Variant CJD and Blood Transfusion
Roger Y. Dodd, Ph.D.
Dr. Dodd is the Vice-President of Research and Development at the American Red Cross Holland Laboratory.
First described in 1996, variant CJD (vCJD) is a new human spongiform encephalopathy, characterized by a different presentation and slower progression than classical CJD and by its unique neuropathologic appearance1. Most cases of vCJD have appeared in a much younger age group than is usual for the classical disease. The etiology of vCJD is almost undoubtedly due to consumption of tissue from animals infected by the agent of bovine spongiform encephalopathy (BSE). As such, the vast majority (152 of 160) of reported cases of vCJD have been identified in the United Kingdom, or have been associated with residence there. Currently, the incidence of vCJD cases is declining. This is thought to be a consequence of efforts to eliminate BSE and to control the safety of the food chain for cattle and humans. Intriguingly, all cases of vCJD to date have occurred among patients who are homozygous for methionine at codon 129 of PrP, the gene for the prion protein, although only 37 percent of the United Kingdom population has this particular genetic pattern.
Over the years, there has been considerable concern about the potential for transmission of transmissible spongiform encephalopathies (TSEs) by transfusion of blood or blood products. The obvious bases for this concern include the facts that TSEs are dread diseases that are invariably fatal and incurable, that no effective test or screening measure exists, and that the infectious agent is highly resistant to disinfection. However, to date there has been no epidemiologic evidence of classical CJD infection among blood or plasma component recipients, despite their use for many decades. Animal model studies have suggested that the infectious titer of classical TSE agents in blood is quite low (on the order of 10 IU/mL) and that the fractionation process both reduces the titer significantly and probably dilutes any infectious agent present to a level that eliminates risk of infection 2, 3. Currently, there is a moderate level of comfort that classical CJD transmission probably does not offer much, if any, risk to recipients of blood or plasma derivatives 3,4. However, classical CJD has clearly been transmitted by pituitary-derived growth hormone, shared use of stereotactic instruments, and dura mater transplant.
As vCJD emerged, it was recognized that there were significant differences from classical CJD in terms of the "natural" infection route, the extent to which lymphoid tissue expressed the pathologic prion, and the absence of extensive observational experience. Although small animal model studies again suggested a low infectious dose in blood 5, studies in sheep clearly showed that animals orally infected with BSE could transmit the disease to other sheep by blood transfusion 6,7, validating concerns about transfusion safety.
In 2004, a case of vCJD occurred in a British individual some six years after a blood transfusion. One of the transfused units had been collected from an individual who had died of vCJD about three years after the donation. It was estimated that the likelihood of this event occurring by chance was approximately 1 in 30,000, strongly implying transfusion as the route of infection 8. The United Kingdom has maintained a capability of cross-referencing vCJD cases with transfusion and donation records. In 2004, a second incident was reported, in which the vCJD prion was found in the spleen and cervical lymph node of a patient who received blood from another individual who subsequently died of vCJD. The recipient died of unrelated causes and without vCJD symptoms 9. However, this observation essentially confirms the transmissibility of vCJD by transfusion. Another issue of some concern is the finding that the second patient, unlike the first, was heterozygous at codon 129. This has raised the specter that individuals who are not homozygous for methionine may also be susceptible to vCJD and that there may be a second wave of cases yet to appear 10.
A variety of measures to prevent or reduce the risk of transmission of vCJD by transfusion have already been put in place. In the U.S., reliance has been placed upon control of BSE in the food chain and deferral of potential blood donors who have spent time in, or have been transfused in, areas in which BSE has been endemic 11. A number of countries implemented universal leukodepletion as a reaction to early data suggesting that the infectious agent was associated with leukocytes; this concept has subsequently been disproven. In the United Kingdom, domestic plasma is no longer used for preparation of plasma derivatives, and care is taken to limit the extent of transfusion to those judged most susceptible to vCJD, such as pediatric patients. Additionally, extensive efforts are made to recall manufactured products found to contain plasma from individuals subsequently found to be affected by vCJD. No suitable test is available to detect infectious donors, but there have been early reports suggesting that it may be possible to use affinity methods to deplete infectious prions in blood components.
References:
- Will RG, Ironside JW, Zeidler M, et al. Lancet
1996;347:921-5.
- Brown P, Rohwer RG, Dunstan BC, et al.
Transfusion 1998;38:810-6.
- Brown P, CervenE1kovE1 L, McShane LM, et al.
Transfusion 1999;39:1169-78.
- Brown P. Curr Opin Hematol 1995;2:472-7.
- Cervenakova L, Yakovleva O, McKenzie C, et
al. Transfusion 2003;43:1687-94.
- Houston F, Foster JD, Chong A, et al.
Lancet 2000;356:999-1000.
- Hunter N, Foster J, Chong A, et al.
J Gen Virol 2002;83:2897-905.
- Llewelyn CA, Hewitt PE, Knight RS, et al.
Lancet 2004;363:417-21.
- Peden AH, Head MW, Ritchie DL, et al.
Lancet 2004;364:527-9.
- Carrell RW. Science 2004;306:1692-3.
- FDA: Guidance for Industry: Revised preventive measures
to reduce the possible risk of transmission of Creutzfeld-
Jakob Disease (CJD) and Variant Creutzfeldt-Jakob disease
(vCJD) by blood and blood products.
http://www.fda.gov/cber/gdlns/cjdvcjd.pdf
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2005 ASH Officers
President
James George, M.D.
James George, M.D., is President of the American Society of Hematology and Professor of Medicine at the University of Oklahoma Health Sciences Center. Dr. George's research has primarily focused on idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP). He earned his medical degree from Ohio State University and completed an internship and residency at Vanderbilt University as well as a residency and fellowship at the University of Rochester.
Dr. George has been active within the American Society of Hematology as a member of the Scientific Subcommittee on Platelets, the Committee on Educational Affairs and Training, and the Committee for Optimization of Hematologic Care. He has also been Chair of the ASH ITP Practice Guideline Panel (1994-1996), Councillor on the Executive Committee (1999-2002),Editor of the first edition of the ASH Self-Assessment Program (2001-2002), and Director of the ASH Clinical Research Training Institute (2003). In addition, he served on the Blood Editorial Board from 1985-1990 and has been an author on 91 published papers.
Dr. George served on the Food and Drug Administration's Advisory Panel on Platelet Transfusion Substitutes (in 1998 and 1999) and has also Co-Chaired National Institutes of Health Workshops on ITP and TTP (in 1997 and 1999, respectively). For his work, he has received many honors, including the Lyndon B. Johnson Research Award from the American Heart Association in 1976 and the Tibor Greenwalt Career Research Award from the American Association of Blood Banks in 2003.
President-Elect
Kanti Rai, M.D.
Kanti Rai, M.D., is President-Elect of the American Society of Hematology, a Professor of Medicine at the Albert Einstein College of Medicine, and Chief of the Division of Hematology/Oncology at the Long Island Jewish Medical Center. He is also a Consultant Hematologist at the Parker Institute for Geriatric Care.
Dr. Rai received his medical degree from S.M.S. Medical College in Jaipur, India, and completed his medical residency at Mahatma Gandhi Hospital in Jodhpur, India, and at Lincoln Hospital and North Shore Hospital in New York. He was also a Leukemia Society Fellow in Hematology and Nuclear Medicine at the Long Island Jewish Medical Center.
Dr. Rai is a distinguished hematologist known worldwide as an authority on chronic lymphocytic leukemia (CLL). He has published many scientific papers on the disorder, including his landmark paper detailing the Rai Staging system for CLL, which remains the standard in the field.
Dr. Rai has served on the ASH Nominating Committee and has been a member of ASH's Executive Committee since 1999. He has participated in several ASH annual meetings as Education Session Chair and speaker, a Plenary Session speaker, and a speaker at the Meet-the-Expert sessions. In addition, he has served as an abstract reviewer.
Vice President
Andrew Schafer, M.D.
Andrew Schafer, M.D., Vice President of the American Society of Hematology, is Chairman of the Department of Medicine and the Frank Wister Thomas Professor of Medicine at the University of Pennsylvania School of Medicine.
Dr. Schafer's major fields of interest include coagulation, thrombosis, and hemostasis. He earned his medical degree from the University of Pennsylvania, completed residency at the University of Chicago, and concluded fellowship at the Peter Bent Brigham Hospital (Brigham and Women's Hospital) and Harvard Medical School. Prior to his current appointment he served on the faculties of Harvard Medical School and Baylor College of Medicine.
An ASH member for over 25 years, Dr. Schafer has been active within the Society as a member of the Executive Committee, the Committee on Educational Affairs, the Public Information and Governmental Affairs Committee, the Nominating Committee, the Committee on Investment and Audit, and the Committee on Communications. He served as Chairman of ASH's Finance Strategic Planning Committee in 2000 and as Education Program Chair for the ASH annual meeting in 1991. In addition, he was the founding Editor-in-Chief of ASH's award-winning member newsletter, The Hematologist.
Treasurer
J. Evan Sadler, M.D., Ph.D.
J. Evan Sadler, M.D., Ph.D., is Treasurer of the American Society of Hematology and Professor of Medicine, Biochemistry, and Molecular Biophysics at the Washington University School of Medicine in St. Louis, Missouri. He also works as an investigator for the Howard Hughes Medical Institute.
Dr. Sadler has been active within the American Society of Hematology by serving on the Scientific Committee on Hemostasis and the Program Committee. He was also the annual meeting Scientific Program Co-Chair in 1995 and Chair in 1997. He became a Councillor on the Executive Committee in 1998 and served as Associate Editor of Blood from 1993 to 2002.
Dr. Sadler's major interests are Von Willebrand disease and thrombotic thrombocytopenic purpura. He earned his medical and doctorate degrees from Duke University. He completed his internship and residency in Internal Medicine at Duke University, followed by a fellowship in Hematology at the University of Washington in Seattle.
Dr. Sadler has received many honors, including the Society's William Dameshek Prize (1998) and both the Investigator Recognition Award (1995 and 1997) and the Distinguished Career Award (2001) from the International Society on Thrombosis and Haemostasis.
Secretary
Armand Keating, M.D.
Armand Keating, M.D., is Secretary of the American Society of Hematology and serves as Director, Division of Hematology, and Professor of Medicine at the University of Toronto. He also serves as Chief of Medical Services and Head of the Department of Medical Oncology and Hematology at Princess Margaret Hospital/Ontario Cancer Institute and holds the Epstein Chair in Cell Therapy and Transplantation.
Dr. Keating's research interests include hematologic malignancies, hematopoiesis, stromal cell biology, blood and marrow transplantation, and cell therapy. Dr. Keating earned a Bachelor of Science in biochemistry and his medical degree from the University of Ottawa. He completed residency at the University of Toronto and fellowship at the University of Washington, Fred Hutchinson Cancer Research Center, and VA Medical Center in Seattle.
Dr. Keating has been active within the American Society of Hematology for 20 years, serving on the Executive Committee and the Nominating Committee and as an abstract reviewer for several ASH annual meetings. In addition, Dr. Keating has served as Chair of the Autologous Blood and Marrow Transplant Registry, President of the Canadian Hematology Society, and President of the American Society for Blood and Marrow Transplantation.
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FDA and ASH to Hold Workshop on Acute Leukemia Endpoints
Daniel Rosenblum, M.D.
Dr. Rosenblum is a Medical Officer in the Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.
In August of 2004, the Food and Drug Administration (FDA) invited the leadership of ASH to co-sponsor a workshop on acute leukemia endpoints to be held in 2005 in Washington, D.C. The purpose of the workshop will be to provide a forum for a group of experts to discuss various clinical trial endpoints that have been proposed which might be useful in establishing clinical efficacy when developing new products for treatment of leukemia. The FDA will use the workshop discussion as the basis for seeking formal recommendations on the acceptability of selected endpoints by an advisory committee. The workshop will provide a forum for interested parties representing a variety of areas of expertise to debate the value of proposed alternative endpoints to the conventionally accepted ones, such as durable complete remission (CR), overall survival (OS), and disease free survival (DFS). Of particular interest will be the surrogate endpoints that might be claimed to predict for OS and DFS. Stanley Schrier, ASH President in 2004, appointed Drs. Frederick Appelbaum, Richard Larson, Sharon Murphy, Franklin Smith, and Martin Tallman to chair subgroups on the following topics: Acute Leukemia in the Elderly, Adult ALL, Pediatric ALL, Pediatric AML, and Adult AML, respectively. Drs. Fred Appelbaum and Daniel Rosenblum will serve as co-chairs of the Steering Committee for the workshop.
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International Consortium on Acute Promyelocytic Leukemia (IC-APL)
Robert Lowenberg, M.D., Ph.D., Chair of the International Members Committee
Acute promyelocytic leukemia (APL) is characterized by a predominance of malignant promyelocytes that carry a balanced reciprocal translocation t(15;17) resulting in a PML-RAR fusion transcript. Rare patients have variant translocations. The fusion transcript permits precise diagnosis and provides the marker for the identification of minimal residual or recurrent disease. With current therapy, including all-transretinoic acid (ATRA) and anthracycline-based induction, anthracycline-based consolidation and maintenance, 70 - 80 percent of patients are alive and free of disease at five years.
A high frequency (20-25 percent) of acute promyelocytic leukemia (APL) is noted among acute myelocytic leukemias (AML) in Latin-American Mestizo patients. A lack of infrastructure and funding has prohibited clinical studies on APL in Latin American and other less privileged countries. To facilitate clinical networks on APL in these countries, ASH initiated a network among researchers from Brazil, Jordan, and Mexico, and well-known experts on APL from the U.S., Europe, and Asia. During a workshop held on December 1-2, 2004, in San Diego, the International Consortium on APL was founded.
The workshop to facilitate the infrastructure of clinical networks in developing countries was conceived, planned, and facilitated by the ASH International Members Committee (IMC). As the host committee, the IMC shall catalyze the process for this protocol and shall have oversight throughout the initial phase, during which the Steering Committee shall report to the IMC. Patient enrollment is expected to begin in March of 2006. For further information, contact LaFaundra Neville at lneville@hematology.org.
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2005 ASH SCHOLAR AWARD WINNERS ANNOUNCED
Fifteen outstanding researchers were chosen to receive an ASH Scholar Award from a field of 90 applicants last year. They are set to begin their awards on July 1, 2005. The ASH Scholar Awards are designed to encourage hematologists to pursue a career dedicated to research by providing partial salary or other support during that critical period required for completion of training and achievement of status as an independent investigator.
Basic Research Fellows
Marie-Dominique Filippi, Ph.D.
Cincinnati Children's Hospital
The role of CFC42 in neutrophil functions
M. Golan Mohi, Ph.D.
Beth Israel Deaconess Medical Center
Shp2 mutations in human leukemia
Laurent Mosnier, Ph.D.
The Scripps Research Institute
Mechanisms for cytoprotective actions of activated protein C
David Motto, M.D., Ph.D.
University of Michigan
Functional analysis of ADAMTS13 in the mouse
Matthew Walter, M.D.
Washington University
Genetic progression events in murine APL
Clinical/Translational Research Fellows
Neil Goldenberg, M.D.
University of Colorado Health Sciences Center
Prophylaxis for catheter-related infection and thrombosis in children with cancer (the PediCathClot Trial)
Kimberly Stegmaier, M.D.
Dana-Farber Cancer Institute
Induction of AML differentiation via gene expression-based high throughout screening (GE-HTS)
Roland Walter, M.D.
Fred Hutchinson Cancer Research Center
Regulation of ITIM-dependent internalization of CD33, the target for the anti-leukemia immunoconjugate, gemtuzumab ozogamicin (Mylotarg)
Basic Research Junior Faculty
Alan Cantor, M.D., Ph.D.
Children's Hospital Boston
Transcriptional regulation of megakaryopoiesis
Min Chen, Ph.D.
Baylor College of Medicine
The role of PTEN phosphatase in regulating dendritic cell apoptosis and function
Richard Dahl, Ph.D.
University of New Mexico
The role of the PU.1 to Gfi-1 ratio in directing hematopoietic differentiation
Boris Reizis, Ph.D.
Columbia University
Regulation of plasmacytoid dendritic cell development and function
Clinical/Translational Research Junior Faculty
Jorge DiMartino, M.D., Ph.D.
Cincinnati Children's Hospital
Development of a human in vitro model of leukemia induced by chimeric Mll oncoproteins for the pre-clinical evaluation of DNA methylthransferase
Irene Ghobrial, M.D.
University of Pittsburgh
Study of the P13K pathway in non-Hodgkin lymphoma
Xianzheng Zhou, M.D., Ph.D.
University of Minnesota
Identification of MHC class II restricted male-specific minor histocompatability antigens
For those interested in applying for an ASH Scholar Award, please visit the ASH Web site for eligibility and application information. Contact Karin Lombardi, ASH Development Manager, at klombardi@hematology.org with any questions.
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PNH Registry Open and Enrolling Patients
The Paroxysmal Nocturnal Hemoglobinuria (PNH) Patient Registry is the first comprehensive, observational, multi-national research initiative documenting clinical and humanistic outcomes in the management of patients with the disease. The Registry will bring together physicians and patients from around the world, with the collective goal of increasing understanding of the fundamental and clinical characteristics of PNH. The Registry opened this fall and is currently enrolling patients. Visit www.pnhregistry.org for more information.
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ATTENTION ASH MEMBERS:
ASH 50TH ANNIVERSARY, 2008
In preparation for ASH's upcoming 50th anniversary in 2008, the Planning Committee is looking for historical ASH documents, photographs, and other memorabilia (such as annual meeting posters or programs) that might be of interest to others. If you have materials or memories to share from ASH's younger days, send an e-mail to ASH@hematology.org. You can also send a letter to ASH 50th, c/o The American Society of Hematology, 1900 M Street NW #200, Washington, DC, 20036, but DO NOT send items through the mail. ASH staff will follow up with those willing to contribute items.
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Thanks and Congratulations!
ASH is deeply appreciative of all of the members who took time out of their busy days to respond to our recent member survey. The feedback provided will help ASH better serve members in the future. As a token of appreciation, all members who completed the survey were automatically entered into a drawing for two free round-trip air tickets. Congratulations to the winner, Dr. Paolo Anderlini of M.D. Anderson Cancer Center.
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Call for Award Nominations
ASH members are invited to submit nominations for the William Dameshek Prize, Henry M. Stratton Medal, and E. Donnall Thomas Lecture and Prize for the year 2005. Letters of nomination must include a brief paragraph summarizing the nominee's contributions to hematology as well as a current bio-sketch or curriculum vitae. Send nominations by postal mail to American Society of Hematology, Attn: LaFaundra Neville, 1900 M Street, NW, Suite 200, Washington, DC 20036, or via e-mail to lneville@hematology.org.
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Call for Officers, Committee Nominations
ASH is currently accepting nominations for leadership and committee member positions for the year 2006. Nominations for any of the positions available must include name, institution, and a brief paragraph to describe why the ASH member is being recommended for service. These nominations should be sent to LaFaundra Neville at lneville@hematology.org. Nominations must include all requested information. Visit http://www.hematology.org/about/call_for_nominations.cfm for more information about ASH committees.
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