Page 84 - 2019_04-Haematologica-web

B. Drexler et al.
Table 1. Patients’ and disease characteristics
Gender Female Male
Age at registration [years] Disease
ET PV MF
PMF Post-ET MF Post-PV MF
WHO status
0
1
Blood counts
Hemoglobin [g/L] Neutrophils [x109/L]
Platelets [x109/L]
White blood cells [x109/L] Burden of mutated alleles [%]
Organomegaly
Liver palpable
Spleen palpable
Liver longitudinal diameter (ultrasound) [cm] Spleen longitudinal diameter (ultrasound) [cm]
Clinical signs of diseases other than MPN Medical history prior to inclusion in study
Venous complications Deep vein thrombosis Pulmonary embolism Splanchnic veins Retinal vein Unknown/Missing
Arterial complications
Cerebral
Extremity
Cardiac
Raynaud's phenomenon Erythromelalgia Unknown/Missing
Hemorrhagic complications Gastrointestinal Mucocutaneous Intraocular Unknown/Missing
Previous therapies Cytoreductive Alkylating agents Hydroxyurea Pipobroman Thioguanin
Value N=39
12 (31%)
27 (69%)
62 (53–72)
7 (18%) 21 (54%) 11 (28%) 5 (13%) 3 (8%)
3 (8%)
32 (82%)
7 (18%)
134 (127–143) 6 (4–8) 392 (310–564) 8 (6–12) 52 (33–73)
4 (11%) 11 (29%) 15 (13–16) 14 (12–18) 28 (72%) 39 (100%) 30 (77%) 3 (8%)
0
1 (3%)
0
26 (67%) 36 (92%) 7 (18%) 2 (5%)
4 (10%) 0
0
24 (62%) 28 (72%) 1 (3%)
3 (8%)
0
24 (62%) 39 (100%) 28 (72%) 0
23 (59%) 0
0
Anagrelide
Antiaggregation
Anticoagulation
Interferon
Phlebotomy
1 (3%)
33 (87%)
7 (19%)
2 (5%)
21 (55%)
MF: myelofibrosis; PMF: primary myelofibrosis; ET: essential thrombocythemia; PV: polycythemia vera;WHO:World Health Organization; MPN: myeloproliferative neo- plasms. Data are presented as number (N) of patients (%) or median (interquartile range).
from all patients prior to enrollment. Details of the inclusion and exclusion criteria are specified in the Online Supplementary Appendix.
Study design and treatment
We performed a multicenter, prospective, single-arm, single- stage and open phase II trial (SAKK 33/14; clinicaltrials.gov identifier: 02311569) with the β-3-sympathomimetic agonist mirabegron (Betmiga®). Before the study began, the drug had already been approved in the US, EU and Switzerland for the treatment of patients with an overactive bladder with a maximal recommend- ed dose of 50 mg daily. The trial consisted of mirabegron treat- ment for at least 24 weeks with an initial dose of 25 mg daily dur- ing the first week followed upon good tolerance by 50 mg mirabegron daily during the remaining treatment period. The fol- lowing treatments were not allowed during the trial treatment phase: other anticancer treatments, drugs known to influence JAK2-V617F allele level (e.g. interferon-α), ruxolitinib, or investiga- tional treatments. Established cytoreductive treatment for MPN (e.g. hydroxyurea, pipobroman, or thioguanin) could be continued as previously prescribed. For further details on the study design see the Online Supplementary Methods.
Primary end point
The primary end point was defined as reduction in the JAK2-V617F allele burden of 50% or more at 24 weeks after regis- tration. Secondary end points and response criteria are described in the Online Supplementary Methods).11,12
Molecular analyses
The JAK2-V617F allele burden was determined on DNA from purified granulocytes isolated from PB sampled in EDTA-contain- ing tubes. The allele-specific PCR of JAK2 genotyping was per- formed as previously described.13 The JAK2-V617F allele burden was validated by retesting. Capture-based next-generation sequencing with a panel of 94 genes to detect somatic mutations in granulocyte DNA was performed in patients who consented to this subproject on a voluntary basis. For details see the Online Supplementary Methods.14
Assessment of myelofibrosis and nestin+ mesenchymal stem cells
Patients who entered the study could also participate on a vol- untary basis in a subproject with the goal to test whether mirabegron can restore the nestin+ niche and may have a beneficial effect on BM morphology and the degree of myelofibrosis. BM trephine biopsies were performed at study entry and at week 24. Reticulin and collagen fibrosis was evaluated following estab- lished criteria.15-18
Statistical analysis
Statistical methods are defined in the Online Supplementary Methods.
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