Abstract
Background: Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis, both Primary (PMF) and secondary to PV or ET (PPV-MF and PET-MF). A MPN is frequently the underlying cause of splanchnic vein thrombosis (SVT). Ruxolitinib, a JAK1/2 inhibitor, efficiently reduced spleen volume (SV) and improved symptoms in patients (pts) with MF and PV in the COMFORT-I/II and RESPONSE phase III trials, and preliminary evidence of efficacy in ET pts has been obtained in a phase II study. A few pts with SVT treated with ruxolitinib were reported in the literature, but the safety and efficacy of ruxolitinib has not been systematically evaluated.
Study Hypothesis: We hypothesized that by decreasing the enlarged spleen, treatment with ruxolitinib could result in reduction of local pressure in splanchnic vessels producing both improvement of splanchnic circulation and splenomegaly-related symptoms. We designed an investigator-initiated multicentre phase 2 study of Ruxolitinib in pts with splenomegaly in the setting of SVT associated with MPN. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis.
Study Design: Primary objective was to evaluate the proportion of pts achieving ≥ 50% reduction in spleen length from left costal margin (LCM) by palpation at any visit and at w24, or a ≥ 35% reduction in SV by magnetic resonance imaging (MRI) or computed tomography (CT) at w24. SV has been measured with a semi-automatic segmentation method by using OsiriX software. Secondary objectives, with measurements done at w24 versus (vs) baseline (bl), included evaluation of: safety of treatment, splanchnic circulation by echo-Doppler analysis, hyperdynamic arterial circulation by echocardiography; stiffness of hepatic/splenic parenchyma by fibroscan; status of esophageal varices, Quality of Life using MPN-SAF questionnaire. Exploratory objectives included: changes in JAK2V617F or MPLW515 allelic burden and in cytokine and microRNAs profiles; correlation of bl mutations with response to treatment; quantification of circulating endothelial progenitor cells (EPCs).
Results: At the time of abstract submission enrolment has been completed; 16/21 pts completed the w24 of treatment. Last patient last visit is planned in next October, therefore final trial data will be available at ASH meeting. Diagnosis of MPN were: PMF 8 (38.1%), PV 5 (23.8%), ET 4 (19.1%), PPV-MF 3 (14.3%), PET-MF 1 (4.8%). Nineteen pts had spleno-porto-mesenteric thrombosis and 3 BCS; one pt had both sites involved. All pts were under oral anticoagulation therapy. Initial dose of Ruxolitinib was 10 mg BID for PV, 25 mg BID for ET, 15 mg BID for MF pts with bl platelet count of 100 to 200x109/L and 20 mg BID for those with bl platelet count >200x109/L. Median values at enrolment were: hemoglobin 12.9 gr/dL (9.4-16.7), platelet count 212 x109/L(100-389), white blood cell count 7.3 x109/L(1.8-16.4). Eleven of 16 pts (69%) obtained a ≥50% spleen length reduction by palpation; 5/16 pts (31%) achieved a SV reduction ≥ 35% by imaging, comparable to previous studies in MF/PV pts without SVT. Spleen stiffness was evaluable in 4/16 pts due to values over the instrument upper limit of detection in the remaining twelve. All the 4 evaluable pts obtained a reduction from a mean value of 55.2 to 45.8 kilopascals. No significant differences in resistive or pulsatility index of splanchnic artery were noted, nor in esophageal varices status. Eleven of the 16 pts obtained a reduction of the cardiac output from mean value of 5.9 to 4.7 L/min. The median total symptom score calculated with MPN-SAF was reduced from 65 at bl to 42 at w24. Preliminary results of JAK2 allele burden did not show significant changes, while the absolute number of peripheral blood EPCs decreased in pts with PMF at w24 vs bl, in particular for Syto+CD34+VEGFR-2+ and Syto+CD45dimCD34+VEGFR-2+ cells (p<0.002 for both). Ruxolitinib was well tolerated, with no serious adverse events (AE) reported. Relevant hematologic toxicities included thrombocytopenia (6 events, only 1 G3), anemia (5 events, only1 G3) and neutropenia (3 events, only 1 G3), that led to temporary withdrawal or dose reduction in 7 pts, each. Seven infectious AE occurred, all G1-2.
Conclusions: Ruxolitinib was safe in pts with MPN associated to SVT and effective in reducing spleen size.
Masciulli:Novartis: Institutional funding Other. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
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