Stephen P. Hunger, MD
This morning’s late-breaking abstract session at 7:30 a.m. in Hall D includes exciting new developments from clinical trials that will influence treatment of patients with benign and malignant hematologic disorders.
Dr. Wendy Zondag from Leiden University Medical Centre will report that outpatient treatment of acute pulmonary embolism (PE) with low-molecular-weight heparin followed by vitamin K antagonists is effective and safe for low-risk patients (selected using the Hestia criteria). These findings will have significant clinical practice implications for treatment of this common disorder that has an increasing number of therapeutic options. In the past, this has almost always included an initial period of in-hospital treatment. A regimen that can be administered completely in the outpatient setting should have major economic benefits and might also impact patient quality of life.
Dr. Adrianna Vlachos of Hofstra North Shore-LIJ School of Medicine will present data on a patient diagnosed with Diamond-Blackfan anemia (DBA) in 1991 who remained transfusion-dependent for 19 years. This patient underwent high-resolution single nucleotide polymorphism analysis as part of a cohort of DBA patients who lacked mutations in the 11 ribosomal protein genes implicated in DBA. A focal interstitial somatic deletion of chromosome 5q was discovered that included RPS14. The patient was then treated with lenalidomide, which is often effective in ameliorating anemia in adults with 5q- syndrome characterized by haploinsufficiency of RPS14, and became transfusion independent. These data exemplify how understanding the genetic heterogeneity of hematologic disorders can help identify effective therapies. Dr. Vlachos remarks that “searching for and finding answers is incredibly rewarding for translational research investigators but is most important for the patients.”
Constitutional RUNX1 and CEBPA mutations have been identified in some families with autosomal dominant familial predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Using a candidate-gene approach, Dr. Hamish Scott of Adelaide, Australia, and colleagues discovered heterozygous GATA2 mutations tracking with disease in four previously unexplained MDS/AML families. These findings will shed new light on the genetics of leukemia predisposition, identify GATA2 as another therapeutic target, and may provide individuals with a family history of MDS/AML with opportunities for pre-symptomatic genetic testing. Dr. Marshall Horwitz, senior author on the study, commented, “People in these families develop all subtypes of AML and MDS. Their GATA2 mutations occur adjacent to an amino acid that is also mutated in some patients with CML in blast crisis, suggesting that this pathway may be critical for several different myeloid malignancies.”
Dr. Phillip Scheinberg from National Heart, Lung, and Blood Institute (NHLBI) will report results of the first randomized clinical trial of cyclosporine (CsA) combined with horse versus rabbit anti-thymocyte globulin (ATG) in severe aplastic anemia (SAA). They found that rabbit ATG/CsA is markedly inferior to horse ATG/CsA as first treatment in SAA, as measured by hematologic response rates at three and six months and by overall survival. Dr. Scheinberg remarks “this trial (re)establishes horse ATG/CsA as the standard immunosuppressive regimen for SAA.”
Dr. Hojun Li from Children’s Hospital of Philadelphia will discuss exciting new findings with in situ correction of factor IX (F9) gene mutations in a murine model of hemophilia B. Investigators increased targeting efficiency by using adeno-associated viral vector delivery of zinc finger nucleases to induce site-specific double-strand DNA breaks at the intended targeting site. With this strategy, they obtained F9 levels of 2 percent to 7 percent of normal and phenotypic correction in clot formation in F9 deficient mice. These results have significant implications for treatment of other inherited hematologic diseases.
Finally, Dr. Jerry Radich will present early results from a randomized trial of imatinib (400 mg/day vs. dasatinib 100 mg/day) in patients with newly diagnosed chronic-phase CML. Progression-free and overall survival rates were outstanding in both arms at 12 months, with very few events. Dasatinib was associated with more grade 3-4 toxicity but also with significantly deeper molecular responses at 12 months and a trend toward higher cytogenetic complete response rates, but not significantly higher rates of > 4 log or > 4.5 log reduction in BCR-ABL transcript levels. Longer follow-up is needed to determine whether the short-term deeper molecular response seen with dasatinib leads to improved long-term outcomes.
These six abstracts were selected for presentation in this setting because they are expected to have important clinical implications. I am certain that those who attend this session will not be disappointed and will return home with new therapeutic options to ponder.
Dr. Hunger indicated no relevant conflicts of interest.