The sympathomimetic agonist mirabegron did not lower -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.

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 -V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a β-3 sympathomimetic agonist, in a phase II trial including 39 -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 -V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in -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)/mm to 3.95 (interquartile range 1.98-8.79)/mm (<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) (=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing -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 -mutant stem cells are maintained. (Registered at ).