New Drugs to Match My New Genes? A Look Back at the 56th ASH Annual Meeting

For us hematologists, the first full weekend in December is typically blacked out in our calendars. During this sacred time, ASH hosts its annual meeting for anyone interested in the basic science, clinical research, education, or industry of hematology. This year’s meeting in San Francisco filled every Starbucks in a two-mile radius with a record attendance of greater than 26,000 participants from around the world. To accommodate the masses and the numerous sessions, ASH made use of five buildings and partnered with more than 65 hotels. The annual meeting always reinvigorates the blood lust for hematology, and the 2014 edition, which showcased 5,600 abstracts, did not disappoint. Indeed, the meeting focused on all things genetic, genomic, and epigenetic. If we weren’t talking about which gene mutations cause blood diseases, we were focusing on exciting new therapies that fix them. The following are some highlights from the meeting.

Setting the rhythm on the first day, the education session “Insights from Pediatric Malignancies” (also known by its reference in ASH News Daily “Do These Genes Make My Cancer Look Bad”) presented new developments in genome-wide profiling of acute lymphoblastic leukemia. From Friday’s Scientific Workshop on Hematology and Aging, to learning about the clinical impact of genetic abnormalities in the acute myeloid leukemia education session chaired by Dr. Gail Roboz, 2014 proved that “one size fits none” is true for jeans, genes, and chemotherapy. Similarly, the education session “Genetics of Chronic Lymphocytic Leukemia and Lymphoplasmocytic Leukemia” echoed the importance of a comprehensive genetic evaluation at diagnosis, as well as the promise of new targeted therapies such as ibrutinib and idelalisib. These medications were further highlighted at the inaugural Special Education Session“Newly Approved Drugs.” This symposium included didactic presentations and a question-and-answer forum that provided audience members with an opportunity to hear from clinical experts about optimal use of these agents. This session was especially useful in highlighting the bench-to-bedside process of drug discovery.

In addition to predicting outcomes and identifying novel targets, disease genetics can be exploited to better understand why specific treatments are more effective than others. For example, in the Plenary Scientific Session, Ms. Emma Fink (from Dr. Benjamin Ebert’s laboratory) laid out an elegant detective story on the mechanism of action of lenalidomide in del (5q) myelodysplastic syndrome. Multiple functional and genetic approaches were used to show that lenalidomide activates cereblon binding to casein kinase 1α, leading to its ubiquitination and subsequent degradation. MDS del (5q) cells with haploinsufficiency of CSNK1A1, the gene in the commonly deleted region encoding casein kinase 1α, are selectively depleted over wild-type cells, explaining lenalidomide’s unique effectiveness in this disease. With new technologies in hand, investigators also discussed encouraging progress in reversing inherited genetic diseases, as presented in the Scientific Program session “Fixing the Broken Helix: Genome Editing for Disease Correction” and in the “Best of ASH” session which highlighted promising gene therapy results with the Lentiglobin BB305TM lentiviral vector (Northstar Study, abstract 549) for patients with β-thalassemia major.

New breakthroughs in multiple myeloma, including understanding the genetic changes in the plasma cell clone, were also highlighted at the 2014 meeting. The Ham-Wasserman Lecture honored Dr. Jesus San Miguel, an international leader in myeloma research, who presented a history of myeloma risk-stratification and therapies. Dr. San Miguel focused on fascinating new data regarding the genomic complexity of myeloma cells and how the emergence of new therapies has challenged the field to develop new methods of disease prognostication. He discussed new methods to assess the depth of treatment response including immunophenotyping (including the “Black Swan” project), as well as molecular and radiologic techniques. The Scientific Program session “The Myeloma Niche and the Immunobiology of Myeloma” further emphasized the progress in understanding how the myeloma clone interacts with the microenvironment and how this relationship can be therapeutically modulated. In sum, these developments in myeloma are nothing to be CRABby about.

I would be remiss if I did not discuss my favorite topic, sickle cell disease (SCD). Indeed, the recipients of the 2014 Ernest Beutler Lecture and Prize are superstars in the SCD field. Dr. Michael DeBaun of Vanderbilt University School of Medicine reviewed the information learned from successful clinical trials in SCD, including his seminal trial in silent cerebral infarcts. However, Dr. DeBaun also took us away from San Francisco to geographic areas with scant resources, reminding us that many global challenges remain. Next, Dr. Robert Hebbel of the University of Minnesota transported the audience on a journey of discovery, starting with the description of the original understanding of the sickle cell in 1910, moving to the more complex pathophysiologic factors that now define SCD. I concur with Dr. Hebbel’s conclusions regarding future SCD treatment: it will likely involve “combination therapy” (akin to therapeutic approaches in cancer). In fact, new research shows that combining agents that both prevent ischemia reperfusion injury and ameliorate inflammation will be necessary to effectively mitigate endorgan damage. The abstracts presented this year further emphasized the promise of new drugs such as glutamine (abstract 86) and GMI-1070 (abstract 2704) for this “old” genetic disease.

Also prize-worthy (and iron-clad) was Dr. Tomas Ganz’s E. Donnall Thomas Lecture, “Iron, Erythropoiesis, and Host Defense: A Ménage à Trois.” Dr. Ganz and his team previously identified the roles of hepcidin and erythroferrone in iron homeostasis. He reviewed the regulators of hepcidin and emphasized the role of iron (and iron overload) in infection. His work will undoubtedly lead to novel therapies for iron overload, as well as the anemia of chronic inflammation. 

The aforementioned presentation by Ms. Fink was representative of the breadth of astounding science presented at 2014’s Plenary Scientific Session. From the use of barcoding to delineate new maps of human hematopoiesis, to the regulation of thrombopoietin by the hepatocyte Ashley-Morell receptor, to CD146+CCR5+ T cells as an early marker of intestinal graft-versus-host disease, the meeting was a whirlwind of breakthroughs.

If that wasn’t enough to shout about, the 2014 Special Symposium on Quality offered a spirited debate about the ethics and consequences of the rising costs of medications. In combination with the “Choosing Wisely” seminar, these sessions reminded attendees to reflect on the intersecting concepts of therapeutic effectiveness, clinical value, and financial toxicity.

Looking back at the annual meeting, I have sincerely appreciated the opportunity to serve as Editor of the 2014 ASH News Daily, and I am indebted to our talented team of authors and ASH staff who produced an amazing product. If you missed any of the articles, catch them online. I hope you will join us in Orlando in 2015.