Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation

Summary

The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.

Timeline

Start

2015-04

Primary completion

2016-12

Completion

2016-12

Outcome

Missed primary endpoint

paper 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. PMID 30409796 ↗

Publications

• Results Drexler B, Passweg JR, Tzankov A, Bigler M, Theocharides AP, Cantoni N, Keller P, Stussi G, Ruefer A, Benz R, Favre G, Lundberg P, Nienhold R, Fuhrer A, Biaggi C, Manz MG, Bargetzi M, Mendez-Ferrer S, Skoda RC; Swiss Group for Clinical Cancer Research (SAKK). 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. Haematologica. 2019 Apr;104(4):710-716. doi: 10.3324/haematol.2018.200014. Epub 2018 Nov 8.

Drugs

Indications