Journal
HAEMATOLOGICA
Volume 104, Issue 4, Pages 710-716Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.200014
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Funding
- Rising Tide Foundation
- Gateway for Cancer Research
- Swiss Cancer League [KFS-3655-02-2015]
- Swiss National Science Foundation [KFS-3539-08-2014, 31003A_166613, ERC-2014-CoG-648765]
- Swiss State Secretary for Education, Research and Innovation
- Swiss Cancer Research Foundation
- Swiss National Science Foundation (SNF) [31003A_166613] Funding Source: Swiss National Science Foundation (SNF)
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The beta-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a beta-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone mar-row biopsies were evaluated in 20 patients. We found an increase in the nestin(+) cells from a median of 1.09 (interquartile range 0.38-3.27)/mm(2) to 3.95 (interquartile range 1.98-8.79)/mm(2) (P<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (P=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin(+) mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained.
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