47th Annual Meeting and Exposition
December 10-13, 2005

Georgia World Congress Center
Atlanta, Georgia

Education Program

Please note that duplication and recording are prohibited in the session rooms.

The 2005 Education Program will be held Saturday, December 10, and Sunday, December 11. Each session will be offered twice unless otherwise noted. Chapters based on these sessions will be published in the Education Program Book, Hematology 2005.

Disorders of the erythrocyte membrane constitute a large percentage of inherited hemolytic anemias. These include hereditary spherocytosis, hereditary elliptocytosis and related disorders, and the stomatocytosis syndromes.

Dr Patrick Gallagher will review the clinical presentation and laboratory methods available for diagnosis of these disorders. Advances in our understanding of the molecular and genetic bases of these disorders will be examined, with an emphasis on the clinical implications of these discoveries. Recent controversies in the management of membrane disorders will also be discussed.

Dr Josef Prchal will discuss mutations that produce red cell enzyme deficiencies. Such deficiencies can be associated with diverse phenotypes that range from hemolytic anemia, methemoglobinemia, polycythemia, and neurological and developmental abnormalities. Most of these mutations occur sporadically; others, such as common glucose-6-phosphate dehydrogenase mutants, are endemic. Common glucose-6-phosphate dehydrogenase mutants likely reached their prevalence because they provide some protection against severe malaria. In this review, glucose-6-phosphate dehydrogenase, pyruvate kinase, 5' nucleotidase, and cytochrome b5 reductase deficiencies will be discussed in detail. Limitations of commonly used screening tests for detection of these disorders will also be emphasized.

Dr Herbert Bonkovsky will provide a brief overview of porphyrin and heme metabolism and the porphyrias, both erythropoietic and hepatic. The major part of the update will be focused on the acute or inducible hepatic porphyrias, which include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the rare acute porphyria due to severe deficiency of 5-aminolevulinate (ALA) dehydratase. He will also touch upon similarities of these syndromes with hereditary tyrosinemia type 1 and lead poisoning, in which there is profound inhibition of ALA dehydratase. The emphasis will be on how an understanding of the biochemical and molecular bases for these disorders explains the clinical features and forms the basis for rational therapy and prophylaxis.

This session will focus on the question of the molecular treatment of beta thalassemia.

Thalassemias have been studied at the biochemical and pathophysiological levels for over 50 years, and they were the first human diseases to be molecularly delineated. The question now is whether the tremendous effort that has been made in the understanding of the thalassemias at the molecular and pathophysiological level will pay off with the development of new molecular therapies which could eventually lead to cures for these disorders.

Dr Swee Lay Thein will discuss the pathophysiology of beta thalassemia as it relates to the development of molecular therapies. The background information on why fetal hemoglobin is beneficial to the disease and why the induction of Hb F is expected to have curative results will be discussed. The pathophysiological data that indicate that globin gene therapy can eventually lead to a cure of beta thalassemia will be presented.

Dr Susan Perrine will discuss state-of-the-art research on the induction of fetal hemoglobin synthesis. She will summarize clinical studies on fetal hemoglobin inducers and will describe recent work that shows that certain fetal hemoglobin inducers can also stimulate in vivo erythropoiesis. She will present the therapeutic potentials of the newer fetal hemoglobin inducers as revealed by studies of animal models. She will outline the steps required for translating discoveries of Hb F inducers to clinical practice and the roadblocks that inhibit progress in that field.

Dr Philippe Leboulch will focus on stem cell gene therapy. She will outline the principles of globin gene therapy and will summarize the recent progress made with the introduction of lentiviral vectors that cure thalassemia and sickle cell disease in preclinical models. She will summarize the known risks of using retroviral vectors for stem cell gene therapy, the expected clinical benefits, and the most likely scenarios of clinical application of gene therapy in the beta thalassemia syndromes.

The major causes of morbidity and mortality in sickle cell disease are the acute and long-term consequences of the combination of hemolytic anemia and vascular occlusive events. It is the polymerization of deoxyhemoglobin S that initiates microvascular occlusion, while subsequent interactions between the sickle erythrocyte and the vascular endothelium serve to potentiate or propagate this process. With the exception of hydroxyurea, current therapies are aimed largely at symptom control during vaso-occlusive episodes and at the prevention of symptoms by prophylactic blood transfusion in at-risk patients. This session will consider recent advances in the pathobiology of sickle cell disease, and, based on this evolving knowledge base, a discussion of rational approaches to the prevention or treatment of complications and strategies with curative intent will take place.

Dr Mark Gladwin will review the cardiopulmonary complications of the sickle cell syndromes, with special emphasis on pulmonary hypertension. Pulmonary hypertension (PHT) is one of the leading causes of death in adult sickle cell patients, with a prevalence of 20-40%, and the risk factors associated with developing PHT will be reviewed. In addition, there is a growing body of literature that posits a link between chronic hemolysis of diverse causes and PHT. Dr Gladwin will review this broader literature and discuss the possible central role of nitric oxide in this process.

Dr Richard Lottenberg will provide an evidence-based approach to the treatment of adults with sickle cell disease. As in all other areas of medicine, the best evidence to assist clinicians in doing their jobs and helping patients best understand their options results from randomized controlled clinical trials. Recommendations that can be made for patients with sickle cell disease based on the existence of this high level of evidence will be presented. However, there is a paucity of prospective clinical trials to guide treatment decisions for the adult population. The development of clinical guidelines using available evidence and tailored to the practice setting will be discussed.

Dr Mark Walters will finish the session by providing an update on the status of stem cell therapy approaches to sickle cell disease. The experience of the US multicenter trial of sickle cell children who have undergone hematopoietic stem cell transplantation (HSCT) will be reviewed and compared and contrasted with the European experience. The current limitations of myeloablative HSCT will be discussed, along with the feasibility and applicability of non-mye-loablative approaches. Finally, a review of the formidable challenges that need to be overcome before gene therapy for sickle cell disease can become a reality will be presented.

Platelets are responsible for primary hemostasis, as well as thrombosis, in arteries and in the microcirculation. Moreover, abnormal platelet function has been found to perturb the former and potentiate the latter. Platelet function disorders can be either inherited or acquired. Congenital disorders are uncommon to rare, but can cause serious bleeding. By contrast, acquired disorders are relatively common and are generally mild. Nonetheless, their clinical importance increases in the presence of thrombocytopenia or additional disorders of hemostasis, and they can be paradoxically associated with thrombosis. This session will comprehensively review the contribution of abnormal platelet function to hemostasis and thrombosis.

Dr Robert Handin will discuss congenital platelet function disorders. He will emphasize the diagnosis and management of disorders of platelet secretion that are often encountered in hematologic practice as well as less well-characterized disorders of metabolic pathways that regulate platelet shape change, secretion, and aggregation.

Dr Michael Kroll will survey clinically significant syndromes of platelet dysfunction secondary to drugs, medical illnesses, and surgical interventions. The paradoxical pro-thrombotic effect of the selective cyclooxygenase inhibitors will be also be considered. Current approaches to restoring full hemostatic function to blood bank platelets will be discussed with a view to the future of platelet transfusion therapy.

Dr Claire Harrison will discuss the pathogenesis of thrombosis in the myeloproliferative disorders, focusing on the role of the platelet in this process. In addition, she will discuss novel biologic features that contribute to thrombosis in these disorders and the basis for current approaches to therapy.

The management of hemophilia, von Willebrand's disease, and other bleeding disorders are critical aspects of coagulation practice. This session will cover current best practices and new developments in the approach to these disorders.

Dr Catherine Manno will review current management of hemophilia A and B, including the use of pre-natal diagnosis in pregnancies at risk and the risks and benefits of prophylactic administration of concentrates to children with hemophilia. She will also review management of other bleeding disorders of childhood including ITP.

Dr Catherine Hayward will review mild bleeding disorders, including clinical presentation, laboratory diagnosis, and common problems in management of these disorders.

Dr Craig Kessler will discuss additional issues in management of hemophilia, including immune tolerance induction and new clotting factor concentrates. He will discuss the issue of inhibitor occurrence in previously treated hemophilia patients who receive B domain-deleted Factor VIII versus full-length protein products. He will also discuss management of acquired inhibitors and progress in development of novel therapies for hemophilia.

Ischemic heart disease and stroke are major causes of morbidity and mortality. More than 1 million Americans have an acute myocardial infarction (AMI) annually, and about 25% of all deaths are due to AMI. Likewise, more than 600,000 Americans have a first or recurrent stroke each year, and stroke is the third leading cause of death and a major cause of long-term disability.

Atherothrombosis, the process underlying most heart attacks and strokes, reflects a complex interplay between atherogenesis, thrombogenesis, and inflammation. Although the pathology is well defined, there is much to learn. For example, how do genetic and environmental factors combine to influence these processes? Is inflammation a cause or a consequence of atherosclerosis? Why do anti-inflammatory agents, such as the coxibs, increase the risk of cardiovascular events? These are but some of the questions that will be addressed in this session.

Dr Mark Crowther will focus on the burden of disease while reviewing the pathogenesis of acute coronary syndromes and ischemic stroke. The role of inflammation in atherogenesis will be described. For example, the association between increased levels of C-reactive protein (CRP) and cardiovascular disease is a consistent finding in prospective clinical and epidemiological trials. Is CRP a marker of underlying inflammation or does it have a causal role in atherogenesis? Data supporting both possibilities will be presented, and the potential utility of inflammatory markers for risk stratification will be discussed.

Dr David Ginsburg will provide an overview of the genetics of atherothrombosis. Atherogenesis represents a complex interplay among such factors as genetic predisposition, classical risk factors, coagulation disorders, and inflammation. Although several thrombophilic defects underlying venous thrombosis have been elucidated, their role in arterial thrombosis is uncertain.
Dr Ginsburg will discuss emerging data that unravel the complex interaction between the genetic and environmental factors involved in atherothrombosis.

Recent studies indicate that coxibs, selective cyclooxygenase 2 (COX-2) inhibitors, increase cardiovascular risk. What is the mechanism for their cardiovascular hazard and which patients are at increased risk? Are there differences among the various drugs within this class? Selective COX-2 inhibitors suppress prostacyclin production but have no effect on thromboxane A2 production. Based on studies in gene-deleted mice, Dr Tilo Grosser will provide evidence that ablation of the prostacyclin receptor (a) exaggerates the response to agonists that elevate blood pressure, (b) accelerates atherogenesis, and (c) enhances thrombosis. This information provides new insights into how COX-2 inhibitors may increase the risk of myocardial infarction and stroke, and whether traditional antiinflammatory agents have similar risks.

The diagnosis and management of hypercoagulable states (thrombophilias) is being increasingly assumed by practicing hematologists. The rational clinical approach to patients with suspected hypercoagulable states depends on an understanding of inherited and acquired risk factors.

Inherited hypercoagulability is due to deficiency of physiological anticoagulant proteins or increased activity of clotting factors. Ironically, rapid recent progress in identifying inherited thrombophilias has complicated diagnostic and therapeutic decision making by the clinician. Dr Mary Cushman will review the inherited disorders associated with the hypercoagulable state. The presentation will include discussion of the associations of these disorders with first and recurrent thrombosis. A clinical approach to the use of laboratory results of thrombophilia testing will be presented.

Dr Paolo Prandoni will review established and recently recognized acquired hypercoagulable states that are associated with thromboembolism in both hospitalized and ambulatory medical patients, including cancer, various medical illnesses, pregnancy, the puerperium and hormonal treatment, air travel, inflammation, and atherosclerosis. Recognition of the incidence and clinical importance of thrombosis will likely encourage more widespread use of antithrombotic prophylaxis in the future.

Dr Thomas Ortel will discuss current concepts of thrombosis in the antiphospholipid syndrome. Antiphospholipid autoantibodies are associated with increased risk for recurrent thromboembolism as well as adverse obstetrical outcomes. Patients with antiphospholipid syndrome who have sustained venous as well as arterial thromboembolic events require indefinite anticoagulant therapy because of the high risk for recurrent events if anticoagulation is discontinued. Standard anticoagulant therapy may prove inadequate in some patients with antiphospholipid syndrome, and other modalities have been used in these patients, including immunomodulatory strategies.

Despite standard procedures for donor evaluation and advances in collection, processing, and quality control of products, donor and patient safety issues persist in transfusion medicine. Safety issues in stem cell donation have become more complex as donor age has decreased. Human error and systems failures have played a prominent role in adverse transfusion outcomes as technology has reduced infectious complications. This session will focus on these aspects of donor and patient safety.

Dr Mary Horowitz will provide an overview of evaluation procedures for pediatric and adult stem cell donors and compare bone marrow harvest to apheresis collection of mobilized peripheral blood stem cells, discussing safety issues for each type of donation. Limited information is available on long-term physical and psychological effects of stem cell donation and possible adverse outcomes from multiple donations. Dr Horowitz will discuss information needed to improve the safety of stem cell donation and the role of registries in promoting donor safety.

Dr Ira Shulman will conclude the session with a discussion of the role of the transfusion service committee and its response to adverse events in improving transfusion safety. Dr Shulman has written extensively on the role of the transfusion service committee and is the webmaster for the California Blood Bank Society, which hosts discussions on all aspects of transfusion medicine.

Dr Walter Dzik will focus on the contribution of human error and systems failures to adverse transfusion outcomes, drawing from national and international experiences in examining how and why such events occur. He will describe technological advances that improve transfusion safety, including “smart” systems, bar code technologies, and related devices.

The understanding of rare diseases often elucidates important general mechanisms of cellular function and provides new insights into normal physiology. In this session, three disorders that illuminate different aspects of the innate immune system will be discussed.

Dr Daniel Kastner will introduce the hereditary periodic fever syndromes, a group of mendelian disorders that present with seemingly unprovoked episodes of serosal, synovial, cutaneous, or even meningeal inflammation. The gene underlying one of these conditions, familial Mediterranean fever (FMF), defines a family of proteins involved in the regulation of cytokine production, NF-kappaB activation, and apoptosis. The talk will summarize the clinical features, genetics, and pathophysiology of FMF and related disorders, including the TNF receptor-associated periodic syndrome (TRAPS), the hyperimmunoglubulinemia D with periodic fever syndrome (HIDS), and neonatal onset multisystem inflammatory disease (NOMID). Important advances in the therapeutic use of cytokine inhibitors in these conditions will also be discussed.

Dr Gritta Janka will then discuss the clinical and pathophysiologic features of the hemophagocytic syndromes. Hemophagocytic lymphohistiocytosis is a life-threatening inflammatory condition characterized by fever, hepatosplenomegaly, cytopenias, CNS symptoms, and coagulopathy. The common basis is an inherited or acquired immune defect which leads to an uncontrolled ineffective immune response with expansion of activated lymphocytes and macrophages exhibiting hemophagocytosis. Initial symptoms are non-specific, often leading to a delay or failure in diagnosis; therefore, emphasis will be placed on the features that should lead the clinician to suspect the diagnosis. Emphasis will be placed on the features that should lead the clinician to suspect the diagnosis, on recent insights into underlying genetic defects causing the disease, and on new information about disease pathophysiology.

Dr Mary Dinauer will provide an update on chronic granulomatous disease and other inherited disorders of phagocyte function. Clinical features, molecular genetics, and management will be discussed. Insights obtained from knock-out mouse models regarding the role of the respiratory burst oxidase in host defense and inflammation will be described. The status of new treatments based on either gene therapy or allogeneic stem cell transplantation with non-mye-loablative conditioning will also be summarized.

Clinical approaches to aplastic anemia are ever-changing and depend on the underlying pathophysiology of the bone marrow failure as well as the age of the patient. This session will present an evidence-based, case-oriented discussion of the similarities and differences in the management in children versus adults.

Dr Blanche Alter will provide an overview of the known causes of bone marrow failure, including inherited as well as acquired conditions, and a summary of the potential modalities of treatment.

Dr Eva Guinan will consider the broader array of underlying disorders seen in children in comparison to adults. These include understanding the methods of testing for inherited marrow failure syndromes and the implications of such test results for implementation and triage of management decisions. As the natural history of patients with acquired or inherited aplastic anemia becomes better appreciated, the importance of considering long-term disease and regimen-related toxicities will be emphasized as a significant part of clinical decision making for the younger patient.

Dr Jaroslaw Maciejewski will discuss the approach to the adult patient, focusing on the age of the patient and the severity of the disease. Therapeutic options which he will examine include observation (for mild or moderate disease), immunosuppression, and stem cell transplantation, as well as salvage therapy to intense immunosuppression for those who are refractory. The potential risk for evolution to clonal disease will be considered in the discussion of management.

The practice of hematology is more complicated than ever. Even beyond the widening array of diagnostic and therapeutic options, the practitioner is challenged with new ways of practicing medicine that are rarely discussed as part of a standard continuing medical education curriculum. This session will focus on three such issues.

Studies suggest that up to a third of medical patients use some form of complementary or alternative medicine (CAM). Dr David Rosenthal will discuss CAM in the context of hematologic diseases and supportive care. Dr Rosenthal is past resident of the American Cancer Society and president of the Society of Integrative Oncology, a non-profit, multidisciplinary medical organization formed to share information and test complementary therapies using rigorous scientific methods.

Genetic screening has been used in the practice of hematology to screen for inherited diseases such as BRCA2/Fanconi anemia, hemophilia, sickle cell disease, and other hemoglobinopathies. Genetic testing is also being used to select healthy embryos for implantation that can serve as stem cell donors to their diseased siblings. Dr John Wagner will discuss practical issues associated with genetic screening and highlight the ethical challenges faced by the practitioner. In addition to the medical, technical, and ethical issues, he will also review implications of genetic testing for other family members.

The United States is a litigious society, yet one that is also increasingly focused on improving processes that reduce medical errors. Ms Angela Holder, a lawyer and bioethicist, will discuss medical errors, particularly those encountered in hematology practice. She will review efforts to decrease medical errors and the factors that are associated with malpractice suits when poor outcomes do occur.

Despite the substantial progress that has been made during the past several decades in improving the rates of cure for hematologic malignancies, the majority of patients relapse from complete remission and die of complications that result from drug-resistant disease. In the last several years, there has been great progress in unraveling the pathways responsible for normal cell survival. Not surprisingly, these pathways are utilized excessively in the malignant cell and form the foundation of chemo-resistant disease. This session will highlight a number of these survival pathways and present novel therapeutics that target members of these pathways with the intent of lowering the threshold of apoptosis and ultimately curing a greater fraction of patients with hematologic malignancies with combination therapies. This session will consist of three novel therapeutic developments.

Dr Aaron Schimmer will provide an overview of the IAP (Inhibitor of Apoptosis Protein) family of caspase inhibitors and the progress being made to develop inhibitors of these proteins for the treatment of malignancy. The talk will include discussions of antisense oligonucleotide and small-molecule IAP inhibitors.

Dr Robert Orlowski will focus on modulation of the multicatalytic proteinase complex, or proteasome, as a strategy against hematologic malignancies. The ubiquitin-proteasome pathway has already been clinically validated as a target for therapy of multiple myeloma and non-Hodgkin lymphoma. Recent studies, however, have shown that proteasome inhibition can impact on several important mechanisms of chemoresistance. These findings suggest that proteasome inhibitors will also have applications as chemosensitizers, and are being used to guide further clinical evaluation of this class of agents.

Dr Gordon Shore will finish this session by describing his studies translating known mechanisms of Bcl-2 function in cancer into approaches to discover compounds that manipulate this family of proteins for therapeutic benefit. The talk will also include a description of the development of the lead compound into a drug, which is currently under clinical investigation for various cancers, including hematologic indications such as CLL.

Although the most common plasma cell disorders are MGUS and multiple myeloma, there are a number of less common plasma cell proliferative processes that are regularly seen both in academic and private practices. These disorders frequently pose major diagnostic as well as therapeutic confusion. Many patients are mislabeled due to the monoclonal gammopathy as having “atypical multiple myeloma,” when in fact the disorder has little in common with myeloma and the therapies vary dramatically. In this session, three of the less common plasma cell proliferative disorders will be reviewed. The learning objectives of this session are to acquaint the clinician with a diagnostic algorithm and recommendations on therapy.

Dr Angela Dispenzieri will provide an overview on POEMS syndrome (osteosclerotic multiple myeloma). Over the past five years, new criteria for diagnosis that extend well beyond the acronym have been described. In addition, a staging system now exists for this disorder, as well as major and minor diagnostic criteria to help ensure that these patients are not confused as myeloma neuropathy, MGUS neuropathy, or amyloidosis. Dr Dispenzieri will be reviewing outcomes on a large cohort of patients and will provide a diagnostic algorithm that can be successfully used to recognize these patients. New therapeutic strategies have also been developed, particularly high-dose therapy with stem cell transplantation, and these results will be reviewed.

Dr Enrica Morra will provide an overview regarding cryoglobulinemia with attention focused on mixed cryoglobulinemia (MC). She will discuss the epidemiology, the clinical and serologic features of MC, its association with hepatitis C infection (HCV), and the link with autoimmunity and lymphoproliferative disorders. Dr Morra will update the current understanding on the role of HCV infection in the pathogenesis of MC and in lymphomagenesis. She will then review the treatment strategies for MC syndrome, emphasizing the issue of eradication of HCV and the clinical and biologic activity of rituximab for selective B-cell control.

Dr Donna Weber will discuss extramedullary and solitary plasmacytomas of bone. These are syndromes that are often curable with the use of radiation therapy, but many patients will go on to develop systemic disease with overt multiple myeloma. She will discuss the use of MRI and the serial measurements of M proteins to determine the risk factors for those patients regarding long-term control. Appropriate radiation options and long-term survival data will be reviewed.

There have been major advances in the genetic and molecular pathogenesis of multiple myeloma which not only enhance our understanding of disease biology, but also have clinical application for improved diagnosis, prognosis, and treatment. This session will focus on translation of these scientific advances to the bedside to improve patient outcome in myeloma.

Dr Vincent Rajkumar will provide an update on the pathogenesis, natural history, and management of Monoclonal Gammopathy of Unclear Significance (MGUS). He will characterize diagnosis and natural history of MGUS, with particular focus on the genetic and molecular phenotype, as well as those factors predicting progression to myeloma and other lymphoproliferative disorders.

Dr Peter Bergsagel will characterize recent advances in our understanding of the molecular pathogenesis of multiple myeloma which have provided the basis for a novel prognostic system
based upon gene expression profiling and cytogenetics. This novel classification will allow not only for biologically based prognostication, but also for selection of therapies appropriate for individual patients.

Dr Donna Reece will describe the changing landscape of clinical management of multiple myeloma. In particular, she will update preclinical and clinical data on thalidomide, Bortezomib, Revlimid,
and other novel agents which can overcome conventional drug resistance in myeloma. She will also relate integration of these novel agents into stem cell transplant protocols in an evolving treatment paradigm in myeloma.

Substantial progress in understanding the pathogenesis and treatment of indolent lymphomas has occurred in the past five years. In addition to insights into the genetic and pathophysiologic mechanisms that contribute to these diseases, this information is also relevant to prognosis. Although indolent lymphomas represent diverse clinical and histologic entities, there are commonalities
in aberrant pathophysiology and approaches to treatment. This session will focus on these areas.

Dr Randy Gascoyne will focus on recent insights into the molecular genetics and pathophysiology of indolent lymphomas, including cytogenetics and gene expression profiling (GEP) studies. The diversity seen clinically in indolent lymphomas is the phenotype of underlying complex biology. Dr Gascoyne will review the genetic alterations present in these diseases at diagnosis and during clonal evolution, which further contributes to the clinical behavior of these diseases and their prognostic utility. Moreover, the data from molecular studies may provide previously unidentified targets and pathways for novel therapies.

Dr Catherine Thieblemont will provide an overview of the clinical presentation and management of marginal zone lymphomas (MZLs). This entity includes three subtypes depending on the site of initial involvement, including extranodal MZL (MALT lymphoma), splenic MZL, and nodal MZL. Besides a common origin of lymphoma cells, patients present with specific clinical features in each of these entities. Epidemiology and diagnostic approaches will be described considering the three subtypes, and therapeutic strategies will be discussed in the context of the recent international analyses.

Dr Arnold Freedman will finish this session by reviewing the biology and management of histologic transformation of indolent lymphomas. This is a final common pathway for all of these diseases.
The molecular genetics, pathophysiology, and clinical presentation of histologic transformation will be discussed. The results of therapeutic approaches toward these patients, including conventional therapy, transplantation, and radioimmunotherapy, will be reviewed.

The classification of lymphomas has become increasingly more complex as new lymphoma subtypes have been identified based on their emerging biology and clinical natural history. This evolution has been driven by advances in technology, such as microarray and microbiology, as well as an increased appreciation of the importance of clinical presentation. While the increasing complexity of lymphoma classification makes clinical management more difficult, it is important for the development of optimal treatment, prognosis, and identification of therapeutic targets. The following session will cover three broad lymphoma categories, including Epstein-Barr virus (EBV)-related lymphomas/lympho-proliferative disorders, peripheral T-cell lymphomas, and the salvage treatment of diffuse large B-cell lymphoma. This session will provide biological and clinical insight into the complexity of these diseases and their management in the emerging era of molecular diagnostics. New technologies, such as microarray and proteomics, and novel treatments, such as cellular therapies for EBV-related diseases, will be discussed.

Dr John Sweetenham will briefly review the currently used clinical risk factors for diffuse large B-cell lymphoma (DLBCL) and will then focus on emerging data regarding the potential of molecular profiling as a prognostic tool in this disease. The potential prognostic impact of germinal center derived versus activated B-cell derived DLBCL will be discussed, as will the apparent prognostic significance of MHC class II expression. The use of dynamic imaging as an early predictor of prognosis in DLBCL will also be described. The current management of relapsed disease will be reviewed, including the use of salvage chemotherapy and high-dose therapy with SCT. These therapies will be reviewed in the context of patients receiving combined chemotherapy and monoclonal antibody therapy as their first line treatment. Novel treatment strategies for relapsed disease will then be discussed in the transplant and non-transplant settings. This will include the use of naked and radio labeled monoclonal antibodies, as well as a discussion of early results from the use of therapies directed at targets such as HLA-DR, Histone deacetylase, bcl-2, bcl-6, mTOR, and TRAIL. The potential value of dynamic imaging as a predictive tool will also be discussed in this context.

Dr Helen Heslop will review the area of EBV-related lymphomas. The development of potent immune suppressants for autoimmune diseases, immunodeficiency diseases, and transplantation has led to an increase in EBV-related lymphoproliferative disorders (LPD) and lymphoma. In this session, the spectrum of EBV LPDs will be discussed, including post-transplant lymphoproliferative disease (PTLD), methotrexate-related (and other iatrogeneic immunodeficiencies) EBV LPD, immune deficiency related EBV LPD, including lymphomatoid granulomatosis, and NK-T cell EBV lymphomas. Tumor biology and novel treatment approaches directed at immune deficiency, including cellular immune therapy, interferon, and targeted approaches, will be reviewed.

Dr Kerry Savage will provide an overview of peripheral T-cell lymphomas to include both specified and unspecified subtypes. The term ‘peripheral T-cell lymphoma’ implies that all are post-thymic in origin; however, this represents a very heterogeneous group of diseases with varied clinical presentations and outcome. This review will highlight the major PTCL subtypes with a special emphasis on the more common diseases: PTCL unspecified, anaplastic large-cell lymphoma (ALK-pos and ALK-neg), and AILT and NK/T nasal and nasal type. The known clinical and biological prognostic factors will be reviewed. Finally, the current treatment approach, role of intensified therapy, and novel therapies currently available will be highlighted.

Eight years ago, rituximab, the first monoclonal antibody therapy targeting CD20, was approved by the FDA in the United States for use as a single agent for patients with relapsed or refractory follicular non-Hodgkin lymphoma. Since that time, numerous clinical trials have suggested efficacy in combination with both chemotherapy and biologic agents and when used alone as initial therapy for the disease. Additionally, alternative schedules of treatment, including maintenance therapy, have been evaluated. Two radioconjugates targeting CD20, (ibritumomab tiuxetan and iodine-131 tositumomab) are now available. For the first time in over 30 years, preliminary data suggests a possible survival benefit for patients with follicular lymphoma when monoclonal antibodies are incorporated in the treatment paradigm. Utilizing data from the laboratory and from clinical trials, this session will focus on the optimal use of monoclonal antibody therapy in the treatment plan for follicular lymphoma.

Dr Michele Ghielmini will begin by discussing optimal scheduling of rituximab and rituximab combinations with chemotherapy for patients with follicular lymphoma. He will discuss in detail various schedules of rituximab maintenance therapy and the data supporting this approach. Dr Ghielmini will focus on randomized trials and discuss the rationale for clinical trials currently open worldwide.

Dr Jonathan Friedberg will then discuss emerging data on mechanisms of rituximab action and resistance. The role of Fc receptor polymorphisms in response to this disease will be covered. Additionally, Dr Friedberg will discuss rational biologic combination immunotherapy to enhance rituximab activity, and how recent laboratory findings can be used to enhance clinical activity.

Dr John Leonard will finish the session, discussing novel monoclonal antibodies targeting CD20 that are under development and the role of conjugated anti-CD20 antibodies in the treatment of follicular lymphoma. He will discuss the rationale of incorporating radioimmunotherapy early in the treatment plan for follicular lymphoma and the status of ongoing clinical trials of radioimmunotherapy.

Insights from the laboratory and the clinic continue to improve our understanding of Hodgkin lymphoma, an uncommon but fascinating and regularly curable neoplasm seen around the world. This session on Hodgkin lymphoma will focus on aspects of the disease, ranging from the basic biology and immunology of the malignant cell to recent developments in the treatment of the lymphoma at primary presentation and at relapse.

Dr Sibrand Poppema will open the session by discussing the pathophysiology and immunobiology of Hodgkin lymphoma. After reviewing major past insights into this neoplasm’s underlying biology, he will emphasize new findings that have been derived from the sophisticated new techniques of single cell analysis and immuno-profiling.

Dr Joseph Connors will provide an update on evolving approaches to primary treatment of limited and advanced stage disease, focusing on how best to balance treatment intensity, high levels of effectiveness, and late toxicity.

Dr Nancy Bartlett will address the less common, but challenging, problem of optimizing therapies for refractory or relapsed disease. She will describe the rational management of such patients, integrating hematopoietic stem cell transplantation and nontransplant approaches and new research initiatives including immunotherapy. The intent of this educational presentation is to move from the basic biology of the neoplastic cells to optimal approaches to primary and secondary treatments, emphasizing concepts relevant to providing the best and most informed management in 2005.

There have been exciting and important advances in the past decade which have resulted in improved understanding of pathobiology as well as treatment approaches in chronic lymphocytic leukemia (CLL). This session on CLL will use a case-based format to highlight these advances by orienting the discussion around the clinical course of a patient.

Dr Kanti Rai will briefly present the clinical history of a CLL patient.

Dr Guillaume Dighiero will cover some of the recently published work which has led to a new and revised definition of the pathophysiology of CLL. The role of signaling from B-cell receptors (BCR), its impact on prevention of apoptosis, and correlation with worse prognosis in cases of unmutated IgVH genes will be explored. The biologic significance of expression of ZAP-70 and CD 38 and their respective correlation with prognosis in CLL patients will be discussed. The cytogenetic aberrations in CLL as studied by the fluorescence-in-situ hybridization technique and the clinical consequences of del 13q, del 11q, del 17p, del 6q, and trisomy 12 will be reviewed.

Dr Michael Hallek will discuss the current status of initial therapeutic approaches in CLL. He will review the role of fludarabine (and other nucleoside analogs, such as pentostatin and cladribine) and other chemotherapy drugs, monoclonal antibodies such as alemtuzumab (anti-CD52, Campath-1H), and rituximab (antiCD20) either singly or in combination (concurrently or sequentially) in CLL. The need and place for supportive therapy with growth factors will also be discussed. Dr Hallek will define the therapeutic objective according to the clinical characteristics of CLL patients and present evidence of improving the life expectancy with some of these strategies.

Dr John Gribben will cover the therapeutic options in CLL patients with advanced disease. He will discuss the available data with autologous as well as HLA-matched allogeneic stem cell transplants following myeloablative or non-myeloablative conditioning regimens in CLL. Dr Gribben will also review newer approaches in therapy currently under clinical investigation, including vaccines, gene therapy, re-infusion of in vitro expanded autologous T-cells, and some of the new drugs which seem to hold promise in treating this disease.

The therapeutic approach to the patient with acute myeloid leukemia (AML) has evolved to one that is based upon a progressively diverse arsenal of therapeutic options applied on a more
and more rationalized and individualized basis. The identification of the complex genetic basis of AML is central in this evolution. Precise diagnostic insights, the development of drugs that target
pathogenetic mechanisms of the disease, and recent advancements in hematopoietic stem cell transplantation are exemplary of the mainstream of therapeutic development in AML. This session
will highlight recent insights in these areas that are directly relevant to the treatment algorithm in patients with AML.

Dr Jonathan Licht will review the molecular pathobiology of acute myeloid leukemia and how this impacts clinically on disease classification and risk stratification. He will also discuss how recent advances in the understanding of AML pathogenesis have led to the identification of new therapeutic targets.

Dr Martin Tallman will review the importance of integrating drugs in combination in the treatment plan. These combinations include classical chemotherapeutic compounds, antibodies, signaling inhibitors, and various other novel agents applied with the objective to maximize therapeutic efficacy.

Allogeneic hematopietic stem cell transplantation (alloSCT) remains a particularly potent postremission immunotherapeutic modality in AML but is associated with significant morbidity and treatment-related mortality. Dr Jan Cornelissen will review variants of alloSCT, including unrelated donor transplants, reduced intensity conditioning SCT, approaches exploiting graft-versusleukemia effects, and preventive methods of infectious complications and discuss how they impact clinical decision making. This subject will be discussed in view of the appreciation of the genetic heterogeneity of AML in regard to the inherent risk of relapse.

Acute lymphoblastic leukemia (ALL) is an uncommon disease in adults. Considerable heterogeneity exists among both clinical and biological characteristics in this disease. Increasingly, treatment strategies are being developed to individualize therapy within defined subsets of ALL; this session will focus on four of the largest and best-characterized subsets.

Dr Oliver Ottmann will examine Philadelphia chromosome positive ALL, a subset that includes at least one-quarter of all adults with ALL. Until recently, conventional chemotherapy programs that have been relatively effective in other precursor B-cell ALL cases have been unable to cure patients with this diagnosis. Allogeneic stem cell transplantation early in first remission has been the recommended therapy. The availability of imatinib mesylate and other tyrosine kinase inhibitors and small molecules that affect the BCR/ABL signaling pathways may be changing the treatment paradigm and the prognosis for these patients. Dr Ottmann will present data from clinical trials using imatinib in the frontline setting and in relapsed patients, as well as preliminary experience treating imatinib-resistant Ph+ ALL.

Dr Daniel DeAngelo will discuss the treatment of adolescents and young adults with ALL. Recent data suggest that adolescents enrolled on prospective pediatric studies have had a better outcome than similar patients enrolled on adult cooperative group studies. Comparative clinical trials are now underway. T-cell ALL is most commonly seen within this age group and often has a favorable outcome using chemotherapy alone, without requiring allogeneic stem cell transplantation. The recognition that NOTCH1 pathways are critically involved in T-cell ALL has led to novel possibilities for treatment.

Dr Richard Larson will focus on the management of older adults with ALL. Co-morbidities and unfavorable cytogenetic features within this population present considerable challenges for successful treatment using conventional chemotherapy programs. Although the median age for adult ALL is older than 60 years, relatively few of these patients have been enrolled in clinical trials. Dr Larson will also describe preliminary data with several new agents that have shown promise for patients with ALL.

The natural history of myelodysplastic syndrome (MDS) has become better understood over the past decade. In particular, patients can be categorized as low-risk (median life expectancy 2-10 years) or high-risk (median life expectancy 2 years or less). Furthermore, new treatments have become available for both low- and high-risk patients. This session will discuss integration of these treatments into the management of MDS and how further knowledge of the biology of MDS may generate newer, more effective, treatment strategies.

Dr Thomas Look will review the molecular pathogenesis of MDS, a very heterogeneous group of diseases whose molecular bases are rapidly emerging. Improved delineation of molecular pathogenesis will have at least two consequences. First, it will allow physicians to refine prognoses, particularly for patients with low-risk disease. Currently, such patients have a wide range of incompletely understood prognoses, which complicates the task of recommending a specific therapy (eg allogeneic transplant). Second, increased knowledge of how MDS cells differ from their normal counterparts is critical for development of new therapies.

Dr Eva Hellström-Lindberg will address management of low-risk MDS. She will discuss the goal of treatment in these patients, eg, induction of complete remission versus improvement in quality of life. She will note which patients should receive specific treatment and which are likely to benefit from older therapies, such as erythropoietin, darbopoietin, or G-CSF, or immunosuppressive agents, such as antithymocyte globulin. She will review the use of newer agents, such as tipifarnib, 5 azacitidine, decitabine, and lenalidomide, and discuss if particular groups of patients should begin treatment with one of these agents rather than another.

Dr Joachim Deeg will discuss management of high-risk MDS. He will discuss the role, if any, of chemotherapy as used to treat AML. He will detail recent developments in allogeneic transplant as applied to MDS, or to AML evolving from MDS. These include the use of non-myeloablative/reduced intensity conditioning regimens (given the advanced age of many MDS patients), the influence of co-morbid conditions on transplant outcome, and alternative sources of stem cells such as unrelated donors or umbilical cord blood.

The treatment of chronic myelogenous leukemia (CML) has continued to rapidly evolve. Despite the substantial progress that has been made, many questions remain. These include the durability of responses to imatinib and the optimal dose of imatinib. There is now substantial information available on the mechanism of resistance to imatinib, and new agents are in clinical trials to combat resistance. Thus, defining resistance and identifying patients with a higher risk of relapse is critically important. As it is not known if any strategy utilizing kinase inhibitors can eradicate the disease, the issue of how best to integrate transplant and non-transplant therapy remains a key topic. This session will focus on these related areas.

Dr Michael Deininger will provide an update on management of early stage disease. This will include the most current data on the durability of responses to imatinib. Dr Deininger will review molecular and cytogenetic monitoring strategies and the impact these factors have on the risk of relapse. He will also discuss the potential role of high-dose imatinib therapy and a variety of novel approaches that may further improve the therapeutic outcome for patients with CML.

Dr Neil Shah will focus on the management of resistance to imatinib. He will begin with definitions of resistance and recent insights into the pathophysiology of imatinib resistance. Dr Shah will discuss the management of imatinib resistance, including up-to-date information on several new BCR-ABL kinase inhibitors that are in clinical trials to circumvent imatinib resistance.

Dr Robert Ilaria will finish the session by reviewing the current knowledge of the pathobiology of lymphoid and myeloid blast crisis and their management. In addition, he will discuss whether new agents target leukemic stem cells and the role and timing of allogeneic stem cell transplantation.

In the last few years, a great deal has been learned about the genetic origins of the Philadelphia chromosome negative myeloproliferative disorders. Such findings will potentially have a great impact on the way we diagnose, classify, and treat these disorders. Importantly, these genetic lesions will likely serve as targets for the development of novel therapeutic agents for targeted therapy of these disorders. This session will focus on these related areas.

Dr William Vainchenker will provide a review of the fast-breaking events that have led to the discovery of an activating mutation of the JAK2 kinase in 80-90% of patients with polycythemia vera, 40-50% of patients with essential thrombocythemia, and 40-50% of patients with chronic idiopathic myelofibrosis, but not in normal controls or patients with secondary forms of erythrocytosis. The majority of patients with the Val617Phe mutation carry one copy of the gene, although approximately one-third are homozygous. This mutation certainly contributes to the biogenesis of these myeloproliferative disorders. Introduction of the Val617Phe JAK2 into murine marrow cells and their transplantation into lethally irradiated mice leads to the development of erythrocytosis. Dr Vainchenker will discuss the sequence of events that led to the discovery of this mutation and its clinical implications.

Dr Anthony Green will discuss the clinical management of patients with polycythemia vera and essential thrombocythemia. Because of a glaring lack of Phase III trials dealing with these disorders, therapeutic options for the treatment of these disorders have not been evidence-based. The Medical Research Council has recently completed a randomized trial comparing hydroxyurea to anagrelide therapy in a large cohort of patients with essential thrombocythemia. The surprising findings of this trial and their implications to the practicing physician will be discussed.

Dr Jamie Robyn will deal with the diagnosis and management of a group of disorders characterized by increased numbers of eosinophils. These disorders, which include idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, and variants of systemic mastocytosis, are classified by the World Health Organization as myeloproliferative disorders. Acquired and familial forms of hypereosinophilic syndromes will be described and their clinical sequelae outlined. Patients with hypereosinophilic syndromes have a variable clinical course. Dr Klion has identified a subset of such patients with a myeloproliferative variant of the hypereosinophilic syndrome, which is associated with tissue fibrosis and a poor prognosis. These patients have elevated serum tryptase levels and the FIPIL1-PDGFRA mutation that results in a constitutively activated platelet-derived growth factor receptor; notably, these patients experience remarkable clinical responses to imatinib therapy with reversal of the myelofibrosis and not infrequently molecular remission. Therapeutic options in other forms of the hypereosinophilic syndromes will be further discussed.

While hematopoietic stem cell transplantation has been used successfully for over 30 years, new approaches to broaden the availability and applicability of transplantation therapies are expanding. Alternate donor sources, including volunteer unrelated donors, umbilical cord donors, and haploidentical related donors, are being more widely used. Modified conditioning regimens can reduce the toxicities of transplantation, thus limiting mortality, and allow the availability of transplant curative potential to be expanded to older and sicker populations previously denied such treatment opportunities. This session will review these new approaches.

Dr Mary Laughlin will discuss umbilical cord blood transplantation with attention to the possibilities and limitations of this stem cell source. The importance of cell dose, HLA matching, delayed hematopoietic recovery, immune reconstitution, and the use of multiple cord blood units will be discussed in treatment of both children and adults. Family cord blood banking and its issues will also be addressed.

Dr Sergio Giralt will discuss issues related to reduced intensity allotransplants, including conditioning regimen choice, its anticancer potency and immunosuppressive capacity, techniques for choosing suitable recipients, and disease-specific outcomes.

Dr Thomas Spitzer will explore prior barriers to the successful use of family donors, including the hazards of graft-versus-host disease, graft failure, and profound or prolonged immune compromise. New conditioning regimens and graft manipulations, which may expand the utility of haplotransplantation, will also be discussed.

Continuous progress in the treatment of hematological malignancies and of non-malignant hematological disorders has led to increasing numbers of long-term survivors. Both hematologists and general practitioners are now confronted with these cured patients who are now prone to develop late complications and have to face re-insertion into normal life. This session will cover both pediatric and adult issues on cancer survivorship and will point out issues regarding fertility and sexuality in long-term survivors.

Dr Smita Bhatia will focus on survivorship issues in pediatric cancer survivors. With the use of risk-based therapies, the overall five-year survival rate after pediatric cancer is approaching 80%. This improvement in survival has resulted in a growing population of childhood cancer survivors. Approximately two out of every three survivors will experience at least one late effect, and about one out of four will experience a late effect that is severe or life-threatening. These complications involve all organ systems. Dr Bhatia, as Chair of the Late Effects Committee of the Children’s Oncology Group, has focused her research efforts on the epidemiology of second cancers among childhood cancer survivors and has been instrumental in the development of the Committee of the Children's Oncology Group Long-Term Follow-Up Guidelines. Dr Bhatia will discuss issues related to the potential adverse events faced by the survivors, the options for obtaining health care, the development of standardized follow-up guidelines, and the future research opportunities that need to be explored.

Dr André Tichelli will review the considerations for adult cancer survivors. This review will focus on morbidity and mortality in adult long-term cancer survivors, with exclusion of sexuality and fertility aspects. With improvements in outcome, increasing numbers of adult cancer patients survive free of the disease for which they were treated. Immediate survival is no longer their sole concern. The aim of the cancer treatment now is not only to cure a patient’s underlying disease, but also to minimize the incidence of post-treatment complications and ensure the best possible quality of life. Late effects after initial treatment with or without stem cell transplantation include secondary cancers, late toxicity from the treatment regimen, infections or autoimmunity due to altered immune reconstitution, endocrine dysfunction, alteration in health-relat-ed quality of life, impact on psychological behavior, and complications due to graft-versus-host disease in the case of allogeneic stem cell transplantation. With these late effects in mind, Dr Tichelli will provide recommendations for prevention or treatment.

Dr Leslie Schover will conclude the session by reviewing the prevalence, causes, and treatments of cancer-related sexual dysfunction and infertility in men and women. With improved outcome of cancer treatment, reproductive health is an increasingly important part of quality of life during survivorship. She will discuss the most common sexual problems seen after cancer treatment and provide examples of how counseling can be combined with medical treatments to achieve optimal sexual rehabilitation, although evidence-based empirical data on treatment efficacy is badly needed. She will also define patient groups most at risk for post-treatment infertility and will discuss practical issues, financial barriers, and ethical concerns in new methods of reproductive tissue, gamete, and embryo cryopreservation.

NIH Representatives from these Institutes:

• National Cancer Institute
• National Heart, Lung, and Blood Institute
• National Institute of Diabetes & Digestive & Kidney Diseases
• National Institute on Aging

Securing funding from federal sources remains a challenge for many young researchers. The 2005 Hematology Grants Workshop explores the wide range of funding sources available and provides guidance on what federal agencies are looking for and what applicants need to do to be successful. Special attention will be paid to the NIH K-award series for research support.

Representatives from NIH Institutes that support hematology and hematology-related research will highlight the specific funding requirements of their respective institutes.