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
Beatrice Drexler,
Jakob R. Passweg,
Alexandar Tzankov,
Martin Bigler,
Alexandre PA Theocharides,
Nathan Cantoni,
Peter Keller,
Georg Stussi,
Axel Ruefer,
Rudolf Benz,
Geneviève Favre,
Pontus Lundberg,
Ronny Nienhold,
Andrea Fuhrer,
Christine Biaggi,
Markus G. Manz,
Mario Bargetzi,
Simon Mendez-Ferrer,
Radek C. Skoda
Affiliations
Beatrice Drexler
Division of Hematology, University Hospital Basel and University of Basel, Switzerland
Jakob R. Passweg
Division of Hematology, University Hospital Basel and University of Basel, Switzerland
Alexandar Tzankov
Institute of Pathology, University Hospital Basel and University of Basel, Switzerland
Martin Bigler
Swiss Group for Clinical Cancer Research, Bern, Switzerland
Alexandre PA Theocharides
Hematology and Oncology, University Hospital Zurich and University of Zurich, Switzerland
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge, UK
Radek C. Skoda
Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Switzerland
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
