O079 : Calr somatic mutations in a prospective cohort of 308 patients with splanchnic vein thrombosis

ORAL PRESENTATIONS O079 CALR SOMATIC MUTATIONS IN A PROSPECTIVE COHORT OF 308 PATIENTS WITH SPLANCHNIC VEIN THROMBOSIS C. Marzac1 , A. Plessier2 , J.-J. Kiladjian3 , A. Andreoli3 , E. De Raucourt4 , O. Goria5 , K. Zekrini2 , C. Bureau6 , F. Lorre1 , F. Durand2 , N. Casadevall1 , D.-C. Valla2 , P.-E. Rautou2 . 1 Laboratoire d’Immunologie et H´ematologie Biologique, Hˆ opital Saint-Antoine, Paris, 2 Service d’H´epatologie, Hˆ opital Beaujon, Clichy, 3 Centre d’Investigations Cliniques, Hˆ opital Saint-Louis, Paris, 4 Service d’H´ematologie Biologique, Hˆ opital Beaujon, Clichy, 5 Service d’H´epatogastroent´erologie, CHU Rouen, Rouen, 6 Liver-Gastroenterology Department, University Hospital and Paul Sabatier University, Toulouse, France E-mail: [email protected] Background and Aims: Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Due to its excellent specificity for MPN, JAK2V617F analysis is very helpful in this setting. Still, 5 to 10% of SVT patients have a JAK2V617Fnegative MPN, requiring bone marrow biopsy and/or cultures of erythroid progenitors for diagnosis. Recently, somatic mutations of the calreticulin (CALR) gene have been described in MPN patients. The aim of this study was to determine the prevalence as well as the features associated with CALR mutations in a large prospective cohort of SVT patients. Methods: CALR, JAK2V617F and MPL mutations were analyzed in all patients with SVT prospectively included in our center. Bone marrow biopsy (searching for clusters of dystrophic megakaryocytes) and/or cultures of erythroid progenitors (searching for endogenous colonies) were performed when spleen size was ≥17 cm by imaging and platelet count >200/mL (Chait, Brit J Haematol 2005) or when considered relevant by the physician. Results: 308 patients (162 F, 146 M), aged 43±16 years have been included (Figure). Facteur II or V gene mutations were detected in 18 (6%) and 20 (7%) patients, respectively. Antiphospholipid syndrome and paroxysmal nocturnal haemoglobinuria were diagnosed in 31 (10%) and 5 patients (2%), respectively. A MPN was diagnosed in 69 patients (23%), including 56 with JAK2V617F. None of the 308 patients had MPL mutation. CALR mutations were found in 5 (2%) patients (3F, 2M; aged 33±5 years; 4 idiopathic myelofibrosis and 1 essential thrombocythemia). All 5 patients had a spleen size ≥17 cm, except for one who had a spleen size of 16.6 cm. None of the 5 patients had JAK2V617F, factor II or V gene mutation, protein C, S or antithrombin deficiency, antiphospholipid syndrome or paroxysmal nocturnal haemoglobinuria. Patients with CALR mutations had more commonly a portal vein involvement than other patients (5/5 vs. 145/300; p = 0.028).

S230

Conclusions: CALR mutations are detected in 2% of SVT patients. When present, these mutations are the only risk factor for thrombosis suggesting that this is a major determinant for SVT. CALR mutations should thus be investigated in patients with SVT without JAK2V617F. These results reinforce the diagnostic strategy based on spleen size and platelet counts since a MPN is present in virtually all JAK2V617F-negative patients with a spleen size ≥17 cm and platelet count >200/mL, vs. only in 3% of other patients.

Autoimmune and genetic liver disease

O080 EARLY CLINICAL FEATURES ASSOCIATED WITH LONG-TERM RISK OF TRANSPLANTATION IN PRIMARY SCLEROSING CHOLANGITIS: RESULTS FROM THE UK-PSC CONSORTIUM E.C. Goode1 , B. Srivastava2 , A.B. Clark3 , K. Spiess4 , G.M. Hirschfield5 , W.T.H. Gelson6 , P.J. Trivedi5 , G.F. Mells4 , R.N. Sandford4 , G.J. Alexander2 , R.W. Chapman7 , S.M. Rushbrook1 , UK-PSC Consortium. 1 Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, 2 Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, 3 Norwich Medical School, University of East Anglia, Norwich, 4 Academic Department of Medical Genetics, University of Cambridge, Cambridge, 5 Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, 6 Department of Hepatology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, 7 Department of Gastroenterology, John Radcliffe Hospital, Oxford, United Kingdom E-mail: [email protected] Background and Aims: Early assessment of new therapies in PSC will be aided by better surrogates of disease outcome. We determined baseline and follow up factors associated with transplantation in a representative UK cohort. Methods: Detailed phenotypic data were collated on patients recruited to the UK-PSC national cohort (August 2008-July 2014). Unadjusted hazard ratios (HR) were estimated using the proportional hazards model; adjusted HRs were estimated using forward selection to identify variables associated with transplantation (Stata 11.2/SE). Results: From a 1700 patient cohort, detailed phenotypic data were analysed in 500 patients (77 hospitals; 5 transplant centres; 59.4% male). Median age at diagnosis was 49.5 years, median follow-up 5.7 yrs. 68.4% had IBD (75.1% UC), 13.4% had another autoimmune disease. 87% were prescribed ursodeoxycholic acid (UDCA) (mean dose 12.8 mg/kg/day). 100 (20%) had a transplant (median age 51 yrs); need for transplantation was associated with cholangiographic disease burden with only 9.4% of patients without cholangiographic changes at baseline undergoing transplantation. 14% of females had transplants compared to 23.9% of males. 9.2% died without transplant, 4.4% due to PSC. 8.8% developed a GI cancer, most commonly colorectal (4.2%) and cholangiocarcinoma (3%). By univariate analysis, factors associated with increased need for transplantation were baseline ALP >2×ULN (p = 0.005; HR = 1.87, 95% CI 1.21, 2.89) and male gender (p = 0.03; HR 1.63, 95% CI 1.05, 2.53). At 1 and 2 years post diagnosis, ALP >1.5 and >2×ULN were associated with transplantation need (p < 0.001; see table). Absence of cholangiographic changes at baseline was protective (p = 0.023; HR 0.38, 95% CI 0.16, 0.87). After multivariate analysis, ALP >2×ULN at baseline (p = 0.001; HR 2.32, 95% CI 1.43, 3.77) and year 2 (p = 0.015; HR 2.96, 95% CI 1.23, 7.13) and ALP >1.5×ULN at year 1 (p < 0.001; HR 2.92, 95% CI 1.85, 4.59) remained associated with need for transplantation. Absence of cholangiographic changes

Journal of Hepatology 2015 vol. 62 | S213–S234