ASH News Daily - Tuesday, December 13, 2011 - (Page A-3)

Tuesday, December 13, 2011 TRANSFUSION ASH NEWS DAILY Can We Take Neutrophils Out Of the Driver Seat of TRALI? By aManda BRandow, do, MS T ransfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. TRALI is defined as a new episode of acute lung injury within six hours of a transfusion and is characterized by hypoxemia, fever, dyspnea, and bilateral pulmonary infiltrates. The pathophysiology of TRALI is not entirely clear; however, neutrophil activation is thought to play an important role. Intriguing studies that focused on the role of neutrophils in TRALI were presented at the Oral session titled “Basic Science and Clinical Practice in Blood Transfusion: RBC Storage Lesion and TRALI,” on Sunday, December 11. Dr. Grace Thomas, Children’s Hospital, Boston, discussed the role of neutrophil extracellular traps (NETs) in TRALI (abstract #37). NETs are DNA fibers decorated with histones and antimicrobial proteins contained in neutrophil granules. NETs protect against infection but can cause tissue injury, activate platelets, and contribute to inflammatory diseases. The authors demonstrated that NETs biomarkers are present in the blood of patients with TRALI and that TRALI-inducing antibodies purified from blood donors activate neutrophils and stimulate NETs generation. Dr. Thomas used a TRALI mouse model to demonstrate that NETs are also abundantly found in TRALI-affected alveoli. Furthermore, the authors showed that pretreatment of mice with intranasal DNase1 prevented alveoli NETs accumulation and improved lung function. “These results support the hypothesis that NETs are indeed formed in the inflamed lungs during TRALI and contribute to the disease process and, thus, could be targeted to prevent or treat TRALI,” Dr. Thomas stated. Dr. Behnaz Bayat and colleagues at Justus-Liebig University, Giessen, Germany, were the first to prove a TRALI mechanism involving the pulmonary endothelium (abstract #40). Their data revealed that 1-HNA-3a antibodies can directly bind to pulmonary endothelial cells and induce breakdown of the endothelial barrier, subsequently causing lung edema. “This is the first report to prove a previously suspected mechanism of TRALI in which a transfused mediator induces TRALI by directly affecting the pulmonary endothelium,” Dr. Bayat stated. Dr. Christopher Silliman, Bonfils Blood Center, Denver, presented data focused on antibody filtration as a preventive measure for TRALI (abstract #41). Dr. Silliman and colleagues hypothesized that filtration of plasma with leukocyte antibodies will decrease antibody-mediated priming of PMNs and TRALI. To test this hypothesis, an antibody filter capable of removing two to three logs of donor IgG was developed and shown to successfully remove antibodies to HLA and HNA antigens as evidenced by loss of priming activity in in vitro assays using PMNs that express the cognate antigen; these filters, tested in a rodent model, also appear to inhibit antibody-mediated TRALI. “Such filters would represent the first PRBC mitigation step to prevent TRALI,” Dr. Silliman stated. This work was further discussed in a poster presentation by Dr. Silliman, titled “Characterization of Packed Red Blood Cells Prepared with Experimental Multifunctional Leukocyte Antibody-Reduction Filters,” on Sunday. Dr. John Semple, Keenan Research Center, St. Michael’s Hospital, Toronto, Ontario, discussed using IVIg infusions to prevent antibodymediated TRALI (abstract #42). Dr. Semple and colleagues induced TRALI in mice that received no pre-treatment with IVIg, were pretreated with IVIg, or received IVIg after TRALI symptoms developed. The authors found IVIg pre-treatment was protective against shock, lung edema, and mortality and significantly reduced production of neutrophil reactive oxygen species. Moreover, mice that received IVIg after TRALI induction had significant protection against lung damage and mortality. In contrast, mice that did not receive IVIg suffered reduced body temperature, pulmonary neutrophil accumulation, and death. “This animal model may be the first to demonstrate a successful therapy for antibody-mediated TRALI. It is a proof-of-concept, at least, that IVIg is effective in antibody-mediated acute lung injury, and it may have a benefit in certain at-risk patient populations. Hopefully, clinical trials may confirm this exciting observation,” Dr. Semple stated. The important insights offered by these scientists bring us one step closer to determining how the neutrophil gets its license to drive the TRALI and the ways in which this license can be revoked! Dr. Brandow indicated no relevant conflicts of interest. Page A–3 ® EHA President Dr. Ulrich Jäger, far left, and ASH President Dr. J. Evan Sadler look on as Dr. Alan Bernstein delivers his presentation at the ASH-EHA Joint Symposium on Sunday. MYELOMA More Flavors For Multiple Myeloma By heatheR landau, Md and Michael a. RoSenzweiG, Md T he last decade has been characterized by significant progress with respect to the treatment of patients with multiple myeloma (MM), predominantly due to the activity and availability of novel agents (thalidomide, lenalidomide, and bortezomib). But despite deeper responses and prolonged progression-free and overall survival, the overwhelming majority of patients eventually relapse on these agents and salvage treatment is required. Fortunately at this year’s meeting, not only did several groups identify resistance mechanisms to immune modulating agents (IMiDs) and proteosome inhibitors, but high response rates to second- and third-generation agents were demonstrated. A handful of new drugs and strategies with promising activity were also introduced, and chocolate and vanilla may no longer be the only flavors around. Translational efforts focusing on drug resistance were presented in several Oral sessions Sunday afternoon. Dr. Xiao Zhu (abstract #127) from the Mayo Clinic in Scottsdale, Arizona, presented data on an important mechanism of IMiD resistance, decreased cereblon expression that will be studied as a biomarker to identify patients destined to fail IMiD therapy. In a murine model of MM, Enrique M. Ocio (abstract #134) from University Hospital of Salamanca, Spain, showed that pERK, pMEK, pRAF, and RAS were upregulated in MM cells that became resistant to lenalidomide and pomalidomide. This was consistent with the clinical data presented. Dr. Paul G. Richardson (abstract #634) from Dana-Farber Cancer Institute, reported that in patients who were refractory to both lenalidomide and bortezomib, 16 percent and 30 percent had at least a PR to single agent pomalidomide and pomalidomide/ dexamethasone, respectively. Dr. Xavier Leleu (abstract #812) from Hôpital Claude Hurez, Lille, France, on behalf of the IFM also showed a 35 percent response rate to pomalidomide/dexamethasone in patients refractory to both lenalidomide and bortezomib. Triplet combinations that included pomalidomide were even more active in heavily pretreated patients. Dr. Antonio Palumbo (abstract #632) University of Torino, Torino, Italy, reported that in patients refractory to lenalidomide the combination of pomalidomide, cyclophosphamide, and dexamethasone resulted in > PR in 73 percent of patients. Despite the limitations of cross-trial comparisons, the antibiotic clarithromycin does seem to potentiate the combination of pomalidomide/ dexamethasone since Dr. Tomer M. Mark (abstract #635) from Weill Cornell Medical College, New York, also showed that the combination of clarithromycin, pomalidomide, and dexamethasone (ClaPD) resulted in responses > PR in 60 percent of patients compared with the ORR of 34 percent reported by Dr. Richardson. Bortezomib resistance has also been investigated and based on the work by Dr. Linda Baughn (abstract #129) from the University of Minnesota in Minneapolis, proposed targeting B-cell differentiation in order to overcome resistance. Combination chemotherapy with lenalidomide, bortezomib and dexamethasone (RVD) is known to be highly effective, but at this meeting Dr. Andrzej Jakubowiak (abstract »» MULTIPLE MYELOMA Page A-6

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ASH News Daily - Tuesday, December 13, 2011

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