At our Editorial Board Meeting last December, a suggestion was made that, moving forward, we should compile an end-of-the-year list of journal articles that we felt merited recognition. This idea was well received by the Board of Contributing Editors, and we made plans to incorporate this concept into a feature for publication in the November/December issue of The Hematologist. What we had in mind was that each member of the Board would identify an article, published in the preceding 12 months, that he/she felt deserved recognition. The Contributing Editors had complete leeway in deciding which article to chose. For example, the article might be chosen because the reported observations were practice-changing or because the article reported a particularly surprising or long-anticipated discovery or because the science was especially innovative. Each citation was to be accompanied by an annotation that focused on why the Contributing Editor chose to acknowledge the paper. We felt that our readers would receive such a feature enthusiastically as it provides a highly select group of papers for review. We also liked the idea of formally recognizing outstanding work both as a bow to our colleagues who have committed so much energy, effort, insight, and imagination to investigation and as a way of encouraging those who are currently invested in tackling an important, challenging problem to press on.

The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059-2074.*

This article is the culmination of the massive effort of dozens of researchers to unravel the mystery of the genetic aberrations of acute myeloid leukemia (AML). Two hundred adult cases were analyzed by DNA sequencing, RNA expression, and epigenetic profiling. On average, each type of leukemia has 13 mutations, only five of which are in recurrently mutated genes. About 260 genes were mutated in more than one patient. Extensive analysis reveals extraordinary complexity of the interrelationships between mutations, gene expression and DNA methylation. These data will serve as the basis for unraveling the pathogenesis of AML and the key to unlocking its vulnerability.

Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516.†

This article is one of the most important papers in 2013 because it identifies Bruton’s tyrosine kinase (BTK) as a valid therapeutic target for mantle cell lymphoma (MCL). This study, performed in relapsed and refractory MCL, demonstrated a high response rate and durable remissions with the first-in-class, irreversible, orally available BTK inhibitor, ibrutinib. The toxicity of ibrutinib was manageable and allowed continuous dosing for an extended period of time. While it is clear that ibrutinib will not cure mantle cell lymphoma, ibrutinib does provide a new tool to work with to improve outcome for patients with this aggressive, often fatal disease.

Zhang C, Srinivasan Y, Arlow DH, et al. High-resolution crystal structure of human protease-activated receptor 1. Nature. 2012;492:387-392.§

Protease-activated receptors (PARs) are a unique family of G protein-coupled receptors that are activated by proteolytic cleavage rather than by soluble ligands. PAR1 connects the coagulation system with platelet activation and is an  important drug target. This high resolution structure demonstrates several unusual features of PAR1, revealing essential details of its activation mechanism.

This was the subject of Dr. Flaumenhaft’s Diffusion article in the May/June 2013 issue.

Coelho T, Adams T, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819-829.

In 2006, Andrew Fire, PhD, and Craig Mello, PhD, shared the Nobel Prize in Physiology or Medicine for their work on RNA interference (RNAi) in C. elegans. RNAi has become a valuable research tool that has allowed for the study of the function of specific genes in cell culture and in model organisms. The application of RNAi to treating human diseases, including cancer, has been stifled by many challenges, most notably the development of a safe and effective delivery method. The paper by Coelho and colleagues provides proof of concept that anti-transthyretin siRNA encapsulated lipid nanoparticles delivered to human liver can modulate gene expression of mutant and non-mutant transthyretin. These data hold promise not only for treatment of this subtype of amyloidosis, but also for other hematologic conditions such as beta-thalassemia and iron-overload disorders, hemophilia, acute intermittent porphyria, and complement-mediated diseases. 

Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516.†

This is the first compelling data showing a high response rate with a molecular targeted agent in this particularly intractable lymphoma, where to date we have simply been investigating ever more intensive cytotoxic therapy. The responses seen were striking and the toxicity minimal. Thus, the availability of ibrutinib will likely alter the standard of care in mantle cell lymphoma.

Dr. Johnson indicated that he was an investigator in the study and is an author on the paper.

Barr J, Chauhan AK, Schaeffer GV, et al. Red blood cells mediate the onset of thrombosis in the ferric chloride murine model. Blood. 2013;121:3733-3741.

This article demonstrates, in a well-established model, that the first response to a thrombogenic stimulus is transient RBC adherence to endothelium with deposition of RBCderived structures that recruit platelets that form thrombi. These results have pathobiologic implications for RBC disorders associated with thromboses such as sickle cell disease, polycythemia vera, paroxysmal nocturnal hemoglobinuria, altitude sickness, and recombinant erythropoietin overuse.

Roccaro AM, Sacco A, Maiso P, et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest. 2013;123:1542-1555.

The article demonstrates how bone marrow stroma in patients with multiple myeloma is uniquely adapted to promote disease progression through trafficking of exosomes, a recently discovered class of cell membrane derived vesicles that are important both physiologically and pathophysiologically.

Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369:438-447.

Despite recent progress in disease management, multiple myeloma-related morbidity and mortality remain high. Conceivably, unfavorable prognosis may correlate with disease burden. The idea to treat earlier is not new, but observation, without myeloma-specific therapy, has remained the standard of care for management of patients with smoldering myeloma. In the paper by Mateos and colleagues, smoldering myeloma patients with high-risk features that were treated with lenalidomide and dexamethasone were found to have a survival advantage compared with the observation group. The results of this study compel us to redefine or subcategorize smoldering myeloma so that those patients with high-risk features can be identified and treated.

Olson ST, Swanson R, and Petitou M. Specificity and selectivity profile of EP217609: a new neutralizable dualaction anticoagulant that targets thrombin and factor Xa. Blood. 2012;119:2187-2195.

I selected this paper as my favorite Blood paper in the last year for two reasons: first, it describes an interesting new approach in the ongoing effort to develop novel antithrombotic agents; and second, it highlights methods developed by Steven Olson and colleagues that represent unprecedented biochemical rigor in the characterization of interactions involving proteinase inhibitors.

Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169-2181.

Atypical hemolytic uremic syndrome (aHUS) is an uncommon, life-threatening thrombotic microangiopathy. Most forms of primary aHUS are caused by disordered regulation and abnormal activation of the alternative pathway of complement. Plasma therapy (exchange or infusion) is, at best, temporizing and often not particularly effective. This manuscript by Legendre et al. describes the results of two small trials of long-term use of eculizumab therapy for aHUS. Eculizumab is a humanized monoclonal antibody that binds to complement protein C5 and blocks the formation of the membrane attack complex of complement. Proof of principle for this therapy has been demonstrated before, but these two trials provide much higher quality evidence that eculizumab therapy improves hematologic parameters, renal function, and quality of life in patients with aHUS – and these beneficial effects are sustained over time while receiving maintenance eculizumab. The toxicity profile is generally acceptable, and no meningococcal disease occurred in these vaccinated patients. In summary, eculizumab is an effective, long-term treatment for aHUS, and it should be started as early as possible after the diagnosis of aHUS is made.

Young G, Sǿrensen B, Dargaud Y, et al. Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of the art and future perspectives. Blood. 2013;121:1944-1950.§

I chose this outstanding article by Young et al. because of the growing importance of global assays of hemostasis in the current and future management of patients with bleeding disorders as long-acting proteins and novel therapeutics come to market. With evidence that global assays (e.g., thrombin generation) are more accurate predictors of bleeding than PT- and APTT-based assays, there is urgency to bring global assays to the clinic. Countless clinical scenarios provide objective data to guide application of global tests to everyday management of patients.

This was the subject of Dr. Ragni’s Diffusion article in the September/October 2013 issue.

The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059-2074.*

Drugs, even major therapeutic advances like imatinib, are only useful until something better comes along. Diagnostic tests also tend to have a vogue: The chest x-ray and complete blood count have had remarkable staying power, but who orders a plasma cell labeling index or a leukocyte alkaline phosphatase score anymore? But insights into disease biology will last forever – or at least as long as humans are around to suffer those diseases. That’s why the article I chose to highlight is the acute myeloid leukemia (AML) genomics survey by The Cancer Genome Atlas Research Network, in which the investigators analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using whole-genome and whole-exome sequencing, RNA and microRNA sequencing, and DNA methylation analysis. Of course, much more work needs to be done in AML, including assessment of the genome in special disease subtypes, functional characterization of the discovered mutations, and discovery of uncommon yet informative anomalies. And AML genomics work has yet to benefit patients; we leukemia specialists continue to prescribe 40-year-old cytotoxic chemotherapy regimens for want of anything better. But the work provides a small-scale map for investigators and will be the foundation of future studies into AML pathobiology and treatment.

Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-21.

This study enrolled a total of 921 patients with severe acute upper gastrointestinal bleeding. Of these, 461 were assigned to a restrictive transfusion strategy (RBC transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 were assigned to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Survival was better in the restrictive group, and the risk of re-bleeding was also less. This paper underscores the overuse of RBC transfusions in medicine today and reminds clinicians that RBC transfusions may, in some instances, do more harm than good. Unfavorable events related to battlefield resuscitation, the potential dangers of transfusion of aged red blood cells, the risk of transfusion-related infection, and transfusion-induced immumunosensitization or immunocompromise are examples of potential untoward consequences of red cell transfusion that necessitate urgent re-education of hematologists about proper transfusion practices.

*Both Pamela Becker and David Steensma selected the same journal article.†Both John Byrd and Peter Johnson selected the same journal article.§ The selected paper was the subject of a Diffusion article in 2013.