ASH News Daily 2012 - Tuesday, December 11, 2012 - (Page A-2)

Page A–2 ® ASH News Daily 2012 Editorial Board Editor Michael R. Bishop, MD University of Chicago Authors Jose A. Bufill, MD Michiana Hematology Oncology, PC Jenna D. Goldberg, MD Memorial SloanKettering Cancer Center Matthew Hsieh, MD National Institutes of Health Marc Kahn, MD, MBA Tulane University School of Medicine Andrew D. Leavitt, MD University of California, San Francisco The information contained in ASH News Daily is provided solely for educational purposes. A diversity of opinions exists in the field of hematology, and the articles in this publication are often intended to inform readers about more than one point of view. These articles are not comprehensive and should not be used as a substitute for traditional sources of hematology information, traditional diagnostic and treatment information, or the individual judgment of health-care providers. The views expressed in ASH News Daily do not necessarily represent ASH’s views, and their inclusion in this publication should not be interpreted as an endorsement by ASH. ASH is not responsible for any inaccurate or inappropriate use of the information, publications, products, or services discussed or advertised within. ©2012 by the American Society of Hematology All materials contained in this newspaper are protected by copyright laws and may not be used, reproduced, or otherwise exploited in any manner without the express prior permission of ASH News Daily. Contributing authors have declared any financial interest in a product or in potentially competing products, regardless of the dollar amount. Any such financial interest is noted with the author byline. LEUKEMIA The Beginning of AML Genomics – Not the End BY MATTHEW HSIEH, MD Y esterday Timothy J. Ley, MD, from Washington University School of Medicine, St. Lou- is, MO, delivered the E. Donnall Thomas Lecture for his research in acute myeloid leukemia (AML). AML, a rare but highly aggressive form of malignancy, is currently classified based on pathology and chromosomal analysis. This classification is helpful but inadequate in a substantial proportion of AML that has typical morphology with normal cytogenetics. Targeted investigations have identified mutations among candidate genes in this group of AML, but critical questions relative to the initiating event/mutation and more efficient ways to study AML with “normal” chromosomes remained unanswered. Dr. Ley began the lecture with his work in the early 1980s using low-dose azacitadine in patients with AML and MDS. He shared that while the low response rate was disappointing, he distinctly remembered his conversation with Dr. Thomas and his challenge: “You should define the genetic determinants of response.” Dr. Ley dedicated the remainder of the lecture to describing his response to this challenge. He and his team at Washington University used whole-genome sequencing in paired samples (skin and AML cells), and reported the initial results from one patient with AML with normal cytogenetics. They uncovered previously known mutations (e.g., NPM1 and FLT3), but also several new ones. After sequencing more patients, they were able to classify which mutations are founding or initiating, and which ones are cooperating. Dr. Ley’s team then applied this same approach to 24 paired AML samples, half from M3 and half from M1, and compared them with seven healthy samples. As Efficacy «« From Page A-1 showed a statistically higher rate of depression among survivors of TTP when compared with the general population (abstract 366). Lara N. Roberts from King’s College in the United Kingdom presented data on the National VTE Prevention Programme (abstract 363). She and her colleagues were able to demonstrate a significant reduction in patient harm with the introduction of a comprehensive risk assessment, thromboprophylaxis, and root-cause analysis program instituted on a na- expected, they found PML-RARA mutations in the M3 samples, but mutations in NPM1, DNMT3A, and IDH all occurred together in the M1 samples. These divergent sets of mutations were mutually exclusive, strongly suggesting that these are the leukemia-initiating lesion(s). There were also mutations that were present in both AML sample sets, with FLT3 being the most common – suggesting that FLT3 mutations (and others) are cooperating lesions in leukemogenesis. They also found that both sets of AML samples had an average of one to five events, fitting with the pattern of one initiating and one or more cooperating lesions. They next tried to identify what happens to the founding clones at the time of relapse. At diagnosis, some patients have one, while others have more clones. It appears that when patients with multiple clones relapse and go through chemotherapy, treatment eliminates only some of the clones. The remaining clones not only retain their founding mu- tation, but acquire additional mutations with proliferation advantage. It is now clear that as we all get older, the more mutations we accumulate. Dr. Ley has convincingly shown us that to develop AML there is one initiating mutation, followed by one or two cooperating lesions. He also has demonstrated the progression of these clones through AML treatment and how the genetics do determine treatment response. I think he has clearly answered Dr. Thomas’ challenge. Now it is time for us to answer his challenge, “To understand AML, it is not enough to know the disease, but it is necessary to know the clones.” Dr. Hsieh indicated no relevant conflicts of interest. Look for an article about the late E. Donnall Thomas in the January/February 2013 issue of The Hematologist by Frederick Appelbaum, MD. ASH NEWS DAILY Tuesday, December 11, 2012 Dr. Daniela Zackova, University Hospital Brno, Brno, Czech Republic, takes advantage of a Wi-Fi Hot Spot sponsored by Incyte and Seattle Genetics. tional level. A meta-analysis presented by Siavash Piran, MD, MSc, from the University of Ottawa on the outpatient treatment of pulmonary embolism suggested that most patients with uncomplicated pulmonary embolism can be treated as outpatients without excess adverse events (abstract 361). Deena Khamees, BS, MLS, from The Ohio State University presented a paper (abstract 477) on the effectiveness of population screening for bleeding disorders among adolescents with heavy menstrual bleeding. Despite available recommendations from the American College of Obstetricians and Gynecologists, these authors found that very few adolescents were actually screened, suggesting that our estimates of the frequency of bleeding disorders in this population are severely underestimated. These papers, as an aggregate, will help the clinician decide what to do in an individual practice and help to show outcomes of diseases over time. Moving the laboratory into the office is the inevitable result of well-designed studies. Dr. Kahn indicated no relevant conflicts of interest.

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ASH News Daily 2012 - Tuesday, December 11, 2012

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