Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Patients undergoing treatment for acute lymphoblastic leukemia (ALL) are at risk for thrombosis, in part due to the use of L-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent VTE and thus might increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatric-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included. The incidence rate of VTE was 16% with 69% of them occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE (8% versus 14%, OR: 0.6, p=0.1). Fibrinogen concentrates administration was associated with an increased risk of VTE (17% versus 9%, OR 2.2, p=0.02) whereas transfusion of fresh-frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE (13% versus 7%, OR 1.9, p=0.04). Prophylactic measures were not associated with an increased risk of grade 3-4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1/34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. Patients developed VTE despite extensive AT supplementation which advocates for additional prophylactic measures. While this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. NCT00327678.