Issue Archive

In this Plenary Paper, Zerella and colleagues describe a novel bone marrow failure syndrome associated with a tendency to hematological malignancy (HM), reflecting a germ line haploinsufficiency of ETS-related gene (ERG). ERG is a transcription factor that is known to be critical for hematopoiesis. Initially identified in 3 family members with inherited thrombocytopenia, a large international collaboration yielded 14 other unrelated individuals with diverse ERG mutations. The pathophysiology underlying the surprising finding that the patients were also predisposed to HM remains to be further delineated.

Venous thromboembolism (VTE) is common in patients with brain tumors, and management is challenging due to the risk of intracranial hemorrhage. Leader and colleagues discuss their approach to the management of acute VTE through 3 illustrative cases that highlight the need to balance hemorrhagic risk with the need for anticoagulation.

Sun et al report results of a phase 2 trial of eltrombopag plus diacerein, an anthraquinone anti-inflammatory drug, vs eltrombopag alone in patients with immune thrombocytopenia (ITP) unresponsive to 14 days of eltrombopag treatment. Overall response rate (44% vs 12%, respectively) and duration of response were improved with the addition of diacerein, although both arms lost response over time. This suggests that the addition of diacerein may improve short-term responses for patients with ITP resistant to eltrombopag.

The megakaryocytic (Mk) and erythroid lineages arise from Mk-erythroid progenitors (MEPs), but the pathways that regulate lineage choice are not defined. RUNX1 is a key modulator of this cell fate decision, and Kwon et al demonstrate that overexpression of RUNX1 in primary human MEPs promotes Mk maturation. The authors show that cyclin dependent kinase 9 (CDK9) phosphorylation of RUNX1 modulated MEPs toward Mk differentiation, while CDK9 inhibition shifted them toward erythroid maturation.

Emerging new drugs for myelofibrosis (MF) are difficult to compare because of the variable approach to defining anemia and response to therapy. Tefferi and other members of the International Working Group–European LeukemiaNet propose revised guidelines for anemia that account for gender-specific differences in hemoglobin levels, redefine transfusion-dependent anemia to account for current restrictive transfusion practices, and provide simple criteria that more accurately assess therapeutic response. These changes should allow for more uniform evaluation comparing interventions for MF-related anemia.

Factor XI (FXI) plays a role in inflammation and increases vascular permeability, but the details of its role in increased permeability is unclear. Puy et al report that activated FXI (FXIa) increases endothelial cell permeability, triggering events that induce cleavage of vascular endothelial (VE) cadherin, which maintains intracellular tight junctions. FXIa binds plasminogen activator inhibitor 1 and very low-density lipoprotein receptor, activating vascular endothelial growth factor receptor 2. This triggers mitogen-activated protein kinase signaling, which increases surface expression of a disintegrin and metalloproteinase 10, which cleaves VE-cadherin.

Kean et al report on a retrospective study comparing abatacept/calcineurin inhibitors/methotrexate (A/CNI/MTX) vs CNI/MTX, CNI/MTX plus antithymocyte globulin (ATG), and cyclophosphamide-based prophylaxis (PT-Cy) for acute graft-versus-host disease prophylaxis for 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) transplants. Two-year relapse-free survival (RFS) was significantly higher for MMUD recipients treated with A/CNI/MTX vs CN/MTX and CNI/MTX plus ATG but was similar to PT-Cy. For 8/8 MUD recipients, although RFS was numerically higher with A/CNI/MTX, results were not statistically significant.