Unknown

Dataset Information

0

The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results of phase II study SAKK 33/14.


ABSTRACT: The β-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 β-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 marrow 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)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (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. (Registered at clinicaltrials.gov identifier: 02311569).

SUBMITTER: Drexler B 

PROVIDER: S-EPMC6442970 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

2008-01-01 | S-EPMC2600434 | BioStudies
2014-01-01 | S-EPMC3903535 | BioStudies
2020-01-01 | S-EPMC7151023 | BioStudies
1000-01-01 | S-EPMC3236121 | BioStudies
2010-01-01 | S-EPMC2892953 | BioStudies
1000-01-01 | S-EPMC3945864 | BioStudies
2012-01-01 | S-EPMC3277458 | BioStudies
2018-01-01 | S-EPMC5736674 | BioStudies
2015-01-01 | S-EPMC4305294 | BioStudies
2014-01-01 | S-EPMC4211877 | BioStudies