Nonmalignant Leukocyte Disorders PDF

PART V Leukocyte Disorders 26 Nonmalignant Leukocyte Disorders Steven Marionneaux* OBJECTIVES Aer the completion of this chapter, the reader will be able to: 6. List acquired conditions associated with quantitative 1. Compare the genetic defects, pathologic mechanisms,...

PART V Leukocyte Disorders 26 Nonmalignant Leukocyte Disorders Steven Marionneaux* OBJECTIVES Aer the completion of this chapter, the reader will be able to: 1. Compare the genetic defects, pathologic mechanisms, and clinical and laboratory ndings in the primary immunodeciencies discussed in the chapter. 2. Explain how the presence of Pelger-Huët cells during blood lm review could be misinterpreted as a neutrophilic le shi. 3. Describe peripheral blood lm abnormalities in Alder- Reilly anomaly and May-Hegglin anomaly and their similarity to other conditions. 4. Associate various lysosomal storage diseases with their underlying pathologic conditions and clinical and laboratory manifestations. 5. Dene neutrophilia, neutropenia, lymphocytosis, lymphocytopenia, monocytosis, monocytopenia, eosinophilia, and basophilia. OUTLINE Primary Immunodeciency Disorders/Inborn Errors of Immunity Severe Combined Immune Deciency Wiskott-Aldrich Syndrome 22q11.2 Deletion Syndrome Bruton Tyrosine Kinase Deciency Chédiak-Higashi Syndrome Congenital Defects of Phagocyte Number and/or Function Lysosomal Storage Disorders Mucopolysaccharidoses Sphingolipidoses Morphologic Abnormalities of Leukocytes Without Associated Immune Deciency Pelger-Huët Anomaly Pseudo– or Acquired Pelger-Huët Anomaly *e author extends appreciation to Scott Dunbar for 464 CASE STUDY After studying the material in this chapter, the reader to the following case study. Answers can be found in Appendix C. A 25-year-old woman was seen by her primary care of fatigue. Physical examination revealed pale conjunctiva. the examination was unremarkable. The patient indicated heavier than normal bleeding during menses. Complete as follows. Reference intervals can be found after WBC 8.1 × 109/L MCHC 29 g/dL HGB 8.6 g/dL PLT 172 MCV 65 fL Because of the low mean cell volume, a blood lm ent immature granulocytes were present (Figure 26.1) was performed: Segmented neutrophils 9 Lymphocytes 30 Bands 21 Monocytes 7 Metamyelocytes 16 Eosinophils 2 Myelocytes 14 Basophils 1 1. Do you agree with the classication of the immature not, provide an explanation in morphologic terms. 2. The patient was subsequently diagnosed with iron on the cell images shown, what other hematologic is chapter focuses on leukocyte disorders not associated with clonal or neoplastic changes in hematopoietic precursor cells. e cause of these disorders can be genetic or acquired, and result in quantitative, functional, and/or morphologic changes in one or more lineages: neutrophils, lymphocytes, monocytes, eosinophils, and/or basophils. Some of these disorders are asso- ciated with signicant clinical manifestations. PRIMARY IMMUNODEFICIENCY DISORDERS/ INBORN ERRORS OF IMMUNITY As of June 2022, nearly 500 (inherited) inborn errors of immu- nity (IEI) or primary immunodeciency disorders have been identied, each originating from a single germline genetic abnormality aecting the innate or adaptive immune system.1 Most individual IEIs are rare; however, as a group, the preva- lence of diagnosed IEIs the United States is approximately 1 in 1200 individuals.2 e mechanisms of disease, clinical manifestations, and disease severity among the IEIs can vary based on the nature of the gene defect and its pattern of inheritance. missense mutation, deletion, or frame shi mutation leads to a reduced quantity and/or quality of the encoded protein, altering normal functioning within the innate or adaptive immune sys- tem. is can have a wide range of eects from life-threatening manifestations that arise in infants to manageable disorders diagnosed in adults. is section illustrates the heterogenous clinical presenta- tions associated with IEI by reviewing a select number of dis- eases within the classication schema from the International Union of Immunological Societies Expert Committee1 and will mainly include diseases associated with peripheral blood mor- phologic abnormalities. 466 PART V Leukocyte Disorders with the disease have no thymus, tonsils, or lymph nodes and oen experience severe life-threatening infections within the rst few months of life as protective maternal immunoglobu lins are depleted. Prompt diagnosis of common gamma chain deciency is key in implementing preventive measures in antic- ipation of these infections. e white blood cell (WBC) count in aected infants is decreased as a result of severely decreased T and NK lymphocytes. B cells are generally adequate in num- ber but are dysfunctional without T cell signaling. In common gamma chain deciency, there is failure to thrive and death usu- ally occurs before 2 years without HSCT. Adenosine Deaminase Deficiency (ADA-SCID) Adenosine deaminase deciency (ADA-SCID) is classied as T–B– SCID1 and represents 10% to 20% of SCID cases. It is an autosomal recessive disorder caused by a mutation in the ADA gene located at chromosome 20q13.12. Adenosine deaminase is a key component in the metabolic breakdown of adenosine triphosphate (ATP) and RNA in all cells. In ADA-SCID, there is intracellular and extracellular accumulation of toxic levels of adenosine and deoxyadenosine in lymphocytes, causing pro- found decreases in T, B, and NK cells. Patients with ADA-SCID experience severe recurring, life-threatening bacterial, viral, and fungal infections beginning early in life. Additional man- ifestations include skeletal abnormalities, neurologic decits, and skin rashes.1 Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome (WAS) is classied as a combined immunodeciency with associated or syndromic features.1 WAS is a rare X-linked disease caused by one of more than 450 mutations in the WAS gene,4 which results in decreased Wiskott-Aldrich syndrome protein (WASP) expression. Disease severity and clinical manifestations in WAS can vary based on the type of mutation present and its impact on WASP expression. WASP controls RNA polymerase II–depen- dent transcription and has a critical role in actin cytoskeleton remodeling of hematopoietic cells. Low WASP levels have an impact on the stability of the immunologic synapse, the site where T-cells and antigen-presenting cells interact. Abnormal reorganization of the cytoskeleton results in defective T cell function and impaired interaction with lymphocytes, lead- ing to decreased B cells. NK cells are normal or increased in number but have diminished cytotoxic activity. Regulatory T cells involved in autoimmunity are dysfunctional.5 WASP deciency also diminishes neutrophil chemotaxis, phagocy- tosis and other steps involved in the killing of microorgan- isms, which increases susceptibility to infections. ere is a risk of bleeding because of thrombocytopenia, small abnormal platelets, and shortened platelet survival, which is the result of increased immune-related and nonimmune-related destruc- tion and ineective megakaryocytopoiesis. WAS diagnosis is typically conrmed through WAS gene sequencing in patients with suspected disease. HSCT can be curative in patients with human leukocyte antigen (HLA)- matched donors.6,7 Gene therapy is a promising approach most appropriate for patients with WAS who lack a matched donor.8 A B Figure 26.2 Chédiak-Higashi Syndrome. Eosinophil. (Peripheral blood, Wright-Giemsa Sweden.) in antimicrobials. Recent studies of gene therapy to restore nor- mal BTK function in mice have shown promising ndings.12 Chédiak-Higashi Syndrome Chédiak-Higashi syndrome (CHS) is a rare autosomal reces- sive disease of immune dysregulation classied as a familial hemophagocytic lymphohistiocytosis syndrome with hypopig- mentation.1 13 CHS is caused by a mutation in the lysosomal tracking regulator (LYST) gene on chromosome 1q42.3. e mutation leads to the formation of giant fused cytoplasmic gran- ules/inclusions in leukocytes, platelets, broblasts, melanocytes, and other granulated cells in nerve tissue, kidney, and gastric mucosa. On peripheral blood lms, the inclusions can be seen in granulocytes (Figure 26.2), monocytes, large granular phocytes (NK and cytotoxic T cells), and platelets. Patients with CHS oen have cytopenias, particularly neutropenia. Clinical manifestations present in infancy as partial albinism, severe recurrent life-threatening bacterial infections, mild bleeding, easy bruising, and progressive neurologic impairment. In sus- pected patients, genetic testing for mutations in LYST is done to conrm the diagnosis. Patients with CHS are at high risk of developing an aggressive, life-threatening syndrome of exces- sive immune activation known as hemophagocytic lymphohis- tiocytosis. Most children with CHS will succumb to the disease before 7 years unless treated with HSCT.14 HSCT using matched donors has proven successful; however, it does not prevent neu- rologic deterioration.15 Pseudo–Chédiak-Higashi (PCH) granules/inclusions resem- ble the fused lysosomal granules in CHS. PCH granules are seen most oen in acute myeloid leukemia (AML). One study reported PCH granules in the leukemic cells of 5 of 20 children with AML.16 PCH granules are also associated with chronic myeloid leukemia, myelodysplastic neoplasms (MDSs), and rarely, in acute lymphoblastic leukemia.17 Congenital Defects of Phagocyte Number and/or Function e congenital defects of phagocytes include a heteroge- neous group of qualitative and quantitative disorders aecting 468 PART V Leukocyte Disorders TABLE 26.1 Severe Congenital Neutropenias Subtype Gene Inheritance Location SCN1 ELANE AD 19p13.3 SCN2 GFI1 AD 1p22.1 SCN3 HAX1 AR 1q21.3 SCN4 G6PC3 AR 17q21.31 SCN5 VPS45 AR 1q21.2 SCN6 JAGN1 AR 3p25.3 SCN7 CSFCR AR 1p34.3 SCN8 SRP54 AD 14q13.2 SCN9 CLPB AD 11q13.4 SCNX WAS XL Xp11.23 *SCN1–SCN9 and SCNX are all associated with severe AD, Autosomal dominant; AR, autosomal recessive; BM, immature granulocytes in blood; NRBC, nucleated red e mainstay of treatment in SCN is long-term granulo- cyte colony-stimulating factor (G-CSF), which is eective in most patients at increasing the absolute neutrophil count and decreasing the rate of infections and mortality. While the risk of malignancy in SCN is thought to be a complication of the disease, long-term G-CSF therapy increases this risk.21 Aer 15 years on G-CSF, the cumulative risk of AML/MDS is 22%.22 Patients who do not respond to G-CSF or require higher doses to maintain adequate neutrophil counts and infection prophy- laxis are oen considered for HSCT. Cyclic neutropenia. Cyclic neutropenia is a CN caused by ELANE mutations but is a less severe disease compared to SCN1, which also stems from ELANE mutations. Patients with cyclic neutropenia experience characteristic episodes of severe neutropenia (less than 0.2 × 109/L) together with absolute monocytosis in approximately 21-day cycles, each lasting or more days. During the ANC nadir, patients oen experience mouth ulcers, sore throat, gingivitis, rash, fatigue, fever, and/ or cervical lymphadenopathy. e risk of life-threatening infections in cyclic neutropenia is much lower than in SCN1 and there is no increased risk of malignant transformation. Shwachman-Diamond syndrome. Shwachman-Diamond syndrome (SDS) is classied as a CN with associated neutrophil functional defects.1 SDS is a rare disease but a common bone marrow failure syndrome. SDS is caused by a mutation in SBDS which encodes SBDS, a key component in ribosome maturation, cell proliferation, and maintenance of the bone marrow microenvironment. Biallelic mutations in SBDS occur in most patients, resulting in a truncated nonfunctional SBDS protein and both neutropenia and impaired neutrophil neutrophils and monocytes to move from peripheral circulation to sites of infection. Patients with LAD have recurring infections and impaired wound healing and, depending on the LAD subtype, they may also have developmental abnormalities and/ or increased risk of bleeding. Absolute neutrophilia is present in LAD, especially evident during infections. LAD subtype is determined through genetic testing, typically DNA sequencing. Allogeneic HSCT has been shown to be a potentially curative therapy in severe LAD-I and LAD-III. A 2021 review of transplant data in 84 patients from 33 sites found a 3-year overall survival estimate of 83%.24 ere are three subtypes of LAD. Leukocyte adhesion disorder type I. LAD-1 is the most common type, caused by a mutation in ITGB2, which encodes the CD18 subunit of β2 integrins. e mutation leads to decreased production or a truncated form of β2 integrin and diminished neutrophil adhesion to endothelial cells, recognition of bacteria, and outside-in signaling. In LAD-I, neutrophils accumulate in peripheral circulation but cannot reach sites of infection in tissues because of the adhesion problem. T-cell function is also impaired in LAD-I. As of March 2023, 177 dierent mutations had been described25 that can have diering eects on the quantity and quality of the encoded β2 integrin. Shortly aer birth, LAD-I infants experience severe recurring infections, most oen of the skin, oral mucosa, gastrointestinal tract, respiratory tract, and perirectal area. In addition, LAD-I infants usually have lymphadenopathy, splenomegaly, neutrophilia, and lack of pus formation. e clin- ical severity of LAD-I is heterogeneous and largely related to the specic ITGB2 mutation and its impact on β2 integrins.25 Leukocyte adhesion disorder type II. LAD-II is caused by 1 of 16 mutations in SLC35C1, which codes for a fucose transporter in the Golgi system.25 e mutation leads to a lack of or a dysfunctional transporter and diminished fucosylation of cell surface glycoproteins that serve as ligands for L-selectins on leukocytes. e adhesion and rolling of leukocytes along endothelial cells of the vessel wall toward the site of infection depends on the binding of L-selectins on leukocytes with E or P selectins on endothelial cells, with their matching ligands on opposite cells. erefore in LAD-II, a lack of fucosylated glycoprotein ligands for L-selectin decreases the adhesion of leukocytes to the vascular endothelium and impairs their transmigration to sites of infection. Fortunately, β2 integrins are also activated through alternate pathways not aected by the SLC35C1 mutation. is provides partial functioning leukocyte adhesion and transmigration that is less impaired than that in LAD-I. Consequently, infections in LAD-II patients tend to be fewer and less severe than in LAD-I. On the other hand, the lack of fucosylation in LAD-II aects glycoproteins other than selectins, leading to severe cognitive impairment, skeletal abnormalities, growth retardation, and distinctive facial features. Leukocyte adhesion disorder type III. LAD-III is caused by 1 of 31 mutations in FERMT3 25 FERMT3 encodes kindlin-3 (fermitin family homolog 3), which is required for normal inside-out signaling of hematopoietic cells and activation of β1, β2, and β3 integrins. In LAD-III, integrin expression is normal; 470 PART V Leukocyte Disorders function tests such as dihydrorhodamine 123 or nitroblue tetra- zolium test can be used to screen suspected patients. Positive screening tests are followed with DNA sequencing to conrm the diagnosis. e optimal management of mild to moderately severe CGD involves long-term antimicrobial prophylaxis plus quick recognition and aggressive treatment of acute infections and inammatory complications. Over the past two decades, studies using HSCT in CGD have shown signicant improve- ments in outcomes and reductions in morbidity and mortality. A 2018 review of data from nine studies reported an overall event-free survival of more than 80% and overall survival of approximately 90% at 3 years aer HSCT.27 Enzymatic White Blood Cell Defects: Myeloperoxidase Deficiency Myeloperoxidase (MPO) deciency is the most common inher- ited disorder of phagocytes. MPO is an enzyme found in high concentration in primary azurophilic granules of neutrophils and in lower concentration in the lysosomal granules of mono- cytes. In neutrophils, MPO catalyzes the conversion of H2O2 to HOCL and other microbicidal reactive oxygen intermediates. MPO plays an important role in the killing of phagocytized bac- teria and yeast and participates in the formation of neutrophil extracellular traps (NETs), another mechanism for eliminating microorganisms.28 e MPO gene is located on chromosome 17q23. Pathogenic mutations lead to decreased MPO pro- duction, limiting its participation in microbicidal activities. Nevertheless, most MPO-decient individuals are asymptom- atic. is is because neutrophils employ additional pathways for generating microbicidal agents. Although less potent, these pathways provide adequate protection against pathogens in the majority of individuals with MPO deciency. However, there have been reports of increased susceptibility to fungal infections in MPO deciency when comorbid diseases are present.29,30 Automated hematology analyzers that use MPO in the WBC dierential method are limited in the analysis of MPO-decient patients (Chapter 13). LYSOSOMAL STORAGE DISORDERS e inborn errors of metabolism consist of 1450 disorders divided into 24 categories and 124 groups.31 ese are mostly single gene defects aecting enzymes that metabolize substrates into various components. In most cases, the enzyme deciency leads to a buildup of toxic substances that are the source of clini- cal manifestations. e inborn errors of metabolism include the lysosomal storage disorders (LSDs) a group of over 70 inherited diseases. In the LSDs, single gene mutations negatively aect the production, transport and secretion of lysosomal enzymes.32 Failed degradation of macromolecules and gradual buildup (“storage”) of undigested substrates within lysosomes result in cell dysfunction, cell death, and a variety of clinical symptoms. All cells containing lysosomes are potentially aected. LSDs are classied according to the undigested macromolecule(s) that accumulates in the cell. Subtypes of LSDs include sphingolipido- ses, pseudobasophilia, mucolipidoses, mucopolysaccharidoses TABLE 26.3 Mucopolysaccharidoses Name Also Known As Enzyme Deficiency MPS I Hurler syndrome,* Alpha-l-iduronidase Hurler-Scheie syndrome,† and Scheie syndrome† MPS II Hunter syndrome Iduronate 2-sulfatase MPS III A Sanlippo syndrome N-Sulfoglucosamine sulfohydrolase MPS III B Sanlippo syndrome Alpha-N- acetylglucosaminidase MPS III C Sanlippo syndrome Heparan-alpha- glucosaminide N-acetyltransferase MPS IV A Morquio syndrome N-Acetylgalactosamine-6- sulfatase MPS IV B Morquio syndrome Beta-galactosidase MPS VI Maroteaux-Lamy Arylsulfatase B syndrome MPS VII Sly disease Beta-glucuronidase MPS IX Natowicz syndrome Hyaluronidase-1 *Most severe. †Attenuated phenotype. AS, Accumulated substrate; CS, chondroitin sulfate; mucopolysaccharidoses. In GD, macrophages containing excess glucocerebroside accumulate in the spleen, liver, and bone marrow and are pri- marily responsible for the disease manifestations. Gaucher cells are lysosome-engorged macrophages with eccentric nuclei and abundant brillar blue-gray cytoplasm with a stri- ated or wrinkled appearance (sometimes described as onion skin-like) (Figure 26.4). Gaucher cells stain positive with trichrome, aldehyde fuchsin, periodic acid-Schi (PAS) and acid phosphatase.39 In untreated patients, Gaucher cells inl- trate the hematopoietic space in bone resulting in anemia and thrombocytopenia. A commercially available test for β-glucosidase (glucocere- brosidase) is available to conrm the GD diagnosis. Genetic testing performed in suspected patients to screen for the most common mutations, including N370S, 84GG, IVS2 +1G>A, and L444P.39 All three types of GD have been associated with an 472 PART V Leukocyte Disorders Figure 26.3 Pathways and Diseases A. T., et al.. Nathan and Oski’s TABLE 26.4 Clinical Subtypes of Gaucher Type I: Nonneuronopathic Age at presentation Childhood/adulthood Hepatosplenomegaly + → +++ Skeletal abnormality – → +++ CNS disease – Life span 6–80+ years internal tandem duplication such as the FLT3-ITD mutation in acute myeloid leukemia (Chapter 31). JAK2 encodes a nonrecep- tor tyrosine kinase associated with the intracellular domain of growth factor receptors, such as the erythropoietin receptor, and 494 PART V Leukocyte Disorders TABLE 27.3 Comparison of Oncogenes Oncogenes Normal functions Promote cell proliferation transduction, apoptosis Effect of mutations Leukemogenic when inappropriately mutation); causes constitutive and/or overexpression of oncogene product Genetics Dominant; only one mutant Examples of mutations Chromosomal rearrangement mutation, internal tandem Examples relevant to ABL1, JAK2, BCL2 hematologic neoplasms “Incidence, Prevalence, and Etiology”), RB1 involved in familial retinoblastoma, and WT1 in Wilms tumor. More importantly, these tumor suppressor genes are deleted or inactivated sporadic (nonfamilial) cancers, including hematologic neo- plasms, which leads to accumulation of additional mutations and a more clinically aggressive state. An example is chronic lymphocytic leukemia, which has a more aggressive course when the TP53 gene is deleted or mutated, warranting a dier- ent approach to therapy (Chapter 34).25 Table 27.3 compares characteristics of oncogenes and tumor suppressor genes. DNA Repair Genes Mutations in DNA repair genes are also involved in hematologic neoplasms. Mutations in these genes cause genetic instability and increased mutation rates, leading to an increased risk of malignant transformation. An example is the Fanconi anemia gene, FA, which is important for maintaining genomic in hematopoietic tissues (mentioned in “Incidence, Prevalence, and Etiology”). Regardless of the type of chromosome or genetic abnormality, oncogene activation or the loss or inactivation of tumor suppres- sor or DNA repair genes has adverse molecular eects on prolif- eration, dierentiation, maturation, survival, apoptosis, cell cycle control, and DNA repair mechanisms in hematopoietic cells and an increased risk of malignant transformation. e list of chro- mosomal and molecular aberrations known to occur in various hematologic neoplasms continues to grow on an almost daily basis. Indexing this list is far beyond the scope of this chapter, but specic examples will be discussed in the chapters that follow. THERAPY Treatment for leukemia and lymphoma may involve chemo- therapy, radiation, supportive therapy, targeted therapies, and hematopoietic stem cell transplantation (HSCT) (Box 27.2). Research in leukemia-specic therapy using molecular targets and immunotherapy and cellular therapy is ongoing and rap- idly advancing. New schemes for risk stratication and treat- ment modalities have resulted in prolonged survival and cures for conditions that were uniformly fatal with conventional chemotherapy drugs vary considerably. Chemotherapy agents can be classied in two ways: by their eects on the cell cycle and by their biochemical mechanism of action. Some che- motherapy drugs can aect cells only in specic phases of the cell cycle (phase specic), whereas other drugs act during any phase of the cell cycle (phase nonspecic). A general biochem- ical classication of chemotherapy agents includes alkylating agents, plant alkaloids, antimetabolites, antitumor antibiotics, and glucocorticoids. Chemotherapy drugs are usually given in combination according to various published protocols or in the context of a clinical trial. Chemotherapy is usually administered in three phases: induction, consolidation, and maintenance. e goal of induc- tion is to rapidly decrease the tumor burden and achieve remis- sion. ere are dierent types of remission depending on the leukemia and the sensitivity of methods used for detection of malignant cells. For example, a hematologic remission in acute leukemia may include a normocellular bone marrow, recovery of peripheral blood cell counts, and no microscopic evidence of leukemia cells, whereas a cytogenetic remission is the absence of the cytogenetic defect determined by karyotyping methods (Chapter 30). A molecular remission is the absence of leukemia cell nucleic acid sequences using highly sensitive molecular methods capable of detecting one leukemia cell among 105 or 106 normal cells (Chapter 29). Aer hematologic remission is achieved, millions of leukemia cells may still be undetected in the body (called minimal residual disease), so a consolidation phase is done with dierent chemotherapy agents to further reduce the number of leukemia cells. A maintenance phase may be incorporated in the treatment plan, which is continued for a longer period with less intensive agents to eradicate any remain- ing leukemia cells to prevent a relapse. Chemotherapy agents aect both malignant and normal cells. eir eects are most pronounced on rapidly dividing cells, such as those in gastrointestinal mucosa and bone mar- row. is limits dosage and usually determines the maximum tolerated dose for a patient. Neutrophil and platelet counts are routinely monitored because they are the rst cells to decrease aer chemotherapy because of their shorter life spans. Radiation Therapy Radiation kills cells by producing unstable ions that damage DNA and may cause instant or delayed death of cells. Toxic eects of radiotherapy can occur during therapy or much later. Complications can be reduced through use of combined ante- rior and posterior treatment ports and application of maximal shielding techniques to prevent damage to normal tissues. e hematopoietic system, gastrointestinal tract, and skin are most oen aected during radiotherapy. Spinal and pelvic irradia- tion can cause marrow suppression, sometimes lowering blood counts to life-threatening levels. Toxic eects are usually revers- ible when radiation is stopped. Supportive Therapy Numerous substances that are naturally produced in the human body have now been developed using recombinant technologies. Some are commercially produced and cleared by the US Food 496 PART V Leukocyte Disorders of patients with APL is dramatically improved with the availability of dierentiation therapy using all-trans retinoic acid (ATRA) as rst-line treatment along with chemotherapeutic agents (Chapter 31). ATRA binds to RARA in the fusion protein and overcomes the block, allowing transcription and expression of genes needed for myeloid dierentiation and maturation.31 In lymphoid neoplasms, treatment includes immunotherapy using monoclonal antibodies for targeted therapeutic strategies. Monoclonal antibodies generally must be delivered intrave- nously or subcutaneously. An example is rituximab (anti-CD20), which binds to the CD20 antigen present on malignant cells in many B-lymphoid neoplasms and has shown ecacy in non-Hodgkin lymphoma and chronic lymphocytic leukemia.32 e antibody targets CD20+ lymphocytes for destruction by antibody-mediated and complement-mediated cytotoxicity.32 Additional modications of immunotherapy are now being developed, such as the bispecic T cell engager (BiTE) monoclo- nal antibody, blinatumomab.33 It can bind both CD19 and CD3, bringing CD3+ T-lymphoid cells closer to CD19+ B-lymphoid cells to promote their destruction by cytokines.33 It has shown ecacy in relapsed or refractory non-Hodgkin lymphoma and precursor acute lymphoblastic leukemia.33 Monoclonal antibodies can also be conjugated with toxins (called immu- noconjugates) to kill target cells. An example is inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated with calicheamicin, an antibiotic with cytotoxic activity.34 e conjugated antibody binds to CD22+ B-lymphoid cells, bring- ing the toxin close to the cell where it rapidly enters, binds to, and damages DNA and induces apoptosis.34 It has been used with encouraging results in relapsed or refractory acute lym- phoblastic leukemia.34 Cellular therapy is also being implemented, with high e- cacy in patients with high-risk hematologic neoplasms. One such therapy uses CD19-specic chimeric antigen recep- tor T (CAR-T) cells, in which patient T cells are collected by pheresis and are genetically engineered exvivo using lentiviral or retroviral vectors to express protein complexes that recog- nize only the patient’s leukemia cells.35 Engineered CAR-T cells then specically bind to patient’s leukemia cells and target them for destruction.35 CAR-T cells have been successful in achiev- ing remission in patients with high-risk, refractory, or relapsed acute lymphoblastic leukemia and non-Hodgkin lymphoma.35 Gene editing technologies, such as CRISPR/Cas9 targeted nuclease, are also being used to improve the potency and safety of CAR-T cells.35 Epigenetic therapies are also used in hematologic neo- plasms to reverse epigenetic silencing of gene transcription. For example, histone deacetylase inhibitors are being used in cutaneous T-cell lymphoma to prevent deacetylation, allowing chromatin to open so that repressed genes can be transcribed and expressed.22,36 Likewise, hypomethylating treatment, using drugs that remove methyl groups from gene promoters allow- ing expression of genes, is used in high-risk myelodysplastic neoplasms.22,37 ese and other targeted therapies will be discussed in more detail in chapters covering specic hematologic neoplasms. Development and optimization of targeted therapies is an area ALLOGENEIC Donor (related or unrelated) 1 Peripheral blood stem cells collected or bone marrow harvested Blood/marrow 2 processing; may include T cell depletion 3 4 marrow Conditioning regimen Recipient Recipient (patient) Figure 27.2 Overview of Hematopoietic Donors. Even with continued improvement in technique and sup- portive care, HSCT carries many risks. Death aer transplan- tation is caused by complications of the conditioning regimens, SUMMARY   Most neoplasms of the hematopoietic system are acquired genetic diseases. ey include leukemias, lymphomas, and myeloid proliferations and neoplasms.   Leukemias originate in bone marrow, and leukemia cells readily pass into peripheral blood, but they can also inltrate lymphoid tissues (spleen, liver, lymph nodes) as well as other organs and tissues of the body. Lymphomas are solid tumors of lymphoid cells that usually originate in the lymphatic system and proliferate in lymph nodes and other lymphoid organs and tissues.   Leukemias are divided into lymphoid, myeloid, and mixed-phenotype lineages, and further into acute (precur- sor cell) and chronic (mature cell) categories. In acute leuke- mias, onset is sudden, progression is rapid, and the outcome is oen fatal in weeks or months if le untreated. In chronic leukemias, onset is insidious, and progression is slower, with a longer survival compared with acute leukemia. 498 PART V Leukocyte Disorders   Hematologic neoplasms illustrate that a single mutation, or more commonly a series of mutations, can lead to malignant transformation by disrupting the molecular machinery of hematopoietic cells.   Most chromosomal translocations in leukemias involve oncogenes. Activation of the dominant transforming onco- gene alters its gene product or its expression and transforms the cell into a malignant phenotype, even in the presence of a residual normal allele.   In contrast to oncogenes, tumor suppressor genes contribute to the malignant process only if both alleles have otherwise inactivated.   Activation of oncogenes or the loss or inactivation of tumor suppressor or DNA repair genes has adverse molecular eects on proliferation, survival, dierentiation, ration of hematopoietic cells. REVIEW QUESTIONS Answers can be found in Appendix C. 1. Lymphomas dier from leukemias in that they are: a. Solid tumors b. Not considered systemic diseases c. Never found in peripheral blood d. Do not originate from hematopoietic cells 2. Which one of the following viruses is known to CAUSE lymphoid neoplasms in humans? a. HIV-1 b. HTLV-1 c. Hepatitis B d. Parvovirus B 3. Loss of function of tumor suppressor genes increase the risk of hematologic neoplasms by: a. Suppressing cell division b. Activating tyrosine kinases, which promote proliferation c. Promoting excessive apoptosis of hematopoietic cells d. Allowing cells with damaged DNA to progress through the cell cycle 4. Oncogenes are said to act in a dominant fashion because: a. Leukemia is a dominating disease that is systemic b. e oncogene product is a gain-of-function mutation c. A mutation in only one allele is sucient to promote a malignant phenotype d. ey are inherited by autosomal dominant transmission 5. Which one of the following is NOT one of the cellular abnormalities produced by oncogenes? a. Constitutive activation of a growth factor receptor b. Constitutive activation of a signaling protein c. Acceleration of DNA catabolism d. Dysregulation of apoptosis REFERENCES 1. Nowell, P. C., & Hungerford, D. A. (1960). A minute chromosome in human granulocytic leukemia (Abstract). Science, 132, 1497. 2. Rowley, J. D. (1973). A new consistent chromosomal abnormality in chronic myelogenous leukemia identied by quinacrine uorescence and Giemsa staining. Nature, 243, 290–293. 3. Taub, R., Kirsch, I., Morton, C., etal. (1982). c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA, 79, 7837–7841. 4. National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER). Cancer Stat Facts: Leukemia. https://seer. cancer.gov/statfacts/html/leuks.html. Accessed December 28, 2022. 5. National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER). Cancer Stat Facts: Non-Hodgkin Lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed December 28, 2022. 6. National Cancer Institute, Surveillance, Epidemiology, and End Results Program (SEER). Cancer Stat Facts: Hodgkin Lymphoma. https://seer.cancer.gov/statfacts/html/hodg.html. Accessed December 28, 2022. 7. WHO Classication of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; forthcoming. (WHO classication of tumours series, 5th ed.; vol. 11). https://publications.iarc.fr. 8. Gaglia, M. M., & Munger, K. (2018). More than just oncogenes: mechanisms of tumorigenesis by human viruses. Curr Opin Virol, 32, 48–59. 9. Fiore, D., Cappelli, L. V., Broccoli, A., etal. lymphomas: from the bench to the clinic. Nat Rev 10. Yin, H., Qu, J., Peng, Q., et al. (2019). Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis. Med Microbiol Immunol, 208, 573–583. 11. Baptista, M. J., Tapia, G., Muñoz-Marmol, A. M., etal. (2022). Genetic and phenotypic characterisation of HIV-associated aggressive B-cell non-Hodgkin lymphomas, which do not occur specically in this population: diagnostic and prognostic implications. Histopathology, 81, 826–840. 12. Sweet-Cordero, E. A., & Biegel, J. A. (2019). e genomic landscape of pediatric cancers: implications for diagnosis and treatment. Science, 363, 1170–1175. 13. Zhang, C., Liu, J., Xu, D., etal. (2020). Gain-of-function in cancer progression and therapy. J Mol Cell Biol, 12, 674–687. 14. Huang, R. X., & Zhou, P. K. (2020). DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target er, 5, 1–27. 15. Labuhn, M., Perkins, K., Matzk, S., etal. (2019). Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome. Cancer Cell, 36, 123–138. 16. Campo, E., Jae, E. S., Cook, J. R., etal. consensus classication of mature lymphoid neoplasms: a report from the clinical advisory committee. Blood, 140, 1229–1253. 17. Arber, D. A., Orazi, A., Hasserjian, R. P., etal. (2022). International consensus classication of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood, 140, 1200–1228. 18. Stam, K., Heisterkamp, N., & Grosveld, G. (1985). Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. N Engl J Med, 313, 1429–1433. 6. List acquired conditions associated with quantitative changes in leukocyte subtypes. 7. Compare invivo and invitro alterations in leukocyte morphology with normal cells. 8. Outline the pathogenesis and clinical and laboratory features of infectious mononucleosis. 9. Given the patient history, clinical and laboratory ndings, and representative cells from a peripheral blood lm or bone marrow smear, interpret results to determine the type of nonmalignant leukocyte disorder, and recommend additional tests to conrm a diagnosis. Neutrophil Hypersegmentation Alder-Reilly Anomaly May-Hegglin Anomaly Quantitative Abnormalities of Leukocytes Quantitative Abnormalities of Neutrophils Quantitative Abnormalities of Eosinophils Quantitative Abnormalities of Basophils Quantitative Abnormalities of Monocytes Quantitative Abnormalities of Lymphocytes Secondary Morphologic Changes in Leukocytes Storage Artifacts in Leukocytes Secondary Changes in Neutrophils and Monocytes Eosinophils and Basophils Lymphocytes Infectious Mononucleosis his assistance with some of the gures in this chapter. CHAPTER 26 Nonmalignant Leukocyte Disorders 465 should be able to respond 3. Provide an approach to correcting the results of the WBC differential that does not require repeating the test. physician with a complaint 4. What are clinical implications of reporting the manual differential results The remainder of above if a left shift does not actually exist? she was experiencing blood count results were the Index at the end of the book. × 109/L review was performed. Appar- and a manual differential granulocytes shown? If Figure 26.1 Examples of Cells Classied as Immature Granulocytes in the Differential for the Patient in the Case. (Peripheral blood, Wright- Giemsa stain, Cellavision DC-1, ×1000.) (Courtesy Cellavision AB, Lund, deciency anemia. Based Sweden.) diagnosis is suspected? Severe Combined Immune Deficiency Severe combined immune deciency (SCID) includes a group of IEIs associated with defects in both cellular and humoral immunity.1 Nearly all patients with SCID experience a marked decrease in circulating T cells, poorly functioning B cells, hypogammaglobulinemia, and profound clinical symptoms that manifest in infancy. Le untreated, most patients with SCID die within the rst 2 years of life from overwhelming bacterial, viral, and/or fungal infections. Potentially cura- tive options in SCID are allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy, in which the goal is reconstitution of the failed immune system. e outcomes in patients treated with HSCT have improved over the past decade. Most patients with SCID who undergo HSCT can expect to survive well into adulthood.3 In the United States, gene therapy is not yet approved for SCID. However, gene ther- apy is an option for patients treated in clinical trials in which there has been promising success. However, even with gene therapy, there remains a signicant risk of leukemic transfor- mation in SCID patients.1 In each IEI, a Common Gamma Chain Deficiency/X-Linked Severe Combined Immune Deficiency Common gamma chain deciency/X-linked SCID is classied as T–B+ SCID1 and is the most common SCID. is disease initiates from a mutation in IL2RG located at Xq13.1. IL2RG normally encodes the gamma chain protein within receptor complexes that bind interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. ese interleukins provide growth, dierentiation, and survival signals for T and natural killer (NK) lymphocytes. In common gamma chain deciency, a mutation in IL2RG leads to truncated gamma chain proteins and faulty signal transduction that impairs T and NK cell development. Infants ere is, however, a signicant risk for the development of acute leukemia. - 22q11.2 Deletion Syndrome 22q11.2 deletion syndrome (22DS)/DiGeorge syndrome/velo- cardiofacial syndrome is classied as a combined immuno- deciency with associated syndromic features.1 e genetic aberration in 22DS is a heterozygous microdeletion of 1.5 to 3 million base pairs on chromosome 22 at q11.2 resulting in a loss of over 100 genes and their encoded protein products.9,10 e deletion breakpoint and genes lost in the deletion can dier among patients, contributing to the variable clinical phenotype. Haploinsuciency caused by the loss of T-box transcription factor 1 gene (TBX1), DiGeorge Syndrome Critical Region 8 (DGCR8), and several microRNAs result in congenital malfor- mations and other clinical manifestations in 22DS.10 Variable degrees of thymic hypoplasia proportionally aect the severity of immune dysfunction, autoimmunity, and T lymphopenia. Abnormal development of the embryonic pharyngeal system during gestation produces characteristic cardiac anomalies, thy- mus and parathyroid hypoplasia, and craniofacial deformations in 22DS patients. A wide array of additional clinical ndings includes intrauterine growth restriction, major infections, fail- ure to thrive, short stature, skeletal defects, neuropsychiatric diseases, developmental delays, gastrointestinal diseases, oph- thalmologic disorders, hypocalcemia, immune thrombocy- topenia, and autoimmune hemolytic anemia. Genetic testing conrms the 22DS diagnosis in patients with the characteristic presentation. e survival of aected infants is oen less than 1 year without thymic tissue transplantation or HLA-matched HSCT with memory T cells. Gra-versus-host disease is a common complication aer HSCT. In a survey of 17 athymic patients with 22DS who underwent HSCT between 1995 and 2006, 41% were alive at a median followup of 5.8 years.11 Bruton Tyrosine Kinase Deficiency Classied as an antibody deciency, Bruton tyrosine kinase (BTK) deciency/X-linked agammaglobulinemia is caused by a mutation in the gene encoding BTK (Xq21.3-Xq22), a signal transduction protein that promotes B-cell lineage develop- ment.1 A mutation in BTK leads to marked reduction in B cells, absent tonsils and adenoids, inability to produce plasma cells, and therefore severe decreases in all immunoglobulin isotypes and grossly defective antibody responses. e lack of a humoral immune response leaves the patient susceptible to infections from encapsulated bacteria, bloodborne enteroviruses, and cer- tain fungal and parasitic infections. e disease manifests clinically aer maternal antibodies clear from the BTK-decient infant’s circulation, between 3 and 18 months. Recurrent otitis, conjunctivitis, diarrhea, and sinus and skin infections are common. e disease is oen rst suspected when the child experiences a severe life-threatening bacterial infection. Molecular genetic testing is needed to conrm the diag- nosis. e management of BTK deciency consists primarily of immunoglobulin replacement therapy. Most patients diagnosed today will live well into adulthood because of earlier recognition, advancements in immunoglobulin therapies, and improvements CHAPTER 26 Nonmalignant Leukocyte Disorders 467 C Fused cytoplasmic granules in (A), Neutrophil. (B), Basophil. (C), stain, Cellavision DC-1, ×1000.) (Courtesy Cellavision AB, Lund, phagocytic cells of the innate immune system, primarily neutro- phils, monocytes, and/or macrophages. As of 2022, there were 42 distinct disease entities, each originating from a unique genetic abnormality.1 ese diseases are organized into four subgroups, (1) congenital neutropenias, (2) defects of motility, (3) defects of respiratory burst, and (4) other nonlymphoid defects. A com- mon thread in all phagocyte diseases is an increased susceptibil- ity to bacterial and fungal infections. Dermatologic symptoms, delayed wound healing, growth failure, and inammation of the oral mucosa are also common. A wide array of additional clin- ical symptoms are associated with the individual diseases. is section highlights several phagocyte disorders that arise from dierent underlying mechanisms. lym- Congenital Neutropenia Congenital neutropenia (absolute neutrophil count [ANC] less than 1.5 × 109/L) is associated with a variety of nonmalignant conditions covered in this chapter in which the decrease in neu- trophils results from decreased production, increased destruc- tion, or apoptosis. e congenital neutropenias (CNs) are a group of inherited diseases in which the primary defect is in the production of neutrophils.1 Common to all CNs is early clinical onset, frequently in infancy, and an increased risk of primarily bacterial and fungal infections arising from neutropenia rather than some other immune deciency. In some CNs, there are nonhematologic manifestations such as neurologic/cognitive defects, dysmorphic features, and organ dysfunction. Severe congenital neutropenia. Severe congenital neutropenia (SCN) is a subset of CN characterized by an ANC less than 0.5 × 109/L (oen less than 0.2 × 109/L) and recurring, severe, oen life-threatening bacterial and fungal infections with or without nonhematologic manifestations and an increased risk of malignancy, frequently MDS or AML. Mutations in the neutrophil elastase gene ELANE (causing SCN1) are responsible for 50% to 60% of all SCN cases.18 Ten subtypes of SCN are listed in Table 26.1 1 19 20 Bone marrow examination in patients with SCN shows a maturation arrest in the neutrophil series at the myelocyte/pro- myelocyte stage and dysmorphic changes in neutrophilic cells. Disease Associated Features* Elastase deciency Mild anemia, thrombocytopenia, monocytosis, eosinophilia, osteopenia GFI1 deciency Monocytosis, lymphopenia, IG Kostmann disease Neurologic defects G6PC3 deciency BM dysplasia, anemia, thrombocytopenia, HSM; cardiac, urogenital, skeletal, endocrine, and vascular abnormalities, deafness VPS45 deciency BM brosis, EMH, anemia, anisopoikilocytosis, thrombocytopenia, NRBC, enlarged kidneys, HSM, delayed development, blindness, no response to G-CSF in some JAGN1 deciency Short stature, facial dysmorphia, hypothyroidism, urogenital anomalies GCSF receptor deciency No response to G-CSF SRP54 deciency Groups A and B patients: short stature, pancreas dysfunction, poor response to G-CSF Group B also has developmental delay, autism 3-Methylglutaconic deciency Neurocognitive defects, cataracts, cardiac defects, facial dysmorphia, hypothroidism X-linked neutropenia Low normal platelets, monocytopenia neutropenia and recurring acute, severe, life-threatening infections. bone marrow; EMH, extramedullary hematopoiesis; HSM, hepatosplenomegaly; IG, blood cells in peripheral blood; SCN, severe congenital neutropenia; XL, sex-linked. chemotaxis. Patients are usually diagnosed in infancy with pancreatic insuciency and associated malabsorption and steatorrhea. ere are also skeletal abnormalities, severe infections, and failure to thrive. Additional manifestations of SDS oen include developmental delays and bone marrow failure with dysplasia, cytopenias, and increased risk of AML or MDS, particularly in patients who develop multiple hematopoietic cell clones with TP53 mutations.23 e diagnosis of SDS in suspected patients is achieved though molecular genetic testing, typically DNA sequencing. G-CSF is used in patients with neutropenia and severe infections. Allogeneic HSCT can potentially cure SDS patients with bone marrow failure and MDS or AML; however, there is no eect on the nonhematologic manifestations. Outcome data in SDS patients treated with HSCT are limited. 3 to 5 Defects of Motility As leukocytes (primarily neutrophils and monocytes) leave cir- culation to move to a site of infection, they adhere to the vascu- lar endothelium and tissue matrix and roll along the vessel wall. Adhesion molecules such as selectins and integrins expressed on endothelial cells and leukocytes mediate this process, interact- ing with ligands on the surface of leukocytes to slow the speed of neutrophils in circulation. Ligand binding induces high-anity attachment of integrins with endothelial cell receptors, facilitat- ing leukocyte transmigration between gaps in endothelial cells (diapedesis) (Chapter 10). Leukocyte adhesion disorders. Leukocyte adhesion disorders (LADs) are rare autosomal recessive primary immunodeciency disorders characterized by the inability of CHAPTER 26 Nonmalignant Leukocyte Disorders 469 however, the integrins fail to respond to external signals, which limits neutrophil adhesion, NK cell activity, and platelet function. Patients with LAD-III experience severe recurrent infections, osteoporosis, and bleeding. Without treatment with HSCT, the prognosis of infants with LAD-III is poor. Defects of Respiratory Burst: Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is a rare condition caused by the decreased ability of neutrophils, monocytes, macrophages, and eosinophils to kill phagocytized bacteria and yeast. This is due to a failure in the respiratory burst and failed production of powerful antimicrobial superox- ide anions and other reactive oxygen species, including hydrogen peroxide, hypochlorous acid, and others. The failed respiratory burst in CGD is caused by a mutation in one of six genes that encode protein components in the reduced form of nicotinamide adenine dinucleotide phos- phate (NADPH) oxidase, which is required in the respiratory burst. Approximately two-thirds of CGD cases are inherited as X-linked recessive and one-third are autosomal recessive. X-linked recessive patients generally have a more severe dis- ease course with shortened survival compared with autoso- mal recessive patients. In normal individuals, phagocytosis of foreign organism leads to phosphorylation and binding of cytosolic p47phox and p67phox. Primary granules con- taining antibacterial neutrophil elastase and cathepsin G and secondary granules containing the cytochrome com- plex gp91phox and p22phox migrate to the phagolysosome. NADPH oxidase forms when p47phox and p67phox, along with p40phox and RAC2, combine with the cytochrome complex. The principal antimicrobial agent, superoxide, is generated in the phagolysosome during the respiratory burst, when an electron from NADPH is added to oxygen. In addition, NADPH has regulatory functions in the generation of other antimicrobial agents. Most cases of CGD are due to mutations in the genes coding for gp91phox or p47phox. The six genes implicated in CGD and their encoded protein products are listed in Table 26.2 26 Patients with CGD experience life-threatening catalase- positive bacterial and fungal infections, as well as inammatory complications such as colitis and granuloma formation in the gastrointestinal tract, urinary tract, and other organs. Neutrophil TABLE 26.2 Genes Involved in Chronic Granulomatous Disease Gene Location Inheritance Protein Product CYBB Xp21.1 XLR gp91phox CYBA 16q24 AR p22phox NCF1 7q11.23 AR p47phox NCF2 1q25 AR p67phox NCF4 22q13.1 AR p40phox CYBC1(EROS) 17q25.3 AR Essential for reactive oxygen species (EROS) AR, Autosomal recessive; XLR, sex-linked recessive. (MPSs), lipoprotein storage disorders, and lysosomal transport defects. e more common LSDs are presented in this chapter. Mucopolysaccharidoses e MPSs are a rare group of inherited disorders of mucopoly- saccharide or glycosaminoglycan degradation. e combined incidence in the United States for all subtypes is 1 per 100,000 live births.33 MPS types I, II, and III have the highest incidence. As of 2021, only four cases of MPS type IX had been reported.33 e MPSs are caused by reduced activity in enzymes necessary for the degradation of one or more substrates: dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate, and hyaluronan. e partially degraded material builds up in lysosomes, causing serious clinical consequences and shortened survival. Table 26.3 provides genetic, biological, and clinical information about MPS subtypes, along with the decient enzymes and accumulated substrates.32,34,35 e peripheral blood lms of patients with MPS may show metachromatic Reilly bodies (acquired Alder-Reilly anomaly [ARA]) in neutrophils, monocytes, and lymphocytes. Bone marrow macrophages (histiocytes) also can demonstrate cyto- plasmic metachromatic material. Diagnosis relies on assays that measure the specic enzymes decient in each subtype. Genetic testing to identify pathologic mutations can be performed for diagnostic conrmation. MPS treatment includes supportive care, enzyme replacement therapy, and/or HSCT. Gene therapy is a promising treatment approach and clinical studies are ongo- ing in patients with MPS types I, II, IIIA, and IV.36 Sphingolipidoses e sphingolipidoses are a group of LSDs with functional deciencies in enzymes needed for lysosomal breakdown of sphingolipids, causing harmful accumulation of various phos- pholipids in tissues. e pathways involved in sphingolipid catabolism, specic enzyme deciencies, and corresponding storage diseases are outlined in Figure 26.3. Gaucher disease and Niemann-Pick disease are examples of sphingolipidoses and are described in more detail in the following sections. Gaucher Disease Gaucher disease (GD) is the most common LSD. It is an auto- somal recessive disorder triggered by a defect or deciency in the catabolic enzyme β-glucocerebrosidase, which is necessary for glycolipid metabolism. As a result, unmetabolized substrate sphingolipid glucocerebroside accumulates in the lysosomes of macrophages throughout the body, including osteoclasts in bone and microglia in the brain.37 GD stems from a mutation in GBA located at 1q21-q22. More than 400 pathogenic mutations have been reported and, although some correlations have been found between specic mutations and patient outcomes, most clinical phenotypes cannot be predicted by genotype.38 ere are three types of GD, and type I is by far the most common. Neurologic symptoms are key factors in dierenti- ating subtypes. e phenotype is quite heterogeneous. Some patients are asymptomatic, whereas others experience a multi- tude of clinical problems. Clinical information associated with the three types of GD is provided in Table 26.4. CHAPTER 26 Nonmalignant Leukocyte Disorders 471 Gene and AS Location Clinical Features DS + HS IDUA Severe phenotype (Hurler): coarse facial features, 4p16.3 skeletal abnormalities, severe intellectual disability, hepatosplenomegaly, corneal clouding, umbilical hernia, frequent upper respiratory tract infections DS + HS IDS Severe phenotype: coarse facial features, Xq28 hepatosplenomegaly, short stature, skeletal deformities, cardiovascular disorders, deafness, neurocognitive issues HS SGSH Hirsutism, coarse facial features, behavioral problems, 17q25.3 aggressive behavior, speech delay, hepatomegaly HS NAGLU Cardiomegaly, coarse facial features, progressive 17q21.2 dementia, convulsions, HS HGSNAT Delayed psychomotor development, behavioral problems, 8p11.21 sleep disorder, hearing loss, coarse facial features, recurring infections, diarrhea, epilepsy, and retinitis pigmentosa KS + CS GALNS Musculoskeletal abnormalities, short stature, pulmonary 16q24.3 and cardiac dysfunction, hearing loss, corneal clouding KS GLB1 Musculoskeletal abnormalities, short stature, pulmonary 3p22.3 and cardiac dysfunction, hearing loss, corneal clouding DS + CS ARSB Severe form: coarse facial features, severe skeletal 5q14.1 abnormalities, joint stiffness, respiratory disease, cardiac disease, sleep apnea, pulmonary hypertension, corneal clouding, hepatosplenomegaly, macrocephaly, hearing loss HS + DS + GUSB Varies widely CS 7q11.21 Infantile: hydrops fetalis Severe: like MPS I (Hurler) Intermediate: skeletal abnormalities, coarse facial features, variable cognitive impairment Mild: skeletal abnormalities HYAL HYAL1 Facial dysmorphism; hepatosplenomegaly; cardiac, 3p21.31 respiratory, and skeletal involvement; and neurologic, hematologic, and ocular symptoms DS, dermatan sulfate; HYAL, hyaluronan; HS, heparin sulfate; KS, keratan sulfate; MPS, increased risk for developing hematopoietic neoplasms, most frequently plasma cell (multiple) myeloma.40 41 Treatment of GD includes enzyme replacement therapy and substrate reduction therapy.42 HSCT oers the potential for cure; however, it is not oen used because treatment-related mortality is high.43 Gene therapy, genome editing, and chaper- one therapy are additional modalities being pursued. Pseudo-Gaucher cells. Psuedo-Gaucher cells are seen in bone marrow specimens from patients with thalassemia, myeloid neoplasms,44 45 acute lymphoblastic leukemia,46 non- Hodgkin lymphoma,46 and plasma cell neoplasms.47 In these diseases, pseudo-Gaucher cells are thought to result from increased cell turnover overwhelming the glucocerebrosidase enzyme, causing accumulation of glucosylceramide in macrophages. erefore pseudo-Gaucher cells result from a relative rather than true decrease in enzyme. Pseudo- and true of Sphingolipid Metabolism. (From Orkin, S. H., Fisher, D. E., & Look, Hematology of Infancy and Childhood. [7th ed.]. Philadelphia: Saunders.) Disease* Type II: Acute Neuronopathic Type III: Subacute Neuronopathic Infancy Childhood/adulthood + + → +++ – ++ → +++ +++ + → +++ T) mutation in polycythemia vera (Chapter 32) and Numerous tumor suppressor genes have now been identi- ed, and many have been found to be associated with autosomal dominant familial cancer predisposition syndromes. Some well- known examples of loss or inactivation of tumor suppressor genes include TP53 in Li-Fraumeni syndrome (mentioned in and Tumor Suppressor Genes Tumor Suppressor Genes and differentiation, signal Detect damaged DNA and delay cell cycle to allow for DNA repair or apoptosis activated (gain-of-function Leukemogenic when inactivated or deleted (loss-of-function mutation); (continuous), dysregulated, causes inability to prevent cells with damaged DNA from progressing through the cell cycle; helps sustain malignant phenotypes allele needed for leukemogenesis Recessive; deletion or inactivation of both alleles needed for leukemogenesis (translocation, inversion), point Deletion, inactivating mutation, epigenetic silencing duplication, gene amplication TP53, RB1, WT1 BOX 27.2 General Categories of Therapy for Hematologic Neoplasms in many Chemotherapy Cell cycle effects: phase-specic or phase-nonspecic agents Biochemical mode of action: alkylating agents, plant alkaloids, antimetabo- lites, antitumor antibiotics, glucocorticoids Radiation therapy Supportive therapy Growth factors and cytokines Targeted therapy Targeted molecular therapy Immunotherapy Cellular therapy Hematopoietic stem cell transplantation Syngeneic Allogeneic Autologous stability treatment. In contrast to many solid tumors, numerous hema- tologic neoplasms now have cure rates that are substantially higher than they were two or three decades ago. Many exciting new therapies that are less toxic are now under development or are already employed in patient settings. ese therapies are bringing more optimism to the care of patients with hematologic neoplasms. Selection of the best therapy must start, however, with an accurate diagnosis. Even the most eective therapies do not work if they are applied in the wrong circumstances. Curative treatment strategies are now a realistic goal for patients with Hodgkin lymphoma, CML, hairy cell leukemia, some forms of non-Hodgkin lymphoma, and for children with acute lymphoblas- tic leukemia. Cure may be attainable in other patients with acute lymphoblastic or myeloid leukemia, and long-term remissions may be achievable in adults with multiple myeloma. For patients with other hematologic neoplasms such as mantle cell lymphoma, chronic lymphocytic leukemia, or a therapy-related leukemia, cure remains elusive, and therapy must be directed more toward attain- ing remissions or providing supportive care. Chemotherapy Chemotherapy is oral or parenteral cancer treatment with com- pounds that possess antitumor properties. Methods of action of CHAPTER 27 Introduction to Hematologic Neoplasms 495 and Drug Administration (FDA) for supportive care of patients with cancer, including patients with hematologic neoplasms. Growth factors and colony-stimulating factors (CSFs), a class of cytokines, normally act in the bone marrow microenvironment to stimulate blood cell formation (Chapter 5). Erythropoietin promotes red blood cell formation, and recombinant forms are administered to cancer patients with anemia induced by che- motherapy. Similarly, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating fac- tor (GM-CSF) are used to rapidly expand the number of mature neutrophils to ght or prevent infection. Recombinant forms of G-CSF and GM-CSF are administered to cancer patients with chemotherapy-induced neutropenia. ese agents not only have improved patients’ quality of life but also have allowed more ecient and eective delivery of chemotherapy regimens by preventing delays of or dosage reductions in chemotherapy courses as a result of low blood cell counts. Targeted Therapy As more has been learned about specic genetic lesions that cause hematologic neoplasms, researchers have worked to develop targeted therapies that act specically on malignant cells and leave normal cells untouched. As a result of these advances, cancer therapy is realizing the dream of targeted ther- apeutics and is moving away from nonspecic therapies such as chemotherapy and radiation. In 2001 the FDA cleared ima- tinib mesylate for treatment of chronic-phase CML as the rst rationally designed molecular targeted therapy for a cancer.26 e t(9;22) translocation in CML results in production of the BCR::ABL1 gene fusion, creating a fusion protein with consti- tutive and unregulated tyrosine kinase activity. Imatinib is an orally administered, small tyrosine kinase inhibitor (TKI) mol- ecule that binds to the ABL1 domain of the fusion protein and selectively blocks its tyrosine kinase activity.26,27 It reduces the massive cell proliferation and induces apoptosis of CML cells and remission with very few side eects.27 Imatinib is now the rst-line treatment for chronic-phase CML and has resulted in long-term remissions of 10 years and longer (Chapter 32).26,27 Newer and more potent TKIs have also been developed (such as dasatinib and nilotinib) to treat imatinib resistance that devel- ops in some patients with CML; these second-generation drugs have also been cleared by the FDA for rst-line treatment in CML.26–28 Imatinib is also used in combination with chemo- therapeutic agents to treat BCR::ABL1 positive acute lympho- blastic leukemia.28 Other TKIs are in development, and their eectiveness and safety are being evaluated in other hemato- logic neoplasms with dysregulated kinases, such as JAK2 inhib- itors in polycythemia vera and FLT3 inhibitors in acute myeloid leukemia.29,30 In APL, the t(15;17) translocation, results in fusion of the ret- inoic acid receptor gene, RARA, with the PML gene. RARA pro- tein is a ligand-dependent transcription factor that when bound to retinoic acid, upregulates expression of target genes required for myeloid dierentiation.31 However, RARA in the PML::RARA fusion does not respond to retinoic acid, resulting in silencing of transcription of genes needed for dierentiation and a block in maturation beyond the promyelocytic stage.31 Now the prognosis of intense research, and their use will continue to improve patient outcomes and survival as they more specically target malignant cells and not patients’ normal cells. Hematopoietic Stem Cell Transplantation As more has been learned about hematopoietic stem cells (HSCs), the therapeutic method of bone marrow transplanta- tion has evolved to be more aptly termed hematopoietic stem cell transplantation (HSCT) because dierent sources in addition to bone marrow can be used to obtain HSCs. Along with bone marrow, peripheral blood and umbilical cord blood (UCB) are rich sources. Bone marrow is harvested through multiple nee- dle aspirations, typically from the posterior iliac crests, and it is done in a sterile surgical environment, usually under general or regional anesthesia.38 Collection of peripheral blood stem cells is less invasive in that they are harvested by pheresis aer mobi- lization out of bone marrow by cytokines and chemokines such as G-CSF and plerixafor.38 UCB is collected by inserting a sterile needle into the umbilical vein aer the infant is delivered and the cord is clamped and cut, either before or aer delivery of the placenta.38 Regardless of the source, HSCs are considered adult stem cells, even when they come from umbilical cord blood, as opposed to embryonic stem cells, which are the subject of con- siderable ethical debate. HSCT remains an expensive and di- cult treatment alternative. When the decision to perform HSCT has been made and a donor has been found, an extensive hospital stay is usually required. Pretransplantation conditioning regimens use high- dose therapy to kill the patient’s malignant cells and normal bone marrow cells. is regimen reduces the body’s immunity to dangerously low levels and necessitates special protective isolation. Granulocyte counts approaching zero are commonly seen immediately before and aer transplantation. Aer infu- sion of donor HSCs, the recipient remains in a severely immu- nosuppressed condition for 2 weeks or longer. Strict isolation at this point is crucial. Prophylactic antibiotics and intrave- nous nutrition are also essential to keep the patient alive until marrow engrament. Recovery of granulocytes, reticulocytes, and platelets to normal levels is monitored closely in periph- eral blood. Evaluation and management of red blood cell and platelet transfusions are crucial components of HSCT. Aer discharge, peripheral blood cell counts and bone marrow con- tinue to be monitored to measure the progress of engrament of donor HSCs. HSCs for treatment of malignant disease come from donors of three general types: (1) syngeneic, or from an identical twin; (2) allogeneic, usually from an HLA-identical sibling or HLA- matched unrelated donor; or (3) autologous, in which the patient’s own marrow or peripheral blood stem cells are used (Figure 27.2). Most HSC donors are allogeneic, but for optimal outcomes, it is important to match as many HLA antigens as possible. Within any given family, there can be only four HLA haplotypes (two maternal and two paternal), and there is one chance in four that a sibling will be HLA identical. If an HLA- identical sibling or fully HLA-matched unrelated donor is not available, HLA-partially matched, related, or unrelated donors have been used. CHAPTER 27 Introduction to Hematologic Neoplasms 497 AUTOLOGOUS Recipient Treatment (patient) 1 Peripheral blood stem cells collected or bone marrow harvested Blood/marrow processing and 2 storage; may include purging of malignant cells Blood/ 3 4 Blood/marrow infusion infusion Conditioning regimen Recipient Recipient (patient) Stem Cell Transplantation in Allogeneic and Autologous such as infections or bleeding from bone marrow suppression, gra-versus-host disease, regrowth of malignant cells, and fail- ure of donor HSCs to engra.   For most hematologic neoplasms, causes directly related to development of the malignancy are unknown, but a few exceptions exist. Some known causes include environmental toxins, certain viruses, previous chemotherapy, and familial predisposition.   Classiĕcation schemes for hematologic neoplasms include the older French-American-British (FAB) system, based pri- marily on morphology and cytochemical staining, and the World Health Organization (WHO) system, which retains some elements of the FAB scheme but emphasizes molecular and cytogenetic abnormalities.   Types of mutations found in hematologic neoplasms include chromosomal rearrangements (such as translocation or inversion), gains or losses of chromosomes (aneuploidy), total or partial gene deletions, point mutations, insertions, and gene duplication/amplication.   Most hematologic neoplasms are systemic (diČusely involv ing the peripheral blood and/or bone marrow) at initiation of the malignant process. erefore with rare exceptions, most treatments for hematologic neoplasms given with cura- tive intent are not localized, such as radiation or surgery, but must by nature be systemic treatments.   Current treatments for hematologic neoplasms can be gen erally divided into the following categories: chemotherapy, radiation therapy, supportive therapy, targeted therapy, and hematopoietic stem cell transplantation. been lost or Now that you have completed this chapter, go back and read again the case study at the beginning and respond to the questions pre- sented. Answers can be found in Appendix C. and matu- 6. Which one of the following is an example of a tumor sup- pressor gene? a. ABL1 b. RARA c. TP53 d. JAK2 7. G-CSF is provided as supportive treatment during leuke- mia treatment regimens to: a. Suppress GVHD b. Overcome anorexia c. Prevent anemia d. Reduce the risk of infection 8. Imatinib is an example of what type of leukemia treatment? a. Supportive care b. Chemotherapy c. Bone marrow conditioning agent d. Targeted therapy 9. Which one of the following statements is FALSE about epi- genetic mechanisms? a. Epigenetic mechanisms control how genes are expressed and silenced. b. MicroRNAs can bind to specic mRNAs and block their translation. c. Hypermethylation of CpG islands in gene promoters results in their overactivation. d. Histone deacetylases keep chromatin of target genes in a closed inactive state. 10. Which one of the following is NOT a source of hematopoi- etic stem cells for transplantation? a. Spleen b. Bone marrow c. Peripheral blood d. Umbilical cord blood CHAPTER 27 Introduction to Hematologic Neoplasms 499 19. Daley, G. Q., Van Etten, R. A., & Baltimore, D. (1990). Induction of chronic myelogenous leukemia in mice by the P210 bcr/abl gene of the Philadelphia chromosome. Science, 247, 824–830. 20. Ko, T. K., Javed, A., Lee, K. L., etal. (2020). An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood, 135, 2337–2353. 21. Lodish, H., Birk, A., Kaiser, C. A., etal. (2021). Cancer. In Translocation of the Molecular Cell Biology. (9th ed., pp.). New York: W.H. Freeman MacMillan. 22. Yang, H., & Green, M. R. (2020). Harnessing lymphoma epigenetics to improve therapies. Blood, 136, 2386–2391. 23. Weiss, C. N., & Ito, K. (2017). A macro view of microRNAs: the discovery of microRNAs and their role in hematopoiesis and hematologic disease. Int Rev Cell Mol Biol, 334, 99–175. 24. Knudson, A. G. (1985). Hereditary cancer, oncogenes, and antioncogenes. Cancer Res, 45, 1437–1443. 25. Zenz, T., Eichhorst, B., Busch, R., etal. (2010). TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol, 28, 4473–4479. 26. Sampaio, M. M., Santos, M. L. C., Marques, H. S., etal. (2021). Chronic myeloid leukemia-from the Philadelphia chromosome to specic target drugs: a literature review. World J Clin Oncol, 12, 69–94. 27. Hochhaus, A., Larson, R. A., Guilhot, F., etal. (2017). Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Eng J Med, 376, 917–927. 28. Haddad, F. G., & Short, N. J. (2022). Evidence-based minireview: what is the optimal tyrosine kinase inhibitor for adults with newly diagnosed Philadelphia chromosome-positive acute (2020). Peripheral T cell lymphoblastic leukemia? Hematology Am Soc Hematol Educ Cancer, 20, 323–342. Program, 2022, 213–217. 29. Springuel, L., Renauld, J. C., & Knoops, L. (2015). JAK kinase targeting in hematologic malignancies: a sinuous pathway from identication of genetic alterations towards clinical indications. Hematologica, 100, 1240–1253. 30. Kennedy, V. E., & Smith, C. C. (2020). FLT3 mutations in acute myeloid leukemia: key concepts and emerging controversies. Front Oncol, 10, 612880. 31. Liquori, A., Ibanez, M., Sargas, C., etal. (2020). Acute promyelocytic leukemia: a constellation of molecular events around a single PML::RARA fusion gene. Cancers, 12, 624. 32. Feugier, P. (2015). A review of rituximab, the rst anti-CD20 mutant p53 monoclonal antibody used in the treatment of B non-Hodgkin’s lymphomas. Future Oncol, 11, 1327–1342. 33. Goebeler, M. E., & Bargou, R. (2016). Blinatumomab: a CD19/ CD3 bispecic T cell engager (BiTE) with unique anti-tumor ecacy. Leuk Lymphoma, 57, 1021–1032. 34. Kantarjian, H. M., DeAngelo, D. J., Stelljes, M., etal. (2016). Inotuzumab ozogamicin versus standard care for acute lymphoblastic leukemia. N Engl J Med, 375(8), 740–753. 35. Perales, M. A., Kebriaei, P., Kean, L. S., etal. (2018). Building a (2022). e international safer and faster CAR: seatbelts, airbags, and CRISPR. Biol Blood Marrow Transplant, 24, 27–31. 36. Duvic, M. (2015). Histone deacetylase inhibitors for cutaneous T-cell lymphoma. Dermatol Clin, 33, 757–764. 37. Voso, M. T., Lo-Coco, F., & Fianchi, L. (2015). Epigenetic therapy of myelodysplastic syndromes and acute myeloid leukemia. Curr Opin Oncol, 27, 532–539. 38. Zubair, A. C., & Rowley, S. D. (2023). Practical aspects of hematologic stem cell harvesting and mobilization. In Homan, R., Benz, E. J., Silberstein, L. E., etal. (Eds.), Hematology: Basic Principles and Practice. (8th ed., pp. 1653–1666). Philadelphia: Elsevier.

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