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Mirabegron in MPN
A
B
Figure 1. Changes in JAK2-V617F allele burden during the treatment period. (A) Waterfall plot representing the percent changes in JAK2-V617F allele burden at 24 weeks. (B) Time course of JAK2-V617F allele burden in patients treated with mirabegron. The values measured before treatment (week 0), and at week 12 and week 24 of mirabegron treatment are shown for each individual patient, connect- ed by dashed lines. Filled triangles, circles and squares are used for essential throm- bocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) patients, respectively. Within the group of myelofibro- sis (MF) patients, post-ET and post-PV myelofibrosis are indicated by open trian- gles and circles, respectively.
the MPN HSCs and the stem cell niche is being increasing- ly recognized as crucial for the biology of the disease. Nestin-positive mesenchymal stem cells (nestin+ MSCs) within the bone marrow (BM) niche are innervated by sympathetic nerve fibers and are important in regulating normal HSCs.6,7 These nestin+ MSCs are strongly reduced in BM from patients with MPN.8 In a mouse model of MPN expressing human JAK2-V617F, this effect was found to be caused by early glial and sympathetic nerve damage and subsequent apoptosis of nestin+ MSCs trig- gered by the mutant hematopoietic cells. In vivo depletion of nestin+ cells accelerated MPN progression. Conversely, MPN phenotype could be reversed by compensating for the sympathetic neuropathy by systemic administration of a β-3-sympathomimetic agonist. Mice with JAK2- V617F-driven MPN treated with the β-3-sympathomimet- ic drug BRL37344 not only restored nestin+ MSCs num- bers, but also showed correction of thrombocytosis, neu- trophilia, and BM fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in BM and peripheral blood (PB).8 Treatment with BRL37344 also corrected the damage inflicted by the MPN clone on the stem cell niche and led to an increase in nestin+ cells.8 Thus, β-3 sympath- omimetic agonists represent a promising novel therapeu- tic approach to MPN by targeting the stem cell niche rather than the MPN clone itself.
Recently, mirabegron, a β3-adrenoceptor agonist, was approved in North America, Europe, Japan and Australia for the treatment of an overactive bladder.9 Here, we report the results of a phase II study that tested the efficacy of mirabegron in patients with JAK2-V617F-positive MPN.
Methods
Study population
Overall, 39 patients with MPN, including 7 patients with essen- tial thrombocythemia (ET) (18%), 21 with polycythemia vera (PV) (54%), and 11 with myelofibrosis (MF) [28%; of whom 5 were primary myelofibrosis (PMF), 3 post-ET MF and 3 post-PV MF] have been accrued in 10 institutions across Switzerland between May 2015 and February 2016. The patients fulfilled the 2008 World Health Organization (WHO) diagnostic criteria for MPN.10 All patients were JAK2-V617F-positive with a mutant allele bur- den at study entry more than 20% in granulocyte DNA. The trial was planned and conducted in accordance with the Declaration of Helsinki, the Guidelines for Good Clinical Practice (GCP) issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the requirements of the respective national regulatory authorities. The local ethics committees of all participating centers have given approval to the trial and written informed consent was obtained
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