Issue Archive

With the recent approval of ruxolitinib as a treatment for steroid-refractory acute graft-versus-host disease, there is now a need to refine the definition of treatment failure in this still highly challenging clinical setting. In this Perspective, the authors put forward a provisional proposal for consideration by the transplant community and cooperative groups.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, but families have often been left without a firm diagnosis because of imprecision in clinical criteria and an incomplete mutational database. Shovlin et al identify more than 100 new likely pathogenic variants in the 4 known HHT genes and provide justification for a systematic approach to the diagnosis of HHT incorporating mutation analysis, modeling, and detailed clinical information.

In an elegant investigation of a familial predisposition to acute leukemia, Matsumura and colleagues implicated mutation of a specific methylation site in the RUNX1 gene. They went on to reveal how altered methylation of this regulatory gene in mice confers on hematopoietic stem cells the hallmark leukemic features of resistance to apoptosis and survival advantage under stress.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, and CASP10). Through analysis of 215 patients with suspected ALPS, Molnár and colleagues report improved diagnostic accuracy through measurement of double-negative T-cell number, soluble FAS ligand, and apoptotic function.

Using data from a randomized trial of ibrutinib vs chemoimmunotherapy for patients needing first treatment for chronic lymphocytic leukemia, the authors calculated that the incremental cost per quality-adjusted life year gained of using ibrutinib as a first treatment rather than as a later treatment exceeds $2 million. They explore scenarios that influence the cost-effectiveness of ibrutinib and price reductions necessary to meet willingness-to-pay thresholds.

Sims et al comprehensively studied 47 patients with gray platelet syndrome, expanding both the palette of causal mutations in the NBEAL2 gene and the spectrum of clinical manifestations to include immune dysregulation and autoimmunity. They describe granule defects in multiple leukocyte lineages as well as the classical α-granule defects in platelets, potentially explaining the broader clinical phenotypes.

Thalassemias are characterized by anemia, ineffective erythropoiesis, splenomegaly, and systemic iron overload. In this preclinical murine study, the authors provide data indicating that the impact on anemia of iron restriction therapies, such as hepcidin activators, increases when these therapies are used in combination with erythroid stimulators like erythropoietin.