By Margaret V. Ragni, MD, MPH
2008-01-01
Dr. Ragni is Professor of Medicine in the Department of Medicine, Division Hematology/Oncology at the University of Pittsburgh and Director, Hemophilia Center of Western Pennsylvania. She was also the Editor-in-Chief of ASH News Daily 2007.
Continuing in the rich tradition of ASH meetings, the 49th annual meeting in Atlanta was notable for outstanding presentations on new genetic mechanisms of disease, inhibitors of novel molecular pathways, host response in gene transfer, new targeted therapies in clinical trials, and pressing public health issues. Among the firsts were a phenomenal Trainee Day, a one-hour "Best of ASH" meeting summary, and late-breaking abstracts. The emphasis on young physicians and scientists in workshops and sessions about writing a successful grant, finding a good mentor, and landing the ideal career was outstanding. Perhaps not coincidentally, three of the six late-breaking abstracts were authored by a fellow or medical student! And, in a new tack, a French edition of ASH News Daily was published.
On behalf of the dedicated ASH News Daily authors, Drs. Jay Coghill, Naomi Galili, Irene Ghobrial, Xavier Leleu, Alice Ma, Ruben A. Mesa, Vida Almario Passero, Azra Raza, and Robert L. Redner, the top ten hits at the ASH meeting are…The envelope please…
10. Targeting P13K/AKT for T-ALL may be a NOTCH above the rest.
New targets for T-ALL include the activating mutations in the NOTCH1 receptor. Among these, the gamma-secretase inhibitors (GSIs), which block NOTCH1 activation, have been of great interest. Their use is limited, however, by the development of resistance. In his presentation, Dr. Adolfo Ferrando described the molecular sequelae of resistance to NOTCH inhibitor therapies in T-ALL and the molecular basis for use of the alternative inhibitors of the P13K/AKT pathway, which are now in clinical trial.
9. Hepcidin regulation of dietary iron absorption is unmasked.
Investigating the role of hepcidin in the regulation of iron absorption, Dr. Bruce Beutler (standing in for his father) described elegant studies of mice with the Mask phenotype. These mice have iron deficiency and regional alopecia of truncal hair, which is corrected with iron supplementation. In contrast to typical iron deficiency in which the iron regulator hepcidin is greatly decreased, and with it, hepcidin inhibition of iron absorption and iron release from macrophages, Mask mice have elevated hepcidin and profound iron deficiency. Utilizing positional cloning, Dr. Beutler's group (along with his father's research group) identified a splicing error in the Tmprss6 gene as the cause of the Mask phenotype. TMPRSS6 is required for normal absorption of dietary iron. In mice with the Mask phenotype, the hepcidin gene transcription is inhibited, resulting in inhibition of hepcidin upregulation and the Mask phenotype.
8. RNAi identifies RPS14 as the cause of 5q- MDS.
In a tour de force, Dr. Benjamin Ebert reported at the Plenary Session on exciting research using RNA interference that led his team to identify the causal gene of the 5q- syndrome, a subset of MDS. Patients with this disorder have a block in RBC maturation. Thus, by assessing each of 41 candidate genes for capacity to induce hematopoietic differentiation in CD34+ cells, RPS14 gene, which encodes for ribosomal protein, was identified as the causal gene. Subsequent simultaneous sessions described targeted therapeutics taking advantage of these findings, such as lenalidomide, which has eliminated transfusion dependence in up to 75 percent of individuals with the 5q- MDS syndrome.
7. Imatinib for childhood ALL comes of age.
The successes of the tyrosine kinase inhibitor imatinib in CML have led to studies of the drug in childhood Ph+ ALL. In this Plenary abstract, Dr. Kirk Schultz detailed the results of his Children's Oncology Group protocol in which imatinib was given, with high-dose chemotherapy, for 42 to 280 days. What the group found was that the longer imatinib was used, the better the event-free survival: 84.7 percent among those receiving imatinib for 280 continuous days, as compared with 41.2 percent among those given imatinib for the shortest duration.
6. AMG 531 does for platelets what EPO does for RBCs.
AMG 531, the novel thrombopoietin (TPO) receptor stimulating agent, garnered great attention. In a phase III randomized, double-blind, placebo-controlled trial in splenectomized ITP patients reported by Dr. Terry Gernsheimer, AMG 531 increased platelet counts to a significantly greater degree than placebo. The primary endpoint, maintaining a platelet count greater than 50,000/ul for at least six weeks of the last eight weeks on study, was achieved by 38 percent of those treated versus none of the placebo group. The drug was considered safe, although one patient developed thrombosis. More studies are warranted for this promising agent.
5. Oral agent prevents clots at the Xa intersection.
Among the hot topics of discussion at the Plenary Session was the new oral anti-Xa inhibitor, rivaroxaban, currently in phase III clinical trials. This new oral anticoagulant requires no monitoring and has no interaction with food. When compared with enoxaparin for thromboprophylaxis following hip arthroplasty, rivaroxaban showed a four-fold lower incidence of VTE, PE, and all-cause mortality, with a similar safety profile. Review by the FDA is projected for late 2009.
4. Hematologists and consumer groups aggregate to prevent thrombosis.
Venous thromboembolism (VTE) headlined several special sessions at the annual meeting, bringing together advocacy groups, grassroots organizations, and hematologists. The presentations made from diverse perspectives underscored the heavy toll VTE disorders take and the major advances that are needed to bring new understanding and new treatment to the field. With more than 600,000 individuals developing VTE each year in the United States, this disorder is a major cause of morbidity and mortality. There are ongoing epidemiologic studies to determine VTE risk, based on age, race, and gender, which will be useful in the development of optimized prevention and treatment approaches. Mechanistic studies of age-related cellular and molecular changes that affect the vascular epithelium are also in study. Health-care delivery, outreach and education programs, development of multidisciplinary teams, and heath-services research are among the programs already underway.
3. The formidable partners, infection and inflammation, assume a malignant role.
A discussion of molecular mechanisms of infectious agents in cancer development was highlighted at the ASH/ASCO Joint Symposium. Dr. Francis Megraud discussed the role of genetic mutations and epigenetic changes in malignant transformation, using the examples of Helicobacter pylori and inflammation in the development of gastric cancer. Dr. Maura Gillison focused on the malignant transformation with human papillomavirus (HPV) and oropharyngeal squamous cell carcinoma. Dr. Eric Klein completed the session with a talk on the new gamma retrovirus XMRV in patients with prostate cancer who have a common polymorphic variant of the RNASEL gene, which is involved in antiviral activity of interferons. Understanding the pro-inflammatory pathways activated by these pathogens should lead to potential new targeted treatments and preventions of some of these common cancers.
2. Getting to know JAK opens up the world of MPD.
The Ham-Wasserman Lecture was presented by Dr. Radek Skoda in recognition of his seminal work with c-MPL and hereditary thrombocythemia. It was his initial report with Dr. Kralovics of the JAK2V617F defect that generated the explosion of myeloproliferative disorders (MPDs) research. In his talk, Dr. Skoda provided an exciting journey through mutated genes, delineating, on a molecular basis, why some MPDs affect red cells, others white cells, and still others platelets. Further, these findings at the bench have provided molecular markers for disease as well as targets for treatment, and will also be the basis for the upcoming revised WHO diagnostic criteria for MPDs.
1. Cutting the cord launched the field of stem cell transplantation.
In recognition of his research leading to the first ever cord blood stem cell transplant that launched the field of cord blood transplantation, Hal E. Broxmeyer, PhD, was awarded the E. Donnall Thomas Lecture and Prize. He was honored for his prescient work on stem cells and its profound influence on research. His research has revolutionized clinical outcomes for many hematologic diseases and has provided hope for many previously considered untreatable.
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