Introduction and Historical Perspective Chronic myeloid leukemia (CML), a rare condition, has had a profound impact on the development of hematology/oncology and modern medicine as a whole ( Fig. 69.1A and B ). The story started in the 1830s with Alfred Francois Donné of Paris, a remarkable innovator who pioneered the use of microscopy in medicine and was the first to describe the different types of…
Acute lymphoblastic leukemia (ALL) is a heterogeneous group of diseases characterized by clonal proliferation of lymphoid progenitors (lymphoblasts). Improved diagnostic tools permit accurate and prompt diagnosis and aid in evaluation of minimal residual disease (MRD). There have been significant advances in the past decade toward understanding disease pathogenesis, refinement of prognostic groups, and the development of exciting new therapies directed toward specific disease subsets. These molecular…
Serial risk-directed clinical trials have optimized the combination of chemotherapeutic agents and, along with advances in supportive care, have led to current cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85% compared with those of less than 10% in the 1960s. However, because ALL is the most common cancer in children, relapsed ALL remains a leading cause of death from disease in this age group.…
Introduction Normal lymphoid precursors undergo somatic recombination at their immunoglobulin (Ig) or T-cell receptor (TCR) gene loci, and the successful completion of V(D)J recombination, with the resultant formation of a functional Ig or TCR, is required for the survival of lymphocyte precursors. Positive and negative selection steps ensure that only lymphocytes with Ig or TCRs that function appropriately within the context of an individual’s immune microenvironment…
Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal stem cell disorders that result in ineffective hematopoiesis and an increased risk of developing acute myeloid leukemia (AML). Whereas in MDS ineffective hematopoiesis results in progressive cytopenias, in MPN ineffective hematopoiesis leads to excessive proliferation frequently characterized by increased peripheral blood counts. MDS and MPN are rare in children, and the only malignancy…
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematopoietic-derived malignancy thought to occur by transformation of plasmacytoid dendritic cells (pDCs) or pDC progenitors. Normal pDCs are immune cells that recognize microbes via Toll-like receptors and are the principal producers of type 1 interferons in the setting of infection. The disease was formally named BPDCN in 2008, based on recognition that the malignant cells shared features with…
Acute myeloid leukemia (AML) is a complex and heterogeneous group of malignancies in which genetic and epigenetic alterations lead to differentiation arrest and/or uncontrolled expansion of myeloid cell precursors. Pediatric AML is characterized by a wide array of genetic aberrations that are often not seen or differ in frequency when compared to AML diagnosed in adults and mainly comprise different fusion genes. Though the mutational landscape…
Recent advances in molecular diagnostics continue to shed light on genetic underpinnings of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, with notable exceptions, both diseases remain therapeutic challenges. Fortunately, our ability to provide more precise prognostic information has corresponded with advances in transplantation technology. We are increasingly able to apply transplantation to older people and those with comorbidities and to use alternative donors in…
The myelodysplastic syndromes (MDS) include a group of clonal hematopoietic disorders characterized by ineffective hematopoiesis and blood cytopenias, abnormal blood and bone marrow cell morphology ( Fig. 61.1 ), and a risk of clonal evolution including progression to acute myeloid leukemia (AML). The syndromes have a highly variable clinical course, manifesting in some patients as indolent asymptomatic cytopenias or only necessitating occasional transfusions over a course…
Acute myeloid leukemia (AML) is a clonal neoplasm of hematopoietic stem or myeloid progenitor cells characterized by block in differentiation and unregulated proliferation of hematopoietic cells in the marrow, blood, and extramedullary sites. The major consequence of this malignant transformation is bone marrow failure with mortality predominantly due to infectious and hemorrhagic complications of the disease. Knowledge of the pathobiology of AML as it relates to…
Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells, characterized by recurrent genetic and epigenetic alterations. Historically, human leukemias were distinguished according to clinical and histological features and subsequently by morphology. Analysis of the AML genome at increasing resolution, from the level of whole chromosomal changes to individual base pairs, together with an appreciation of epigenetic changes and interactions within the bone marrow microenvironment,…
The treatment of patients with hematologic malignancies has been revolutionized over the past decades as new therapeutic targets continue to be identified through cellular and molecular studies of these conditions. These investigations have spawned the discovery, clinical evaluation, and US Food and Drug Administration (FDA) approval of new mechanistic-based therapeutic agents. A surprising number of these agents have progressed rapidly from the discovery phase to validation,…
Dedicated to the loving memory of Eta Najfeld, MD, a Holocaust survivor and an amazing mother . Over the past 66 years the cytogenetic analysis of hematologic malignancies has been an area of prolific growth. Chromosome studies and karyotype analysis provide information of both biologic and clinical significance. Refinements in cell culture methods and the application of chromosome banding techniques have advanced our understanding of disease-specific…
Defining and classifying tumors of the hematopoietic and lymphoid tissue accurately is critical for providing optimal treatment to patients with hematologic malignancies. Explicit definitions and terminologies are prerequisites for the precise classification of hematologic malignancies. A reproducible classification that is based on consensus definitions and terminologies is fundamentally essential for proper medical practice and the advancement of medical knowledge. Generally, such classifications should be based upon…
The initial clinical descriptions of primary Epstein-Barr virus (EBV) infections are credited to Filatov and Pfeiffer at the end of the 19th century. Pfeiffer coined the term glandular fever , which described an illness consisting of fever, malaise, sore throat, and lymphadenopathy. In 1920, Sprunt and Evans introduced the term infectious mononucleosis (IM) to describe a series of patients with fatigue, fever, lymphadenopathy, and prominent mononuclear…
Lysosomal Storage Diseases Lysosomal storage diseases (LSDs) are genetic disorders caused by deficiencies in single lysosomal hydrolases. Deficiencies result in cellular and organ damage due to subsequent accumulation of a specific substrate for that particular enzyme, hence the term “storage” disease. However, the diverse role of the lysosome in cellular metabolism means that the pathological consequences of enzyme deficiency extend beyond substrate accumulation. Although individually rare,…
The histiocytic disorders comprise a broad grouping of hematologic and immunologic diseases united by aberrant function, differentiation, and/or proliferation of cells of the mononuclear phagocyte system. The term histiocyte historically referred to tissue phagocytes but now more precisely defines cells of the monocyte/macrophage lineage ( Fig. 53.1 ). The ontogeny of these cells and their role(s) in pathogenesis continue to be studied and refined. In the…
Over 350 molecular defects that result in primary immune deficiency are known to date. Many of these gene defects have been identified in recent years with the advent of whole-exome and whole-genome sequencing. The study of patients with primary immune deficiencies has unraveled fundamental mechanisms that govern lymphocyte development and function. Importantly, characterization of the molecular basis of these diseases has revealed unanticipated heterogeneity of the…
Phagocytic leukocytes are an essential component of the innate immune system that has evolved to rapidly respond to the presence of invading bacteria, fungi, and parasites. This first line of host defense also includes natural killer (NK) lymphocytes, complement, and other plasma proteins. As reviewed in Chapter 28, Chapter 49 , phagocytes are responsible for ingesting, killing, and digesting pathogens. Granulocytic phagocytes (neutrophils and eosinophils) circulate…
Any discussion of quantitative abnormalities of lymphocytes and immunoglobulins is necessarily linked because the B-cell compartment is responsible for immunoglobulin production and the T-cell compartment helps to provide the stimulus. Nevertheless, clinicians are often consulted when a quantitative disorder of one or the other is recognized. Thus, although overlapping, the defects are presented separately. Quantitative Disorders of Lymphocytes The normal number and distribution of lymphocyte subtypes…