in new window or tab >>Infectious and bleeding complications in patients with hematological malignancies: Studies on diagnosis and prevention
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
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:nbn:se:uu:diva-316461 (URN)978-91-554-9830-6 (ISBN)
Public defence
2017-04-24, Rosénsalen, Akademiska sjukhuset, Ingång 95/96 nbv, Sjukhusvägen, Uppsala, 09:15 (Swedish)
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Available from: 2017-04-03 Created: 2017-03-01 Last updated: 2017-04-18

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Svensson, TobiasCherif, Honar

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