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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.
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.
Holland-Frei Cancer Medicine, Ninth Edition, offers a balanced view of the most current knowledge of cancer science and clinical oncology practice. This all-new edition is the consummate reference source for medical oncologists, radiation oncologists, internists, surgical oncologists, and others who treat cancer patients. A translational perspective throughout, integrating cancer biology with cancer management providing an in depth understanding of the disease An emphasis on multidisciplinary, research-driven patient care to improve outcomes and optimal use of all appropriate therapies Cutting-edge coverage of personalized cancer care, including molecular diagnostics and therapeutics Concise, readable, clinically relevant text with algorithms, guidelines and insight into the use of both conventional and novel drugs Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates