A Phase 2 Study Of Ruxolitinib In Patients With Splanchnic Vein Thrombosis Associated With Myeloproliferative Neoplasm. Preliminary Results
Authors: Pieri Lisa , Paoli Chiara , Guglielmelli Paola , Fjerza Rajmonda , Arena Umberto , Marra Fabio , Colagrande Stefano , Mori Fabio , Marchioli Roberto , Pioggiarella Raffaella , Ruggeri Marco , Nichele Ilaria , Finazzi Guido , Ferrari Maria Luisa , Rosti Vittorio , De Stefano Valerio , Rumi Elisa , Mannarelli Carmela , Fanelli Tiziana , Bosi Alberto , Rambaldi Alessandro , Barosi Giovanni , Cazzola Mario , Barbui Tiziano , Vannucchi Alessandro M 
Published: October 2019

Abstract
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), accounting for 31.5% of portal vein thrombosis (PVT) and 40.9% of Budd Chiari syndrome (BCS). In patients (pts) with MPN and SVT, splenomegaly can arise as the consequence of the hematological disease and/or blood flow abnormalities consequent to the thrombosis itself. Splenomegaly and the compensatory enlarged splanchnic vessels are responsible for several complications including esophageal and gastric varices. Splenomegaly may cause abdominal discomfort; furthermore pts may present symptomatic burden due to the MPN. Current treatment strategies for MPN pts with SVT include anticoagulants and cytoreductive therapy (ie hydroxyurea, interferon) that have little influence in the control of splenomegaly and symptoms and do not improve flow abnormalities. Ruxolitinib, a JAK1/2 inhibitor, was highly effective in reducing spleen volume and improving symptoms in patients with MF and PV in phase II and III studies. We hypothesized that the decrease of the enlarged spleen determined by Ruxolitinib could result in a reduction of the local pressure in splanchnic vessels, producing both symptomatic improvement of splenomegaly-related symptoms and of splanchnic circulation. We designed an investigator-initiated multicentre phase 2 study of Ruxolitinib in pts with splenomegaly due to an underlying MPN associated with SVT. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis. The primary study objective was to evaluate the proportion of subjects achieving ≥ 50% reduction in spleen length from left costal margin (LCM) measured by palpation at any time from baseline to week 24 (w24) and at w24, or a ≥ 35% reduction in spleen volume by MRI or CT at week 24. The secondary objectives included: evaluation of safety of Ruxolitinib in MPN-associated SVT; assessment of splanchnic circulation through Doppler analysis, measurement of hyperdynamic arterial circulation by echocardiography and stiffness of hepatic/splenic parenchyma by fibroscan; status of esophageal varices at w24 compared to baseline. Quality of Life assessment was performed using MPN-SAF questionnaire. Exploratory objectives include evaluations of changes in JAK2V617F or MPLW515 allelic burden, association of baseline mutations with response to treatment, changes in cytokine and microRNAs profiles, quantification of circulating endothelial cells. At the time of abstract submission 7 out of 21 pts have been enrolled, of which 5 completed the 24 weeks of treatment; two additional pts are in screening phase. Three pts had PMF, two ET, one PV and one PPV-MF, associated to spleno-porto-mesenteric thrombosis (5 pts) and Budd Chiari syndrome (2 pts). 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 baseline platelet count of 100 to 200x109/L and 20 mg BID for those with baseline platelet count >200x109/L. A palpable splenomegaly greater than 5 cm below LCM was a criterion for enrollment; the 5 patients who completed the 24 weeks of treatment had a median splenomegaly of 8 cm below LCM at baseline, and obtained a median reduction of 69% measured by palpation at week 24, associated with a significant reduction in abdominal discomfort as measured by MPN-SAF questionnaire (median score at screening 5 vs 1.5 at week 24). The total symptom score calculated by using BFI and MPN-SAF was reduced from 50 at screening to 35 at week 24. Instrumental evaluations of splanchnic and systemic circulation showed that 3 pts obtained a reduction of the spleen stiffness from a median value of 66 to 49.6 kilopascals (KPa), 2 pts had a reduction of the liver stiffness from a median value of 23.85 to 18.2 KPa and 1 pt a reduction of the cardiac output from 5.871 to 4.6 L/min. Evaluation of esophageal varices at week 24 showed stabilization with neither worsening nor need of banding. Ruxolitinib was well tolerated, with no SAE reported; one pt developed anemia G2 and one G3 leading to dose reduction. Other adverse events include G1 asthenia and G≤2 AST/ALT increase in 3 pts, one case of Herpes Zoster and one case of abdominal pain both G1. Updated results will be presented at the meeting.

Disclosures:
Marchioli: Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Vannucchi:NOVARTIS: Honoraria, Membership on an entity’s Board of Directors or advisory committees.