Michael R. Bishop, MD
Director, Hematopoietic Stem Cell Transplantation Program, Professor of Medicine, University of Chicago
Editor-in-Chief, ASH News Daily 2012
As a writer for ASH News Daily, the expectation is to come up with clever, catchy titles directly or indirectly related to the subject matter of your assigned articles. Upon reflecting on the recent ASH annual meeting, the usual Atlanta icons popped into my mind: Coca-Cola®, peaches, the Civil War, and Gone With the Wind. The latter of these embodiments of our congenial host city initially struck me as a particularly apropos source for creating a title for this summary article, as this year’s meeting “turned the pages” on several aspects of hematology. However, upon further reflection on the meeting, I feel myself being drawn more to the sentiments expressed in Bob Seeger’s song “Turn the Page,” than to the events portrayed in the Margaret Mitchell classic.
The sense of turning the page was captured most poignantly in the E. Donnall Thomas Lecture, delivered by Dr. Timothy Ley, from Washington University School of Medicine in St. Louis. I have always been a sports fanatic, and in my eyes, Dr. Thomas, who died this past October and whose accomplishments are commemorated in this issue of The Hematologist, was the Babe Ruth not only of my field of hematopoietic stem cell transplantation but of hematology in general. There have been many “Hall of Famers” in hematology, but for me, nobody can argue the magnitude of Dr. Thomas’ “stats” or his right to be in the “Hall.” Dr. Ley began his lecture by reminiscing about how Dr. Thomas had personally challenged him to identify and characterize the genetic basis of acute myeloid leukemia (AML). Dr. Ley went on to describe the results of experiments from his laboratory that used whole-genome sequencing to investigate the genetic basis of AML. Those landmark studies have demonstrated that an initiating somatic mutation in conjunction with one or two other cooperating somatic mutations, arising in a hematopoietic stem cell, together account for the proliferative/survival advantage that underlies the clonal expansion characteristic of AML. Dr. Ley and colleagues have also shown that accumulation of additional somatic mutations in the original initiating clone leads to development of subclones, some of which are resistant to standard AML chemotherapy. It is this Darwinian process that accounts for the treatment failure that has plagued the field for decades. Dr. Ley’s work has important clinical implications, providing both an approach to more precise disease classification and new insights into genetic characteristics that influence prognosis and management. The overarching aim of these studies is to use the genetic signature to tailor therapy for each individual patient who has AML. While reaching this goal seems futuristic, the dedication and imagination embodied in the work of Dr. Ley and colleagues inspire us to believe that impossible really is just a matter of opinion. I’m confident that Dr. Thomas would agree.
The Plenary Scientific Session further exemplified how we are turning the pages on several aspects of hematology. A very practical issue, both clinically and monetarily, which confronts clinicians on daily basis, is the prophylactic use of platelet transfusions. Dr. Simon Stanworth, representing an international team of collaborating investigators presented “The Effect of a No-Prophylactic Versus Prophylactic Platelet Transfusion Strategy on Bleeding in Patients with Hematologic Malignancies and Severe Thrombocytopenia (TOPPS trial): A Randomized Controlled, Non-Inferiority Trial.” The study included 600 adult patients who were undergoing treatment for hematologic malignancies. Both patients receiving chemotherapy only and those receiving high-dose chemotherapy with hematopoietic stem cell rescue were included in the study. The trigger point for prophylactic transfusions was a platelet count <10 x 109/L. The study demonstrated that patients who were enrolled on the prophylactic transfusion arm had significantly fewer bleeding episodes and a longer time between study enrollment and their first bleeding event. Another important and practical clinical question addressed in the Plenary Session was whether there is benefit in maintaining hematocrits lower than 45 percent in patients with polycythemia vera (PV). Dr. Tiziano Barbui presented data from the first randomized study comparing the relationship between hematocrit and the incidence of thromboembolic complications in patients with PV. The comparison groups were those whose hematocrits were maintained below 45 percent versus those whose hematocrits were maintained between 45 and 50 percent. The results of the study showed that the patient group whose hematocrit was maintained below 45 was four times less likely to experience a thromboembolic complication. A colleague commented to me that the two clinical studies described above confirmed what we already knew. However, I can think of many trials where we “knew” what the results were going to be, and we turned out to be wrong. More importantly, the results of these two trials provide us with rigorous data upon which to base treatment decisions.
The remaining presentations in the Plenary Session transitioned from old questions to relatively current questions and suggested new questions to be addressed by future studies. We heard Dr. Francesco Lo-Coco present the results of an international phase III study that supported use of the combination of arsenic trioxide and all-trans retinoic acid as first-line treatment for non-high-risk patients with acute promyelocytic leukemia. Dr. Dan-Avi Landau showed how knowledge of the past can be used to anticipate the future. In this case, the molecular characteristics of malignant subclones were shown to predict clinical outcome in patients with chronic lymphocytic leukemia. A newly discovered participant in the pathobiology of myeloid neoplasms was introduced to us by Dr. Hideki Makishima. The focus of this presentation was SETBP1, the gene that is mutated in the congenital disorder, Schinzel-Giedion syndrome (characterized by skeletal deformities, mental retardation, and neuroepithelial tumors). SETBP1 was found to be somatically mutated in subgroups of patients with CMML, secondary AML, and blast-phase CML; and in patients with AML arising out of myelodysplastic syndromes, SETBP1 mutations were shown to be acquired in the process of leukemic evolution. Like normal cells, malignant cells have to be able to repair DNA damage in order to survive. Dr. Kimberly Cramer, representing investigators from the United States, Poland, and the United Kingdom, described how advantage can be taken of addiction to a particular type of DNA repair mechanism to eradicate leukemic stem cells. In this case, homologous recombination repair of DNA double-strand breaks in CML cells was shown to be dependent on RAD52, and targeting the DNA binding site of RAD52 using a small-molecule inhibitor induced synthetic lethality in the tumor cells. This strategy holds promise for treating other types of neoplastic disease in which the malignant cells are addicted to RAD52, as normal cells have other mechanisms for homologous recombination repair and are therefore unaffected by RAD52 inhibition.
The breadth of the meeting is astounding, and at times overwhelming, but in the end, most participants leave the sessions inspired, optimistic, and invigorated. Credit for the success of the annual meeting goes in large part to the vision of the program chairs and to the leadership of last year’s ASH President, Dr. Armand Keating, whose interest in the biologic diversity of regenerative medicine provided the focus of the Presidential Symposium. Of course many of our clinician members practice oncology as well as hematology. The Society recognizes both this important demographic and the close association between ASH and the American Society of Clinical Oncology (ASCO) by organizing a combined seminar series that is reciprocated at the annual ASCO meeting. This year’s ASH/ASCO Joint Symposium, co-chaired by Dr. Keating and ASCO President Dr. Sandra M. Swain, was titled “Clinical Oncology Update: Studies from the 2012 ASCO Annual Meeting.” Attendees were rewarded with an expert overview of recent development in clinical oncology through a series of four lectures. Progress in the management of hematologic malignancies was highlighted by the presentation of abstracts that reported the results of clinical trials that investigated the efficacy of brentuximab vedotin in CD30+ lymphomas, carfilzomib, and pomalidomide in multiple myeloma, and ibrutinib in chronic lymphocytic leukemia.
Recognizing the diversity of interests of the membership, meeting sessions focused on such varied topics as a “toolbox” for quality improvement in practice, hematology in pregnancy, new approaches to teaching hematology in medical school, and epigenetics in hematopoiesis. It is noteworthy that a decade ago epigenetics was viewed largely as an arcane area of investigation with little apparent clinical relevance. At this year’s meeting, a special symposium was devoted to the subject, and we learned not only of the progress that has been made in understanding how DNA modification regulates normal hematopoiesis but also of the role of aberrant epigenetic regulation in the pathogenesis of hematologic malignancies. These discoveries have led to the development of targeted therapies, some of which are now in use or are in clinical development, reminding us again of how fundamental research provides the basis for creation of novel approaches to therapy. Coagulation held center stage in a Special Symposium on the Basic Science of Hemostasis and Thrombosis, and Dr. Alan Burnett masterfully reviewed progress in the treatment of AML in the Ham-Wasserman Lecture. We were reminded of the extraordinary intricacy and the beauty and power of the immune system in the Ernest Beutler Lecture delivered jointly by Dr. Bruce Blazer and Dr. Carl June.
My experience as this year’s ASH News Daily editor was made easier by some remarkable people including Dr. Joe Mikhael, last year’s editor, who showed me the ropes and taught me how to have fun with a hard task and by my fantastic team (“the Fab Five”) on the editorial board: Jose Bufill, MD; Jenna Goldberg, MD; Matt Hsieh, MD; Marc Kahn, MD, MBA; and Andy Leavitt, MD. Importantly, I want to thank the dedicated ASH staff, particularly Tiffany Reid, Jen Hamilton, and Karen Learner for their expert support. For those unable to attend this year’s ASH annual meeting or for those who would like to read any articles they missed or reread those they particularly enjoyed, all four copies of 2012 ASH News Daily are available on the ASH website. I hope to see all of you in New Orleans, and next year I will just get to enjoy reading the 2013 ASH News Daily. In the words of Mr. Seeger, it is time for me to “turn the page.”
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