According to a recent hypothesis, venous thrombosis results from the concurrence of several factors. This hypothesis was assessed in patients with portal or hepatic venous thrombosis by simultaneously investigating most of the currently identified prothrombotic disorders, local precipitating factors, and other risk factors such as oral contraceptive use. Patients with a tumorous obstruction and patients with cirrhosis with portal vein thrombosis were excluded. The prothrombotic disorders that were investigated included classical and occult myeloproliferative disorders; antiphospholipid syndrome; protein C; protein S and antithrombin deficiency; factor V Leiden; factor II; and methylene-tetrahydrofolate-reductase gene mutations. We found 1 or several prothrombotic disorders and a local precipitating factor in 26 and 10 of the 36 patients with portal vein thrombosis, respectively; and in 28 and none of the 32 patients with hepatic vein thrombosis, respectively. We found a combination of prothrombotic disorders in 5 and 9 patients with portal and hepatic vein thrombosis, respectively, whereas such a combination is expected in less than 1% of asymptomatic subjects. Of the 10 patients with a local precipitating factor, 8 had a prothrombotic disorder. Of the 13 patients who use oral contraceptives, 10 had a prothrombotic disorder. We conclude that portal or hepatic venous thrombosis should be regarded as an index for 1 or several prothrombotic disorders, whether or not local precipitating factors or oral contraceptive use are found. Concurrence of prothrombotic disorders is more common than expected.

Summary Myeloproliferative disorders (MPD) are reported in 25–65% of patients with splanchnic vein thrombosis (SVT). Diagnostic criteria for MPD have not been fully established in this context. Using clusters of abnormal megakaryocytes in bone marrow (BM) biopsy as a reference standard for Philadelphia negative MPD, we assessed the relevance of other criteria currently recommended for the diagnosis of MPD in SVT (128 consecutive SVT patients). First, usual criteria were compared with BM results: endogenous erythroid colony formation (EEC) was strongly correlated with BM results; splenomegaly, blood cell count, total red cell volume, erythropoietin level and cytogenetic were much less accurate. Then, patients were assigned to three groups according to the combination of BM and EEC findings (group I: both present; group II: both absent; group III: other patients); clinical presentation and outcome were compared in each group. At a mean follow‐up of 6·09 ± 6·6 years, progression to a severe form of MPD occurred in 7 of 31 group I patients (23%), in 1 of 34 group III patients (3%) and 0 of 63 group II patients. The combination of marked splenomegaly and platelet count >200 × 109/l was restricted to groups I and III. In conclusion, in patients with SVT, BM findings and EEC allowed the diagnosis of MPD at risk of aggravation. Marked splenomegaly in association with platelet counts >200 × 109/l constitute a simple index with high specificity but low sensitivity.

Transformation of Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs

Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). One hundred and forty‐nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient‐named program. AML diagnosis was de novo, post‐myelodysplastic syndromes (MDS), post‐MPN, and therapy‐related AML in 51, 55, 13, and 30 patients, respectively. Median age was 74 years, median white blood cell count (WBC) was 3.2 × 109/L and 58% of the patients had ≥30% marrow blasts. Cytogenetics was adverse in 60 patients. Patients received AZA for a median of five cycles (range 1–31). Response rate (including complete remission/CR with incomplete recovery/partial remission) was 27.5% after a median of three cycles (initial response), and 33% at any time (best response). Only adverse cytogenetics predicted poorer response. Median overall survival (OS) was 9.4 months. Two‐year OS was 51% in responders and 10% in non‐responders (P<0.0001). Adverse cytogenetics, WBC >15 × 109/L and ECOG‐PS ≥2 predicted poorer OS, while age and marrow blast percentage had no impact. Using MDS IWG 2006 response criteria, among patients with stable disease, those with hematological improvement had no significant survival benefit in a 7 months landmark analysis. Outcomes observed in this high‐risk AML population treated with AZA deserve comparison with those of patients treated intensively in prospective studies. Am. J. Hematol. 89:410–416, 2014. © 2013 Wiley Periodicals, Inc.

843 Background: AZA prolongs survival in higher-risk MDS including patients (pts) with 20-29 % marrow blasts, now considered WHO-AML ( Lancet Onc, 2009). However, no large AML cohorts (especially with '30% marrow blasts) treated upfront with AZA have been reported. Methods: An AZA compassionate program (ATU) was initiated in France in Dec 2004 for higher risk MDS, and AML considered not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed WHO AML pts having received at least 1 cycle of AZA in the 42 centers with complete pt reporting, excluding those previously treated by IC, allo SCT, low dose AraC or a hypomethylating agent. Results: 138 pts were included between Dec 2004 and Dec 2008; M/F: 86/52; median age 73 years (y) (range 31-87), 117 pts (85%) were > 65 y and 54 (40%) >75y. 65 pts (47%) had prior WHO MDS and 30 pts (22%) therapy related (tAML). 44 pts (32%) had 20-29% marrow blasts. Median WBC was 3.0 G/L [0.8-111.5]. Karyotype (MRC classification), was intermediate (int) in 60 pts,( including 38 normal (NK), and 7 isolated +8 ) adverse in 67 pts (including 42 -7/ del7q, 41 del5q/-5, 45 complex karyotype, two 3q26) and failed in 11 pts. With a median follow-up of 11.3 months, pts received a median of 4.5 AZA cycles (range 1-26). Treatment was according to FDA-EMEA approved schedule for MDS in 95 pts (69%) and a less intensive schedule (5d/4w, or <75 mg/m2/d) in 31% pts, 29 pts (21%) received concomitant valproic acid (VPA). First evaluation was made after 3 to 4 cycles. An overall AML response (ie according to AML-IWG criteria) was observed in 29 pts (21%) including 19 CR (14%), 3 CRp (2%) and 7 PR (5%) after a median of 3 cycles (1 – 11). An additional 25 pts (who had no CR, CRi or PR) achieved hematologic improvement (HI, according to MDS-IWG 2006 criteria). Neither any pretreatment characteristic including age, preceding MDS, tAML, karyotype, WBC, marrow blast %, combination with VPA were correlated with AML response. Median time to progression after AML response was 7.6 months In the 138 pts, 1 y-OS was 40%, 2 y OS 18% and median OS 10.2 months. In univariate analysis, pre-treatment characteristics negatively influencing OS were higher WBC, adverse cytogenetics, higher absolute PB blasts and diagnosis of tAML. In multivariate analysis: higher WBC (p=0.018), and adverse cytogenetics (p=0.0006) retained prognostic significance for OS. In particular, pts with WBC >10 G/L (32 pts in our cohort) carried poorer prognosis ( 1 y OS of 27% vs 44% ,p=0.01); NK had better OS (1-y OS: 66%) than adverse cytogenetics (1-y OS: 30%, p=0.01) but also other “intermediate-risk” abnormalities (1-y OS: 30%, p=0.03). Marrow blast % did not influence OS and survival, whatever the cut off chosen. In particular, pts with 20-29 % marrow blasts had 22% AML response and 1 y OS of 50%, compared to 21% and 1 y OS of 35%, respectively, in pts with >30% marrow blasts (p=NS and NS, respectively). Prior MDS also had no influence on survival. Overall, 33 pts required hospitalization during treatment, mainly for neutropenic fever. A landmark analysis at the time of evaluation showed that achievement of CR, CRi or PR was associated with improved OS (1y-OS 55% vs 31%,p=0.007). In pts with no AML-IWG response, however, achievement of HI also predicted better survival: 1 y-OS 55% vs 19 %, p=0.02. In the 54 pts older than 75 y (ie pts generally considered unfit for IC), 12 (22%) had AML response including CR in 9 (17%) and 3 PR (5%). 1y-OS was 41 % vs 38% for younger pts (p=NS). Hospitalisation was needed in 31% of them vs 32% in younger pts (p=NS). Conclusion: In this untreated cohort of generally older AML pts considered non candidates for intensive chemotherapy, response rate was 21% and 1 y OS 40%. Higher WBC counts and adverse karyotype were associated with poorer OS, but marrow blast %, whatever the threshold chosen, had no influence on outcome. Age above 75 y was associated with similar response and 1y OS. Finally, pts without AML IWG responses but with improved cytopenias also appeared to have improved survival. Disclosures: Off Label Use: Azacytidine is approved by FDA and EMEA in the treatment of high risk MDS and AML up to 30% of bone marrow blast.. Fenaux:CELGENE: Research Funding; AMGEN: Research Funding.