Mastocytosis van Anrooij, Bjorn
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Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
van Anrooij, B. (2019). Mastocytosis: A disease at the crossroads of hematology and allergology. University of Groningen.
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2
SCOPE OF THE THESIS
Due to the large variety in symptoms presented by mastocytosis patients a complete overview of the frequency of mastocytosis symptoms is difficult. Moreover, the approval of new therapies is ever
more reliant on patient reported outcome measures. Chapter 3
describes the development and validation of a disease specific quality of life questionnaire and symptom assessment form for mastocytosis. It also provides a comprehensive review of the symptom epidemiology and highlights unmet therapeutic needs, particularly in the field of fatigue, which could be filled by novel
tyrosine kinase inhibitors. Chapter 4 is a review of the tyrosine
kinase inhibitors with known in-vitro activity to the D816V mutated C-kit receptors and the current clinical and pre-clinical standing, usually as a therapy for aggressive systemic mastocytosis. Chapter 5 is a
report on a phase II trial of midostaurin in 20 indolent systemic mastocytosis patients, demonstrating midostaurin to be both safe and reasonably effective in the reduction of symptoms and mast cell load. However, this trial was not suitable to determine if midostaurin could also prevent anaphylactic reactions.
The relevance of anaphylaxis is underscored by Chapter 6,
describing a recent fatal anaphylactic reaction and illustrating the need for a predictor of risk for insect sting allergy in mastocytosis. We postulate that the development of sensitization could be sufficient indication to start immunotherapy in mastocytosis.
Chapter 7 describes that an opposite, inverse, relation between mast
cell load as measured by bsT and the risk of insect sting anaphylaxis exists in mastocytosis. This is a surprising finding, as it was previously intuitively assumed that a higher mast cell load indicated a higher possible effector cell population and thus an increased risk in mastocytosis. One possible explanation is for the found discrepancies between mastocytosis and non-mastocytosis patients lies in the CD30 receptor that is aberrantly expressed on mast cells.
Chapter 8 is a review of the expression of CD30 under physiologic
and pathological conditions. Briefly, CD30 is an important co-stimulatory receptor for Th2 driven immunologic responses that is
often found to be aberrantly expressed in lymphomas and T and B cell associated malignancies. CD30 is also cleaved into the soluble form of CD30 (sCD30), whereby it can act as a decoy receptor for CD30 ligand. Effectively reducing CD30-CD30L signaling and possibly hampering Th2 immunological reactions, such as the production of wasp venom specific IgE.
Chapter 9 is a study of the relation between sCD30 and
mastocytosis. As per our previous hypothesis, an inverse relation was found between sCD30 and the risk of insect sting anaphylaxis in mastocytosis. Moreover, high sCD30 levels correlated with low or absent specific IgE, further supporting the notion that mastocytosis derived sCD30 might be reducing the risk of insect sting anaphylaxis through impairment of CD30-CD30 ligand signaling and specific IgE production.
2
SCOPE OF THE THESIS
Due to the large variety in symptoms presented by mastocytosis patients a complete overview of the frequency of mastocytosis symptoms is difficult. Moreover, the approval of new therapies is ever
more reliant on patient reported outcome measures. Chapter 3
describes the development and validation of a disease specific quality of life questionnaire and symptom assessment form for mastocytosis. It also provides a comprehensive review of the symptom epidemiology and highlights unmet therapeutic needs, particularly in the field of fatigue, which could be filled by novel
tyrosine kinase inhibitors. Chapter 4 is a review of the tyrosine
kinase inhibitors with known in-vitro activity to the D816V mutated C-kit receptors and the current clinical and pre-clinical standing, usually as a therapy for aggressive systemic mastocytosis. Chapter 5 is a
report on a phase II trial of midostaurin in 20 indolent systemic mastocytosis patients, demonstrating midostaurin to be both safe and reasonably effective in the reduction of symptoms and mast cell load. However, this trial was not suitable to determine if midostaurin could also prevent anaphylactic reactions.
The relevance of anaphylaxis is underscored by Chapter 6,
describing a recent fatal anaphylactic reaction and illustrating the need for a predictor of risk for insect sting allergy in mastocytosis. We postulate that the development of sensitization could be sufficient indication to start immunotherapy in mastocytosis.
Chapter 7 describes that an opposite, inverse, relation between mast
cell load as measured by bsT and the risk of insect sting anaphylaxis exists in mastocytosis. This is a surprising finding, as it was previously intuitively assumed that a higher mast cell load indicated a higher possible effector cell population and thus an increased risk in mastocytosis. One possible explanation is for the found discrepancies between mastocytosis and non-mastocytosis patients lies in the CD30 receptor that is aberrantly expressed on mast cells.
Chapter 8 is a review of the expression of CD30 under physiologic
and pathological conditions. Briefly, CD30 is an important co-stimulatory receptor for Th2 driven immunologic responses that is
often found to be aberrantly expressed in lymphomas and T and B cell associated malignancies. CD30 is also cleaved into the soluble form of CD30 (sCD30), whereby it can act as a decoy receptor for CD30 ligand. Effectively reducing CD30-CD30L signaling and possibly hampering Th2 immunological reactions, such as the production of wasp venom specific IgE.
Chapter 9 is a study of the relation between sCD30 and
mastocytosis. As per our previous hypothesis, an inverse relation was found between sCD30 and the risk of insect sting anaphylaxis in mastocytosis. Moreover, high sCD30 levels correlated with low or absent specific IgE, further supporting the notion that mastocytosis derived sCD30 might be reducing the risk of insect sting anaphylaxis through impairment of CD30-CD30 ligand signaling and specific IgE production.
