Disorders of White Blood Cells

Definition

Disorders of white blood cells (WBCs) in dental patients can substantially influence clinical decision making as well as the delivery of care because WBCs constitute the primary defense against microbial infections and are critical for mounting an immune response ( Box 23.1 ). Defects in WBCs can manifest as delayed healing, infection, or mucosal ulceration and, in some cases, may be fatal. To ensure the health of the patient, the dentist should be able to identify possible WBC abnormalities through history, clinical examination, and screening laboratory tests and should provide prompt referral to a physician for further evaluation and management before invasive dental procedures are performed. Patients with known life-threatening disorders who are under medical care should not receive dental care until after the dentist has consulted with the patient’s physician.

Box 23.1
Classification and Features of White Blood Cell (WBC) Dyscrasias

Leukocytosis: increased number of circulating WBCs

Leukopenia: decreased number of circulating WBCs

Myeloproliferative disorders

  • 1.

    Acute myeloid leukemia: immature neoplastic malignancy of myeloid cells

  • 2.

    Chronic myeloid leukemia: mature neoplastic malignancy of myeloid cells

Lymphoproliferative disorders

  • 1.

    Acute lymphoblastic leukemia: immature neoplastic malignancy of lymphoid cells

  • 2.

    Chronic lymphocytic leukemia: mature neoplastic malignancy of lymphoid cells

  • 3.

    Lymphomas

    • a.

      Hodgkin lymphoma: malignant growth of B lymphocytes, primarily in lymph nodes

    • b.

      Non-Hodgkin lymphoma: B- or T-cell malignant neoplasms, many types and locations; most are of B-cell lineage

      • (1)

        Burkitt lymphoma: non-Hodgkin B-cell lymphoma involving bone and lymph nodes

  • 4.

    Multiple myeloma: overproduction of malignant plasma cells involving bone

Three groups of WBCs are found in the peripheral circulation: granulocytes, lymphocytes, and monocytes. Of the granulocyte population, 90% is composed of neutrophils; the remainder consists of eosinophils and basophils. Circulating lymphocytes are of three types: T lymphocytes (thymus mediated), B lymphocytes (bursa derived), and natural killer (NK) cells. Lymphocytes are subdivided by the surface markers they exhibit and by the cytokines they produce.

The primary function of neutrophils is to defend the body against certain infectious agents (primarily bacteria) through phagocytosis and enzymatic destruction. Eosinophils and basophils are involved in inflammatory allergic reactions and mediate these reactions through release of their cytoplasmic granules. Eosinophils also combat infection by parasites. Whereas T lymphocytes (T cells) are involved with the delayed, or cellular, immune reaction, B lymphocytes (B cells) play an important role in the immediate, or humoral, immune system involving the production of plasma cells and immunoglobulins (IgA, IgD, IgE, IgG, and IgM). Monocytes have diverse functions that include phagocytosis; intracellular killing (especially of mycobacteria, fungi, and protozoa); and mediating of the immune and inflammatory response through the production of more than 100 substances, such as cytokines and growth factors that increase the activity of lymphocytes. In addition, monocytes serve as antigen-presenting cells and migrate into tissues. In tissue, these antigen-presenting cells are known as dendritic cells (in lymph nodes) or Langerhans cells (in skin and mucosa). Monocytes in tissue that phagocytose microbes are known as macrophages.

Most WBCs are produced primarily in the bone marrow (granulocytes and monocytes), and these cells form several “pools” in the marrow: (1) the mitotic pool, which consists of immature precursor cells; (2) a maturing pool, which consists of cells undergoing maturation; and (3) a storage pool of functional cells, which can be released as needed.

White blood cells released by the bone marrow that circulate in the peripheral blood account for only 5% of the total WBC mass and form two pools of cells: (1) marginal and (2) circulating. Cells in the marginal pool adhere to vessel walls and are readily available. When infection threatens the body, the storage and marginal pools can be recruited to help fight the invading organisms.

Growth-promoting substances called colony-stimulating factors (CSFs) are responsible for the growth of committed granulocyte–monocyte stem cells. The major function of CSFs is to amplify leukopoiesis rather than recruit new stem cells into the granulocyte–monocyte differentiation pathway. Thus, through the local release of CSFs, the bone marrow can increase the production of granulocytes and monocytes. This process occurs in response to infection.

Lymphocytes localize primarily in three regions: lymph nodes, the spleen, and the mucosa-associated lymphoid tissue (MALT) lining the respiratory and gastrointestinal tracts. At these sites, microbial antigens are trapped and presented to B or T lymphocytes (cells). Antigens bind B cells through cell surface immunoglobulins, whereupon B cells are activated, proliferate, and produce large amounts of immunoglobulin to aid in opsonization. Antigens are presented to CD4+ (helper) T cells by major histocompatibility complex (MHC) class I molecules and to CD8+ T cells by MHC class II molecules. CD4+ T cells activate B cells and macrophages by producing cytokines and through direct contact. CD8+ T cells kill virus-infected cells.

COMPLICATIONS: Shortness of breath caused by anemia and fatigue and bone pain, malaise, pallor, dyspnea, fever; recurrent infections; oral ulcerations; fever; poor healing; infection; bleeding (hemorrhage, petechiae, ecchymoses); enlargement of tonsils, lymph nodes, spleen, and gingiva; skin lesions (leukemia cutis, granulocytic sarcomas, chloromas); central nervous system (CNS) infiltration of leukemic cells; organ failure (liver, kidney); amyloid deposition in oral mucosa; and death.

Leukocytosis and Leukopenia

The number of circulating WBCs normally ranges from 4400 to 11,000/µL in adults. The differential WBC count is an estimation of the percentage of each cell type per microliter of blood. A normal differential count consists of neutrophils, 50% to 60%; lymphocytes, 20% to 34%; monocytes, 3% to 7%; eosinophils, 1% to 3%; and basophils, less than 1%. The term leukocytosis is defined as an increase in the number of circulating WBCs (lymphocytes or granulocytes) to greater than 11,000/µL, and leukopenia as a reduction in the number of circulating WBCs (usually to <4400/µL).

Many causes of leukocytosis are known. Exercise, pregnancy, and emotional stress can lead to increased numbers of WBCs in the peripheral circulation. Leukocytosis resulting from these causes is called physiologic leukocytosis. Pathologic leukocytosis can be caused by infection, neoplasia, or necrosis. Pyogenic infections induce a type of leukocytosis that is characterized by an increased number of neutrophils. If excessive numbers of immature neutrophils (bands or stab cells) are released into the circulation in response to a bacterial infection, a “shift to the left” is said to have occurred. Tuberculosis, syphilis, and viral infections produce a type of leukocytosis that is characterized by increased numbers of lymphocytes. Protozoal infections often produce a type of leukocytosis that increases the numbers of monocytes. Allergies and parasitic infections caused by certain helminths increase the numbers of circulating eosinophils. Cellular necrosis increases the numbers of circulating neutrophils. Leukemia (cancer of the WBCs) is characterized by a substantial increase in the numbers of circulating immature leukocytes. Carcinoma of glandular tissues may cause an increase in the number of circulating neutrophils. Acute bleeding also can result in leukocytosis.

Many causes of deficient numbers of leukocytes (<4400/µL) in the blood are evident. Leukopenia may occur in the early phase of leukemia and lymphoma as a result of bone marrow replacement through excessive proliferation of WBCs. Leukopenia also occurs during agranulocytosis (reduction of granulocytes) and pancytopenia (decreased WBCs and red blood cell [RBCs]) that result from toxic effects of drugs and chemicals. Leukopenia is a common complication that results from the use of chemotherapeutic (anticancer) drugs.

Cyclic Neutropenia

An important form of leukopenia involving the cyclic depression of circulating neutrophils is a disorder called cyclic neutropenia. It is associated with mutations located near the junction of exons 4 and 5 of the neutrophil elastase gene (ELA2) . The estimated frequency of cyclic neutropenia is about 1 in 1 million. In this condition, patients have a periodic decrease (at least a 40% drop) in the number of neutrophils (about every 21–28 days). During the period in which few circulating neutrophils are present, the patient is susceptible to infection and oral manifestations (see under Oral Complications and Manifestations ). Up to 10% of patients die from pneumonia, cellulitis, or peritonitis.

Patients with leukocytosis or leukopenia may have bone marrow abnormalities that can cause thrombocytopenia. Examination of the patient’s bone marrow aspirate is important for making the final diagnosis. Infectious diseases that can cause leukocytosis and leukopenia are discussed in Chapter 7 , Chapter 13 , Chapter 18 .

Leukocytosis and Leukopenia

The number of circulating WBCs normally ranges from 4400 to 11,000/µL in adults. The differential WBC count is an estimation of the percentage of each cell type per microliter of blood. A normal differential count consists of neutrophils, 50% to 60%; lymphocytes, 20% to 34%; monocytes, 3% to 7%; eosinophils, 1% to 3%; and basophils, less than 1%. The term leukocytosis is defined as an increase in the number of circulating WBCs (lymphocytes or granulocytes) to greater than 11,000/µL, and leukopenia as a reduction in the number of circulating WBCs (usually to <4400/µL).

Many causes of leukocytosis are known. Exercise, pregnancy, and emotional stress can lead to increased numbers of WBCs in the peripheral circulation. Leukocytosis resulting from these causes is called physiologic leukocytosis. Pathologic leukocytosis can be caused by infection, neoplasia, or necrosis. Pyogenic infections induce a type of leukocytosis that is characterized by an increased number of neutrophils. If excessive numbers of immature neutrophils (bands or stab cells) are released into the circulation in response to a bacterial infection, a “shift to the left” is said to have occurred. Tuberculosis, syphilis, and viral infections produce a type of leukocytosis that is characterized by increased numbers of lymphocytes. Protozoal infections often produce a type of leukocytosis that increases the numbers of monocytes. Allergies and parasitic infections caused by certain helminths increase the numbers of circulating eosinophils. Cellular necrosis increases the numbers of circulating neutrophils. Leukemia (cancer of the WBCs) is characterized by a substantial increase in the numbers of circulating immature leukocytes. Carcinoma of glandular tissues may cause an increase in the number of circulating neutrophils. Acute bleeding also can result in leukocytosis.

Many causes of deficient numbers of leukocytes (<4400/µL) in the blood are evident. Leukopenia may occur in the early phase of leukemia and lymphoma as a result of bone marrow replacement through excessive proliferation of WBCs. Leukopenia also occurs during agranulocytosis (reduction of granulocytes) and pancytopenia (decreased WBCs and red blood cell [RBCs]) that result from toxic effects of drugs and chemicals. Leukopenia is a common complication that results from the use of chemotherapeutic (anticancer) drugs.

Cyclic Neutropenia

An important form of leukopenia involving the cyclic depression of circulating neutrophils is a disorder called cyclic neutropenia. It is associated with mutations located near the junction of exons 4 and 5 of the neutrophil elastase gene (ELA2) . The estimated frequency of cyclic neutropenia is about 1 in 1 million. In this condition, patients have a periodic decrease (at least a 40% drop) in the number of neutrophils (about every 21–28 days). During the period in which few circulating neutrophils are present, the patient is susceptible to infection and oral manifestations (see under Oral Complications and Manifestations ). Up to 10% of patients die from pneumonia, cellulitis, or peritonitis.

Patients with leukocytosis or leukopenia may have bone marrow abnormalities that can cause thrombocytopenia. Examination of the patient’s bone marrow aspirate is important for making the final diagnosis. Infectious diseases that can cause leukocytosis and leukopenia are discussed in Chapter 7 , Chapter 13 , Chapter 18 .

Leukemia and Lymphoma

The remainder of this chapter focuses on leukemia and malignancies of lymphoid cells (lymphoma and multiple myeloma [MM]). These patients become gravely ill if they are not properly identified and do not receive appropriate medical care. In addition, patients are usually immunosuppressed as a result of the disease itself or because of the treatment used to control it. Hence, they are prone to develop serious infection and often bleed easily because of thrombocytopenia.

About every 3 minutes, a person in the United States is diagnosed with a blood cancer. An estimated combined total of 162,020 people in the United States were expected to be diagnosed with leukemia, lymphoma, or myeloma in 2015. New cases of leukemia, lymphoma, and myeloma were expected to account for 9.8% of the estimated 1,658,370 new cases diagnosed in the United States in 2015. An estimated 1,185,053 people in the United States are either living with or are in remission from leukemia, lymphoma, or myeloma. The most recent survival data available may not fully represent the outcomes of all current therapies and as a result may underestimate survival to a small degree. Approximately every 9 minutes, someone in the United States dies from a blood cancer, accounting for 160 people each day or more than 6 people every hour. Leukemia, lymphoma, and myeloma were expected to cause the deaths of an estimated 56,630 people in the United States in 2015. These diseases were expected to account for 9.6% of the deaths (589,430) from cancer in 2015. A dental practice that manages 2000 patients is predicted to have 1 to 3 patients who have or develop leukemia or a malignancy of lymphoid cells.

Leukemia

Leukemia is cancer of the WBCs that affects the bone marrow and circulating blood. It involves exponential proliferation of a clonal myeloid or lymphoid cell and occurs in both acute and chronic forms. Acute leukemia is a rapidly progressive disease that results from accumulation of immature, nonfunctional WBCs in the marrow and blood. Chronic leukemias have a slower onset, which allows production of larger numbers of more mature (terminally differentiated), functional cells. This section focuses on four types of leukemia: (1) acute myelogenous leukemia (AML), (2) acute lymphocytic leukemia (ALL), (3) chronic myelogenous leukemia (CML), and (4) chronic lymphocytic leukemia (CLL).

The cause of leukemia remains unknown. Increased risk is associated with large doses of ionizing radiation, certain chemicals (benzene), and infection with specific viruses (e.g., Epstein-Barr virus [EBV], human lymphotropic virus [HTLV]-1). Cigarette smoking and exposure to electromagnetic fields also have been proposed to be causative.

Leukemia

In 2016, 60,140 people were expected to be diagnosed with leukemia. There are an estimated 354,422 people living with or in remission from leukemia in the United States. The overall 5-year relative survival rate for leukemia has more than quadrupled since 1960. From 2005 to 2011, the 5-year relative survival rates were 63.2% for CML, 84.8% for CLL, 26% for AML, and 70% for ALL. In 2016, 24,400 people were expected to die from leukemia (14,130 males and 10,270 females). From 2008 to 2012, leukemia was the fifth most common cause of cancer deaths in men and the sixth most common in women in the United States.

Acute Myelogenous Leukemia

Definition

Acute myelogenous leukemia is a neoplasm of myeloid (immature) WBCs, which demonstrate uncontrolled proliferation in the bone marrow space and subsequently appear in the peripheral blood.

Epidemiology

Acute myelogenous leukemia occurs in about 19,950 persons in the United States annually and accounts for 28.6% of all leukemias. AML is a disease of adults. The incidence increases with age and rises rapidly after the age of 50 years, reaching 22 per 100,000 by age 80 years. The mean age of persons with AML in the United States is 65 years.

Etiology

Acute myelogenous leukemia arises de novo in younger adults or secondarily in older adults as a consequence of myelodysplasia. Myelodysplastic syndromes describe a diverse group of clonal disorders of hematopoietic stem or progenitor cells resulting in abnormal cellular differentiation that evolves into AML in 30% of cases. Environmental factors such as tobacco smoke, benzene-containing products, chemotherapies for cancer, and radiation exposure appear to be risk factors for AML. It is estimated that 10% to 20% of all cases of AML are now therapy related. Genetic factors (e.g., translocation and rearrangement of chromosomes) may cause cytogenetic abnormalities that affect transcriptional cascades of myeloid precursor cells and uncontrolled proliferation of these cells. Certain genetic disorders increase the risk for AML, including Down syndrome, Klinefelter syndrome, Fanconi anemia, and von Recklinghausen disease.

Pathophysiology and Complications

Acute myelogenous leukemia has a sudden onset and leads to death in 1 to 3 months if left untreated. It involves increased numbers of immature myeloid WBCs in the bone marrow space and peripheral circulation ( Fig. 23.1 ). As a result, patients are susceptible to excessive bleeding, anemia, poor healing, and infection after surgical procedures. Hemorrhage and infection, frequent complications of chemotherapy, are the chief causes of death.

FIG 23.1
Acute myeloid leukemia. Peripheral blood smear shows many myeloid cells with large nuclei and azurophilic granules.
(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby. Courtesy of Prof. J.M. Chessells.)

Clinical Presentation

Signs and Symptoms

Acute myelogenous leukemia produces a leukemic infiltration of marrow and organs that causes cytopenia and diverse non-specific signs and symptoms, including fatigue, easy bruising, and bone pain. Many patients complain of flu-like symptoms for 4 to 6 weeks before the diagnosis. Anemia and thrombocytopenia usually manifest as malaise, pallor, dyspnea on exertion, and bleeding and small hemorrhage (petechiae, ecchymoses) in the skin and mucous membranes ( Fig. 23.2, A ). Because of granulocytopenia, at least one third of patients have recurrent infections (nonhealing wounds), oral ulcerations, and fever. Enlargement of the tonsils, lymph nodes, spleen, and gingiva ( Fig. 23.2, B ) occurs as a result of leukemic infiltration of these tissues. Infiltration of the CNS occurs in about 35% of the cases of AML with increased eosinophils (the M4Eo variant). Most of these patients are asymptomatic, but some present with meningeal signs and symptoms and symptoms associated with increased intracranial pressure. Skin lesions, consisting of collections of leukemic cells termed leukemia cutis, granulocytic sarcomas, and chloromas, may occur.

FIG 23.2
A, Acute myeloid leukemia presenting as bleeding and ecchymosis of the tongue in a 14-year-old patient. B, Gingival leukemia infiltrate in a patient with acute myeloid leukemia.

Laboratory Findings

The diagnosis of leukemia is made through examination of peripheral blood and bone marrow stained with Wright-Giemsa. Cytochemical staining, immunophenotyping, and cytogenetic analyses are used to characterize the type and subtype, to allow for specific treatment approaches, and to detect residual disease after therapy is provided. Granulocytopenia and thrombocytopenia are common.

The diagnosis of AML is made when myeloblasts are found in the bone marrow or peripheral blood at a rate of at least 20%. Myeloblasts stain positive for myeloperoxidase and are immunotype positive for several of the following markers: CD13, CD33, CD34, CD65, and CD117. The French-American-British (FAB) classification categorizes AML into eight subtypes ( Table 23.1 ). The World Health Organization (WHO) classification describes several subtypes that differ in terms of genetic abnormalities, evolution, and response to therapy.

TABLE 23.1
Classification of Acute Leukemias and Associated Clinical, * Cytologic, and Immunologic Abnormalities
FAB Subtype Common Name (% of Cases) Cell Surface Markers Chromosomal Abnormality(ies)
M0 Acute undifferentiated leukemia (3%–5%) Anti-CD13, CD14, CD33, CD34 Various
M1 Acute myeloblastic leukemia with minimal differentiation (15%–20%) Anti-CD13, CD33, CD33, CD34 Various
M2 Acute myeloid leukemia with differentiation (25%–30%) Anti-CD14, CD15, CD33, CD34 Various, including t(8;21)
M3 Acute promyelocytic leukemia (10%–15%) Anti-CD13, CD15, CD33, CD65 t(15;17)
M4 Acute myelomonocytic leukemia (20%–30%) Anti-CD13, CD15, CD33, CD34 Various, including inv/del (16)
M5a and M5b

  • Type a: 80% monoblasts

  • Type b: >20% promonocytes

Acute monocytic leukemia

  • (5a: 2%–9%)

  • (5b: 2%–5%)

HLA-DR, anti-CD13, CD15, CD33, CD34 Various, including abnormalities of 11q23
M6 Acute erythroleukemia (3%–5%) Antiglycopherin antispectrin
M7 Acute megakaryocytic leukemia (3%–5%) CD41, CD61
L1, childhood variant Acute lymphoid leukemia; small, uniform blasts, nucleoli indistinct ≈65% react with anti-CD10; 20% with T-cell phenotype: anti-CD1, -2, -3, -5, or -7 t(9;22), t(4;11), and t(1;9)
L2, adult variant Acute lymphoid leukemia; larger, more irregular nucleoli present
L3, Burkitt-like Acute lymphoid leukemia; large, with strong basophilic cytoplasm and vacuoles Anti-CD19, -20 t(8;14)
Adapted from Appelbaum FR: Acute myeloid leukemia in adults. In Goldman L, Ausiello D, editors: Cecil medicine, ed 23, Philadelphia, 2008, Saunders, pp 1390-1396.

* Clinical signs of leukemia include pallor, lymphadenopathy, petechiae, ecchymoses, gingival enlargement, oral ulcerations, loose teeth, pulpal abscess, enlarged tonsils, gingival bleeding, and recurrent infections.

The World Health Organization classifies acute myelogenous leukemia into four major categories: acute myeloid leukemia with recurrent genetic abnormalities (four subtypes), acute myeloid leukemia with multilineage dysplasia (two subtypes), acute myeloid leukemia and myelodysplastic syndromes (two subtypes), acute myeloid leukemia, and not otherwise categorized (11 subtypes).

Acute Lymphoid Leukemia

Definition

Acute lymphocytic leukemia is the result of uncontrolled monoclonal proliferation of immature lymphoid cells in the bone marrow and peripheral blood. These neoplastic cells may also expand in the lymph nodes, liver, spleen, or CNS.

Epidemiology

In 2016, 6590 cases of ALL were estimated to occur in the United States. ALL occurs at an incidence of 1.7 in 100,000 and typically occurs in children. It accounts for about 25% of all neoplasms in children and 80% of leukemias in children. A remarkable peak of incidence occurs in children who are 2 to 3 years old, and 57% of cases are reported in persons younger than age 20 years (median age at diagnosis, 15 years). Boys are affected slightly more often than girls. About 20% of cases occur after age 55 years.

Etiology

Although environmental, infectious, and genetic factors are considered likely causes of the disease, causal links for ALL have not been established. The disease is 18- to 20-fold more common in patients with Down syndrome (trisomy 21). Cytogenetic studies frequently display the Philadelphia chromosome [t(9;22)], a shortened chromosome 22, as a result of translocation of genes between the long arms of chromosomes 9 and 22. About 5% of children and 25% of adults with ALL have cytogenetics showing the Philadelphia chromosome. Patients with the Philadelphia chromosome have slightly lower complete remission rates and greatly reduced remission durations. Other chromosomal anomalies are also common.

Pathophysiology and Complications

Similar to AML, ALL results in suppression of normal hematopoiesis, leaving patients susceptible to excessive bleeding, anemia, poor healing, and infection after surgical procedures have been performed. Treatment of children results in remission rates that exceed 90% and cure rates above 70%. In adults, long-term survival from ALL occurs at rates of about 70%.

Clinical Presentation

Signs and Symptoms

The clinical presentation of ALL can be acute or insidious. Presenting signs and symptoms relate to anemia, thrombocytopenia, fever, and neutropenia. Frequently, bone and joint pain have effects on walking. In one large study, one third of the patients presented with infection or fever; one third presented with hemorrhagic episodes; and more than half of the patients with enlargement of the liver, spleen, and lymph nodes. A higher propensity toward CNS disease occurs with ALL compared with AML. Patients may present with cranial nerve deficiencies.

Laboratory Findings

Acute lymphocytic leukemia is diagnosed when massive replacement of the bone marrow space with leukemic blast cells is observed. Fig. 23.3 shows a peripheral blood smear of ALL. A correspondingly high number of lymphoblasts are detected in the peripheral blood smear, and levels of hemoglobin, hematocrit, and platelets are depressed, reflecting large replacement of marrow by lymphoblasts. Immunotyping and flow cytometry is the preferred method of lineage assignment and assessment of cell maturation. Detection of a nuclear enzyme, terminal deoxynucleotidyl transferase (Tdt), along with (B-cell) antigen (CD10, originally designated CALLA) and CD19, CD22, and HLA-DR, allows histologic classification of ALL.

FIG 23.3
Peripheral blood smear of acute lymphoblastic leukemia.
(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby.)

According to the French-American-British Cooperative Group, three distinct subtypes are based on type and size of neoplastic lymphocytes: L1 (cells small and homogeneous), L2 (cells pleomorphic and often large), and L3 (cells homogeneous and of medium size with dispersed chromatin).

Medical Management of Acute Leukemia

The ability to cure a patient of acute leukemia is related to tumor burden and the rapid elimination of malignant WBCs. Normal bone marrow consists of 0.3% to 5% blast cells. Patients with acute leukemia have 100-fold (≈1 trillion) more blast cells. After effective chemotherapy has been given, the number of blast cells is reduced from trillions to billions, leukemic cells can no longer be detected, and the patient is said to be in remission. With a 5-day generation time for the remaining undetectable leukemic cell mass, 10 doublings in 50 days could restore the leukemic cell mass to 1 trillion cells, and the patient would again show signs and symptoms of leukemia. This would constitute a short remission with relapse.

Chemotherapy for acute leukemia consists of three phases. The purpose of the first phase (induction) is to aggressively induce a state of remission by killing tumor cells with cytotoxic agents. Agents used to treat the acute leukemias are shown in Table 23.2 . The second phase (consolidation or intensification) focuses on consolidating the kill of remaining leukemic cells. During the third phase (complete remission), maintenance therapy is provided to prevent expansion of any remaining leukemic cell mass. The criteria for complete remission include the following: platelet count higher than 100,000/µL, neutrophil count greater than 1000/µL, and bone marrow specimen with less than 5% blasts. During induction and consolidation, myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte–monocyte colony-stimulating factor [GM-CSF]) are administered at some institutes to shorten the duration of neutropenia and reduce the incidence of severe infection.

TABLE 23.2
Classes of Drugs Used to Treat Leukemia
Drug Class Chemotherapeutic Agents Mechanism of Action
Alkylating agents Busulfan, carmustine, cyclophosphamide, dacarbazine, lomustine nitrogen mustard derivative : chlorambucil Produce alkyl radicals, causing cross-linking of DNA and inhibition of DNA synthesis in rapidly replicating tumor cells
Antibiotics Bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin C Disrupt cellular functions, such as RNA synthesis, or inhibit mitosis
Antimetabolites Folic acid analogues: methotrexate Disrupt enzymatic processes or nucleic acid synthesis
Purine analogues: cladribine, fludarabine, fluorouracil 6-mercaptopurine, thioguanine
Pyrimidine nucleoside analogues: arabinosyl cytosine (Ara-C, cytarabine)
Biologics Interferon alfa Causes a direct antiproliferative effect on CML progenitor cells
Rituximab
Alemtuzumab
Monoclonal antibody to CD20
Monoclonal antibody to CD52
All- trans retinoic acid (ATRA; tretinoin) Binds antigen target on malignant lymphocyte
Induces differentiation and apoptosis of malignant promyelocytes in APML
Enzymes Asparaginase Inhibits synthesis of asparagines, which is required for protein synthesis in leukemic lymphoblasts
Mitotic inhibitors Vincristine, vinblastine Act as mitotic spindle inhibitors, causing metaphase arrest
Etoposide Topoisomerase II inhibitor
Steroid Prednisone Hormone that has antiinflammatory and antilymphocytic properties
Newer agents Arsenic trioxide
Gemtuzumab ozogamicin
Decitabine
Colofrabine
Imatinib mesylate
Inorganic compound
Monoclonal antibody to CD33
Inhibits DNA methyltransferase
Purine nucleoside antimetabolite
Tyrosine kinase inhibitor (inhibits signal transduction in cancer cells)
Agents in clinical trials Farnesyltransferase inhibitors
Flavopiridol
Lenalidomide
Ofatumumab
Lumiliximab
Signal transduction inhibitor
Kinase inhibitor
Immunomodulatory
Monoclonal antibody to CD20
Monoclonal antibody to CD23
APML, Acute promyelocytic leukemia; CML, chronic myelogenous leukemia.

Patients are cured of leukemia when no leukemic cells remain. Long-term survival occurs when the leukemic cell mass is greatly reduced and is kept from increasing over a long period. In general, when a patient relapses, a second remission is more difficult to induce, and if it occurs, it will be of a shorter duration. Bone marrow transplantation (BMT) generally is reserved for patients younger than 45 years of age and for children and young adults who relapse when a suitable sibling match is available (allogeneic). The marrow transplant or, more recently, the peripheral blood stem cell transplant procedure is preceded by high-dose chemotherapy (including busulfan) and radiation therapy.

Treatment of patients with AML is shown in Table 23.3 . In 1966, the median survival time of adults with AML was 40 days. Today, patients younger than 60 years have complete remission rates of 70% to 80% after induction therapy, but the overall survival rate is only 50% for those who go into complete remission and 26.6% overall. The prognosis of AML in adults who are 60 years or older is poorer. The remission rate for older patients is 52% for patients 60 to 69 years and only 26% for patients 70 years or older with long-term survival rates of only 5% to 10% ( Table 23.4 ).

TABLE 23.3
Medical Treatment for Leukemia and Lymphoma
Condition Induction Chemotherapy Consolidation Chemotherapy Maintenance Chemotherapy Other
AML Daunomycin
Idarubicin
Cytarabine
Daunomycin
Cytarabine
High-dose cytarabine Older patients: gemtuzumab ozogamicin
APML All- trans -retinoic acid (ATRA)
Daunomycin
Cytarabine
ATRA
Daunomycin
ATRA
ALL L-Asparaginase
Doxorubicin
Vincristine
Prednisone
Methotrexate
Cytarabine
6-Mercaptopurine
Methotrexate
Ph chromosome–positive cases: add imatinib mesylate
Stem cell transplantation
CML Imatinib mesylate Imatinib mesylate Imatinib mesylate Stem cell transplantation
Dasatinib, nilotinib (for cases resistant to imatinib mesylate)
CLL Chlorambucil
Fludarabine monophosphate
COP regimen (cyclophosphamide, vincristine, and prednisone)
Rituximab combined with fludarabine
COP adjusted to dosage that obtains desired effect or until thrombocytopenia or neutropenia develops Radiation therapy as a palliative treatment to shrink large nodal masses or enlarged spleen
Stem cell transplantation has no proven benefit
Hodgkin lymphoma Limited stage: ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine)
Advanced stage: ABVD or Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone)
Limited stage: also involved-field irradiation
Advanced stage: postchemotherapy irradiation to sites of initial or residual tumor bulk
Stem cell transplantation for patients not cured by chemotherapy
Non-Hodgkin lymphoma CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab)
CVP-R (cyclophosphamide, vincristine, prednisone, rituximab)
FCR (fludarabine, cyclophosphamide, rituximab)
Surgery for localized MALT lymphomas
Splenectomy to improve cytopenias
Radiation therapy
ALL, Acute lymphocytic leukemia; AML, acute myelogenous leukemia; APML, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; CML , chronic myelogenous leukemia; MALT, mucosa-associated lymphoid tissue.

TABLE 23.4
Clinical Factors in Acute and Chronic Leukemias
Factor Type of Leukemia
ALL AML CLL CML
Age Children (75%) Adults (85%) Older than 40 years 30–50 years
Prognosis Very good Poor Good Poor
Survival time, mean 2 years Stage I (19 months) 3–4 years
Stage IV (12 years)
Remissions 90% 60%–80%
Duration Usually long term 9–24 months
Cures 50%–70% 10%–30%
ALL AML CLL CML
Age Adults (25%) Children (15%) Children (rare) Children (rare)
Prognosis Poor Poor
Survival time, mean 26 months
Remissions 50%–70% 56%–66%
Duration 10–19 months 8–12 months
Cures 20% 20-40%
ALL, Acute lymphocytic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CML , chronic myelogenous leukemia.
Data from Wetzler M, Byrd JC, Bloomfield CD: Acute and chronic myeloid leukemia. In Kasper DL, et al, editors: Harrison’s principles of internal medicine, ed 16, New York, 2005, McGraw-Hill and Armitage JO, Longo DL: Malignancies of lymphoid cells. In Kasper DL, et al, editors: Harrison’s principles of internal medicine, ed 16, New York, 2005, McGraw-Hill.

Treatment for ALL is shown in Table 23.3 . The prognosis for children with ALL is very good, with cure now being attained in more than 70% of cases. The prognosis is worse in persons older than 30 years of age and with a blast count greater than 50,000/µL, with mature B-cell ALL phenotype, multiorgan involvement, and chromosomal translocations t(9;22) and t(4;11). In these patients, remission can be achieved with chemotherapy; however, the duration of remission is short. The overall long-term survival (cure) rate for adults is less than 20%. Relapse can result in second remission in 75%, but fewer than 30% of these patients are cured.

Another concern related to treatment of patients with acute leukemia is that leukemic cells can migrate to areas in the body where chemotherapeutic agents cannot reach them. These areas are called sanctuaries, and they require special treatment. The most important sanctuary in patients with ALL is the CNS. Thus, patients with ALL are treated with systemic chemotherapy plus high-dose methotrexate intravenously and cytarabine or intrathecal methotrexate and radiation to the cranium plus high-dose systemic chemotherapy. Another important sanctuary (in male patients) is the testes.

Oral Manifestations of Acute Leukemia

Patients with leukemia are prone to develop gingival enlargement, ulceration, and oral infection. Localized or generalized gingival enlargement is caused by inflammation and infiltration of atypical and immature WBCs (see Fig. 23.2 ). It occurs in up to 36% of those with acute leukemia (most frequently with the acute myelomonocytic types) and in about 10% of those with chronic leukemia. The gingiva is boggy and bleeds easily, and multiple tooth sites are typically affected. Generalized gingival enlargement is more common and is particularly prevalent when oral hygiene is poor and in patients who have AML (particularly the monocytic type [M5]; see Table 23.1 ). The combination of poor oral hygiene and gingival enlargement contributes to gingival bleeding and fetor oris. Gingival bleeding is exacerbated by the presence of thrombocytopenia. Plaque control measures, chlorhexidine, and chemotherapy promote resolution of the condition.

A localized mass of leukemic cells is specifically known as a granulocytic sarcoma or chloroma. These extramedullary tumors have been observed in the hard tissues (maxilla, palate) and soft tissues (gingiva, tongue, oral mucosa) of the maxillofacial complex.

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Sep 3, 2018 | Posted by in General Dentistry | Comments Off on Disorders of White Blood Cells
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