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Editorials
Figure 1. Bone marrow hematopoietic stem cell (HSC) niche in the development and disease maintenance of myeloproliferative neoplasms (MPN). This niche encompasses complex cellular and signaling networks with multiple interactions and ‘cross-talk’ between HSC, mesenchymal cells (MSC), perivascular cells identi- fied as chemokine ligand 12-abundant reticular cells, osteolineage-derived cells and sinusoidal endothelial cells, amongst others.1-3
this is intrinsically linked to both adaptive and innate tumor-immune responses (reviewed by Qiao et al.22).
In this issue of Haematologica, Drexler et al. report a novel multi-center, phase II trial exploring the refocused use of mirabegron, an oral β-3 adrenergic agonist with a lower receptor affinity than BRL37344 but commonly used for overactive bladder syndrome. This is the first study in MPN to explore the neural-HSC niche.23 Mirabegron (25 mg titrated to 50 mg once daily) was administered to 39 patients with a diagnosis of MPN fulfilling the World Health Organization (WHO) 2008 diagnostic criteria, and in whom the JAK2-V617F mutant allele burden in granulo- cyte DNA exceeded 20% at study entry. The primary end point was defined as the reduction in the JAK2-V617F mutant allele burden of 50% or more after 24 weeks. A sub-project, in which 20 patients participated, assessed whether mirabegron can restore the Nestin+ MSC popula- tion and alter reticulin fibrosis. The primary end point was
not reached in any of the patients, although a 25% reduc- tion in JAK2-V617F allele burden at 24 weeks was recorded in one patient. Twenty-four percent of patients with poly- cythemia vera and 29% of patients with essential throm- bocythemia showed hematologic response in accordance with European LeukemiaNet (ELN) and International Working Group Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. One patient with myelofibrosis became transfusion independent. These clin- ical findings were considered of minor, possibly insignifi- cant, benefit. Evaluation of BM biopsies showed an increase in Nestin+ MSC from a median of 1.09 [interquar- tile range (IQR) 0.38-2.37/mm2] to 3.95 (IQR 1.98- 8.79/mm2) (P<0.0001), and a slight but significant decrease in reticulin fibrosis from a median grade of 1.0 (IQR 0-3) to 0.5 (IQR 0-2) (P=0.01) between the start and end of mirabegron treatment. The decrease in reticulin fibrosis was only observed in patients not previously treated with
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haematologica | 2019; 104(4)