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Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):710-716
Myeloproliferative Neoplasms
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,1 Jakob R. Passweg,1 Alexandar Tzankov,2 Martin Bigler,3 Alexandre PA Theocharides,4 Nathan Cantoni,5 Peter Keller,6 Georg Stussi,7 Axel Ruefer,8 Rudolf Benz,9 Geneviève Favre,10 Pontus Lundberg,1
Ronny Nienhold,11 Andrea Fuhrer,3 Christine Biaggi,3 Markus G. Manz,4 Mario Bargetzi,5 Simon Mendez-Ferrer,12 and Radek C. Skoda;11 on behalf of the Swiss Group for Clinical Cancer Research (SAKK)
1Division of Hematology, University Hospital Basel and University of Basel, Switzerland; 2Institute of Pathology, University Hospital Basel and University of Basel, Switzerland; 3Swiss Group for Clinical Cancer Research, Bern, Switzerland; 4Hematology and Oncology, University Hospital Zurich and University of Zurich, Switzerland; 5Oncology, Hematology & Transfusion Medicine, Kantonsspital Aarau AG, Switzerland; 6University Clinic of Hematology and Central Hematology Laboratory, University Hospital Bern, Switzerland; 7Clinic of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 8Departement Medizin, Luzerner Kantonsspital, Switzerland; 9Kantonsspital Muensterlingen, Switzerland; 10Cantonal Hospital Liestal, Switzerland; 11Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Switzerland and 12Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge, UK
ABSTRACT
The β-3 sympathomimetic agonist BRL37344 restored nestin-posi- tive 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 myeloprolifera- tive 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 mar- row biopsies were evaluated in 20 patients. We found an increase in the nestin+ cellsfromamedianof1.09(interquartilerange0.38-3.27)/mm2 to 3.95(interquartilerange1.98-8.79)/mm2 (P<0.0001)andaslightdecrease 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 onnestin+ mesenchymalstemcellsandreticulinfibrosisisencouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569.)
Introduction
Myeloproliferative neoplasms (MPN) are thought to be initiated and maintained from a mutated hematopoietic stem cell (HSC).1 An acquired mutation in JAK2 (JAK2-V617F) is present in the majority of MPN patients.2-5 The interplay between
Correspondence:
RADEK SKODA
radek.skoda@unibas.ch
JAKOB PASSWEG
jakob.passweg@usb.ch
Received: June 20, 2018. Accepted: November 8, 2018. Pre-published: November 8, 2018.
doi:10.3324/haematol.2018.200014
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/710
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