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This book provides a comprehensive and up-to-date review of all aspects of childhood Acute Lymphoblastic Leukemia, from basic biology to supportive care. It offers new insights into the genetic pre-disposition to the condition and discusses how response to early therapy and its basic biology are utilized to develop new prognostic stratification systems and target therapy. Readers will learn about current treatment and outcomes, such as immunotherapy and targeted therapy approaches. Supportive care and management of the condition in resource poor countries are also discussed in detail. This is an indispensable guide for research and laboratory scientists, pediatric hematologists as well as specialist nurses involved in the care of childhood leukemia.
In the past 10 to IS years there has been dramatic improvement in the survival of children with acute lymphoblastic leukemia. At the present time, over 50% of children with this disease will be alive and free of their disease at least 5 years from the time of their initial diagnosis. Although a number of factors have contributed to this improvement, perhaps none has been as important as the institution of central nervous system preventive therapy (eNS prophylaxis). However, despite the efficacy of eNS prophylaxis, the prevention and treatment of central nervous system leukemia continues to pose a formidable clinical challenge to the pediatric oncologist. Although successful in most cases, eNS preventive therapy remains ineffective for a small but significant subset of patients at high risk for developing eNS disease. Moreover, it has become increasingly evident that some methods of eNS preventive therapy are associated with long-term, adverse eNS sequelae. Thus, considerable controversy exists regarding the optimal method of eNS prophylaxis. Treatment of the patient who develops overt meningeal leukemia has not been as successful and continues to pose a major clinical challenge. Despite the ability of intrathecal chemotherapy and/or radiation therapy to induce eNS remission, most patients suffer subsequent relapse and ultimate survival is usually signifi cantly compromised. It is evident that newer approaches to treatment for this patient group must be identified before major improvement for this patient group is likely to occur.
The use of intensified multiagent and prophylactic central nervous system (CNS)-directed chemotherapy has achieved improved survival for pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL). However, skeletal morbidities and CNS leukemia continue to pose significant clinical challenges in B-ALL patients underscoring the need to identify the underlying mechanisms and to develop effective targeted therapies. My thesis project aimed to elucidate molecular mechanisms of bone destruction and CNS invasion in B-ALL and to provide evidence for potential targeted therapies to ameliorate these complications. Using a genetically sensitized mouse model of spontaneous B-ALL and primary patient-derived xenograft (PDX) mouse models, we demonstrated that B-ALL cells cause bone destruction and identified the receptor activator of nuclear factor kappa-B (RANK-RANKL) ligand axis as critical in these effects. Treatment of PDX mice with a RANKL antagonist recombinant Osteoprotegerin-Fc (rOPG-Fc) conferred robust protection from bone destruction. We examined routes of leukemic cell entry into the CNS and demonstrated that both mouse and primary human B-ALL cells migrated to the skull and vertebral bone marrow (BM) and further transited into the subarachnoid (SA) space of the CNS. Strikingly, rOPG-Fc protected both skull and vertebral BM from human B-ALL cell invasion and prevented transit into the SA space. Moreover, pharmacological inhibition of the C-X-C chemokine receptor type 4 (CXCR4) in human BCR-ABL+ PDX mice prevented leukemic cell migration from skull/vertebral BM into the SA space. Overall, these findings demonstrate two mechanisms of CNS invasion by B-ALL that can be opposed by targeted treatments. Finally, we identified unique transcriptional and functional signatures in pediatric mixed lineage leukemia (MLL) which reveal distinct cell intrinsic behavior of lymphoid- and myeloid-like MLL populations and striking adaptations to the CNS microenvironment. Collectively, this thesis reports novel molecular mechanisms of B-ALL mediated bone destruction and CNS invasion and identifies actionable therapeutic targets to reduce these morbidities.
Brain metastases are the most dreaded complication of systemic cancer, affecting some 170,000 people a year, a far greater incidence than primary brain tumors. This book presents current information on the presentation and management of patients with brain metastases, providing available data, giving guidelines that can be applied in day to day practice, updated information for neurosurgeons, radiation oncologists, medical oncologists, and neuron-oncologists, and as an overview for physicians in training.
The current explosion of new areas of controversy in the treatment of acute lymphocytic leukemia in adults and young adults makes this comprehensive book a much needed reference for hematologists and oncologists. This book assembles leading authorities from around the globe to cover the full spectrum of ALL subtypes and their treatments. Specific topics of discussion include indications for allogeneic bone marrow transplant in first complete remission, the role of minimal residual disease in making treatment decisions, the treatment of young adults, and the treatment of Philadelphia chromosome positive ALL with the advent of the tyrosine kinase inhibitors. This is the first book to focus exclusively on the adult ALL patient. It provides a complete overview of diagnosis, molecular pathogenesis, evaluation, and treatment for this important patient population.
In this book, world-renowned experts in the field express well-reasoned opinions on a range of issues and controversies relating to haploidentical transplantation with the aim of providing practicing hematologists with clinically relevant and readily applicable information. Among the areas covered are graft manipulation and methods to control T-cell alloreactivity, the nature of the ideal graft and donor, haploidentical transplantation in pediatric and adult patients with malignant and nonmalignant diseases, immunologic reconstitution following transplantation, complications, and the prevention and treatment of relapse post transplantation. Attention is drawn to the implications of high-impact clinical trials whenever such trials are available. The readily intelligible text is complemented by numerous helpful tables, algorithms, and figures. The book will provide practical support for hematologists and transplant physicians as they attempt to provide optimal care in this exciting but increasingly complex medical specialty.
Since the original publication of Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Allogeneic hematopoietic stem cell transplantation (HSC) has undergone several fast-paced changes. In this second edition, the editors have focused on topics relevant to evolving knowledge in the field in order to better guide clinicians in decision-making and management of their patients, as well as help lead laboratory investigators in new directions emanating from clinical observations. Some of the most respected clinicians and scientists in this discipline have responded to the recent advances in the field by providing state-of-the-art discussions addressing these topics in the second edition. The text covers the scope of human genomic variation, the methods of HLA typing and interpretation of high-resolution HLA results. Comprehensive and up-to-date, Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Second Edition offers concise advice on today's best clinical practice and will be of significant benefit to all clinicians and researchers in allogeneic HSC transplantation.