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Physiology Review
WBCs are the most diverse of the cellular components of the blood. They arise
from three different precursor cells: myeloblasts, which further differentiate into
the granular leukocytes (granulocytes), neutrophils, eosinophils, and basophils;
monoblasts, which mature into circulating monocytes, and ultimately into
macrophages; and lymphoblasts, which become lymphocytes and mature in
lymphoid tissue to B cells and T cells.
As a whole, the primary function of WBCs is to help maintain the body’s
immune defenses. Neutrophils, the most numerous WBCs in circulation, are
active phagocytes, the first cells to arrive to injured tissue. Monocytes and
macrophages also are phagocytic cells that dispose of foreign and waste
material from tissues. Eosinophils and basophils are more specialized.
Eosinophils are primarily involved in allergic responses and parasitic infections.
Basophils are actively involved in the inflammatory response, releasing
substances such as histamine and heparin into inflamed tissues. Lymphocytes,
the smallest of the WBCs, are an integral part of the immune system. B cells
are part of the humoral immune response, producing antibodies to specific
antigens. T cells are part of the cell-mediated immune response. The normal
WBC count and differential is presented.
Classifications
Leukemias are classified by their acuity and by the predominant cell type
involved. The acute leukemias are characterized by an acute onset, rapid
disease progression, and immature or undifferentiated blast cells. Chronic
leukemias, on the other hand, have a gradual onset, prolonged course, and
abnormal mature-appearing cells. Lymphocytic (or lymphoblastic) leukemias
involve immature lymphocytes and their precursor cells in the bone marrow.
Lymphocytic leukemias infiltrate the spleen, lymph nodes, CNS, and other
tissues. Myeloid (also called myelogenous, myelocytic, or myeloblastic)
leukemias involve myeloid stem cells in the bone marrow, interfering with the
maturation of all types of blood cells, including granulocytes, RBCs, and
thrombocytes (Huether & McCance, 2008). Acute lymphoblastic leukemia is the
most common type of leukemia in children. In adults, acute myeloid leukemia
and chronic lymphocytic leukemia are the most common types (Huether &
McCance, 2008). In summary, the general types of leukemia are as follows:
■ Acute lymphocytic (lymphoblastic) leukemia (ALL)
■ Chronic lymphocytic leukemia (CLL)
■ Acute myeloid (myeloblastic) leukemia (AML)
■ Chronic myeloid (myelogenous) leukemia (CML)
This general system of classifying leukemias does not differentiate subtypes of
acute leukemias. The FAB system for classifying acute leukemias further
differentiates acute leukemias by the predominant cell involved and the degree
of cell differentiation
Clinical Manifestations
Most signs and symptoms of AML result from insufficient production of normal
blood cells. Fever and infection result from neutropenia, weakness and fatigue
from anemia, and bleeding tendencies from thrombocytopenia. The proliferation
of leukemic cells within organs leads to a variety of additional symptoms: pain
from an enlarged liver or spleen, hyperplasia of the gums, and bone pain from
expansion of marrow.
Medical Management
Despite advances in understanding the biology of the AML, substantive
advances in treatment response rates and survival rates have not occurred for
decades, with the exception of advances made in treating APL. Even for those
subtypes that have not benefited from advances in treatment, cure is still
possible. The overall objective of treatment is to achieve complete remission, in
which there is no evidence of residual leukemia in the bone marrow. Attempts
are made to achieve remission by the aggressive administration of
chemotherapy, called induction therapy, which usually requires hospitalization
for several weeks. Induction therapy typically involves high doses of cytarabine
(Cytosar, Ara-C) and daunorubicin (Cerubidine) or mitoxantrone (Novantrone)
or idarubicin (Idamycin); sometimes etoposide (VP-16, VePesid) is added to the
regimen. The choice of agents is based on the patient’s physical status and
history of prior antineoplastic treatment.
Treatment of APL revolves around induction therapy using the differentiating
agent all-trans retinoic acid (ATRA), which induces the promyelocytic blast cells
to differentiate, thereby deterring the cells from proliferating. ATRA is typically
combined with a conventional chemotherapeutic agent, usually an
anthracycline drug. This regimen yields a very high response rate, and cure is
possible.
The aim of induction therapy is to eradicate the leukemic cells, but this is also
accompanied by the eradication of normal types of myeloid cells. Thus, the
patient becomes severely neutropenic (an ANC of 0 is not uncommon), anemic,
and thrombocytopenic (a platelet count of less than 10,000/mm3 is common).
During this time, the patient is typically very ill, with bacterial, fungal, and
occasionally viral infections; bleeding; and severe mucositis, which causes
diarrhea and an inability to maintain adequate nutrition. Supportive care
consists of administering blood products (PRBCs and platelets) and promptly
treating infections. The use of granulocytic growth factors, either G-CSF
(filgrastim [Neupogen]) or GM-CSF (sargramostim [Leukine]), can shorten the
period of significant neutropenia by stimulating the bone marrow to produce
leukocytes more quickly; these agents do not appear to increase the risk of
producing more leukemic cells.
When the patient has recovered from the induction therapy (ie, the neutrophil
and platelet counts have returned to normal and any infection has resolved),
consolidation therapy (postremission therapy) is administered to eliminate any
residual leukemia cells that are not clinically detectable and reduce the chance
for recurrence. Multiple treatment cycles of various agents are used, usually
containing some form of cytarabine. Frequently, the patient receives one cycle of
treatment that is almost the same, if not identical, to the induction treatment
but at lower dosages, therefore resulting in less toxicity.
Another aggressive treatment option is BMT or PBSCT. When a suitable tissue
match can be obtained, the patient embarks on an even more aggressive
regimen of chemotherapy (sometimes in combination with radiation therapy),
with the treatment goal of destroying the hematopoietic function of the patient’s
bone marrow. The patient is then “rescued” with the infusion of the donor stem
cells to reinitiate blood cell production. Patients who undergo PBSCT have a
significant risk for infection, graft-versus-host disease (GVHD, in which the
donor’s lymphocytes [graft] recognize the patient’s body as “foreign” and set up
reactions to attack the “foreign” host), and other complications. The most
appropriate use and timing of PBSCT remain unclear. Patients with a poorer
prognosis may benefit from early PBSCT; those with a good prognosis may not
need transplant at all.
Another important option for the patient to consider is supportive care alone. In
fact, supportive care may be the only option if the patient has significant
comorbidity, such as extremely poor cardiac, pulmonary, renal, or hepatic
function, and/or is extremely old. In such cases, aggressive antileukemia
therapy is not used; occasionally, hydroxyurea (Hydrea) may be used briefly to
control the increase of blast cells. Patients are more commonly supported with
antimicrobial therapy and transfusions as needed. This treatment approach
provides the patient with some additional time outside the hospital (eg, at
home); however, death frequently occurs within months, typically from infection
or bleeding.
Complications of Treatment
Massive leukemic cell destruction from chemotherapy results in the release of
intracellular electrolytes and fluids into the systemic circulation. Increases in
uric acid levels, potassium, and phosphate are seen; this process is referred to
as tumor lysis syndrome. The increased uric acid and phosphorus levels make
the patient vulnerable to renal stone formation and renal colic, which can
progress to acute renal failure. Hyperkalemia and hypocalcemia can lead to
cardiac dysrhythmias; hypotension; neuromuscular effects such as muscle
cramps, weakness, and spasm/tetany; confusion; and seizures. Patients require
a high fluid intake, alkalization of the urine, and prophylaxis with allopurinol to
prevent crystallization of uric acid and subsequent stone formation. GI
problems may result from the infiltration of abnormal leukocytes into the
abdominal organs and from the toxicity of the chemotherapeutic agents.
Anorexia, nausea, vomiting, diarrhea, and severe mucositis are common.
Because of the profound myelosuppressive effects of chemotherapy, significant
neutropenia and thrombocytopenia typically result in serious infection and
increased risk of bleeding.
Clinical Manifestations
The clinical picture of CML varies. Many patients are asymptomatic, and
leukocytosis is detected by a CBC performed for some other reason. The
leukocyte count commonly exceeds 100,000/mm3 . Patients with extremely
high leukocyte counts may be somewhat short of breath or slightly confused
because of decreased capillary perfusion to the lungs and brain from
leukostasis (the excessive volume of leukocytes inhibits blood flow through the
capillaries). The patient may have an enlarged, tender spleen. The liver may also
be enlarged. Some patients have insidious symptoms, such as malaise,
anorexia, and weight loss. Lymphadenopathy is rare. There are three stages in
CML: chronic, transformation, and accelerated or blast crisis. Patients develop
more symptoms and complications as the disease progresses.
Medical Management
Advances in understanding of the pathology of CML at a molecular level have
led to dramatic changes in its treatment. An oral formulation of a tyrosine
kinase inhibitor, imatinib mesylate (Gleevec), works by blocking signals within
the leukemia cells that express the BCR-ABL protein, thus preventing a series
of chemical reactions that cause the cell to grow and divide. Imatinib therapy
appears to be most useful in the chronic phase of the illness. It can induce
complete remission at the cellular and even the molecular level. Imatinib is
metabolized by the cytochrome P450 pathway, which means that drug–drug
interactions are common. Also, antacids and grapefruit juice may limit drug
absorption, and large doses of acetaminophen can cause hepatotoxicity.
In those instances where imatinib (at conventional doses) does not elicit a
molecular remission, or when that remission is not maintained, other treatment
options may be considered. The dosage of imatinib can be increased (with
increased toxicity), another inhibitor of BCR-ABL can be used (eg, dasatinib
[Sprycel]), or allogeneic transplant can be used. CML is a disease that can
potentially be cured with BMT or PBSCT in otherwise healthy patients who are
younger than 65 years of age. However, with the development of tyrosine kinase
inhibitors such as imatinib and dasatinib, the timing of transplant has come
into question. Patients who receive such transplants while still in the chronic
phase of the illness tend to have a greater chance for cure than those who
receive them in the acute phase. The use of imatinib therapy may decrease the
need for transplantation in CML; however, the long-term efficacy of imatinib as
well as its effects on transplant morbidity, mortality, and risk of relapse remain
unknown (Schiffer, 2007).
The transformation phase can be insidious or rapid; it marks the process of
evolution (or transformation) to the acute form of leukemia (blast crisis). In the
transformation phase, the patient may complain of bone pain and may report
fevers (without any obvious sign of infection) and weight loss. Even with
chemotherapy, the spleen may continue to enlarge. The patient may become
more anemic and thrombocytopenic; an increased basophil level is detected by
the CBC.
In the acute form of CML (blast crisis), treatment may resemble induction
therapy for acute leukemia, using the same medications as for AML or acute
lymphocytic leukemia. Patients whose disease evolves into a “lymphoid” blast
crisis are more likely to be able to reenter a chronic phase after induction
therapy. For those whose disease evolves into AML, therapy has been largely
ineffective in achieving a second chronic phase. However, an increased dose of
imatinib or dasatinib can be effective in the later stages of CML. Nonetheless,
life-threatening infections and bleeding occur frequently in this phase.
In rare instances, when a purely palliative approach is desired, the therapeutic
approach focuses on reducing the leukocyte count to a more normal level but
does not alter cytogenetic changes. This goal can be achieved by using oral
chemotherapeutic agents, typically hydroxyurea or busulfan (Myleran). In the
case of an extreme leukocytosis at diagnosis (eg, leukocyte count greater than
300,000/mm3 ), a more emergent treatment may be required. In this instance,
leukapheresis (in which the patient’s blood is removed and separated, with the
leukocytes withdrawn and the remaining blood returned to the patient) can
temporarily reduce the number of leukocytes. An anthracycline
chemotherapeutic agent (eg, daunomycin [Cerubidine]) may also be used to
bring the leukocyte count down quickly to a safer level, where more
conservative therapy can be instituted.
Clinical Manifestations
Immature lymphocytes proliferate in the marrow and impede the development
of normal myeloid cells. As a result, normal hematopoiesis is inhibited,
resulting in reduced numbers of leukocytes, erythrocytes, and platelets.
Leukocyte counts may be either low or high, but there is always a high
proportion of immature cells. Manifestations of leukemic cell infiltration into
other organs are more common with ALL than with other forms of leukemia and
include pain from an enlarged liver or spleen and bone pain. The central
nervous system is frequently a site for leukemic cells; thus, patients may
exhibit headache and vomiting because of meningeal involvement. Other
extranodal sites include the testes and breasts.
Medical Management
The expected outcome of treatment is complete remission. Due to the
heterogeneity of the disease, treatment plans are based on genetic markers of
the disease, as well as risk factors of the patient, primarily age (Pui & Evans,
2006). Because ALL frequently invades the central nervous system, preventive
cranial irradiation or intrathecal chemotherapy (eg, methotrexate) or both is
also a key part of the treatment plan.
Treatment protocols for ALL tend to be complex, using a wide variety of
chemotherapeutic agents. Lymphoid blast cells are typically very sensitive to
corticosteroids and to vinca alkaloids; therefore, these medications are an
integral part of the initial induction therapy. Typically, an anthracycline is
included, sometimes with asparaginase (Elspar). Once a patient is in remission,
intensification therapy (consolidation) ensues. In the adult with ALL, allogeneic
transplant may be used for intensification therapy. Transplant greatly improves
long-term disease-free survival, although the risks of death or long-term
morbidity are associated with the procedure. For those for whom transplant is
not an option (or is reserved for relapse), a prolonged maintenance phase
ensues, when lower doses of medications are given for up to 3 years. Despite its
complexity, treatment can be provided in the outpatient setting in some
circumstances until severe complications develop. Imatinib appears effective in
patients with Philadelphia chromosome–positive ALL. Monoclonal antibodies, in
which the antibody specific for the antigen expressed on the ALL blast cell is
selected for treatment, are also under study (Pui & Evans, 2006). For example,
the CD52 antigen is expressed on approximately 70% of ALL cells; thus,
alemtuzumab (Campath), a monoclonal antibody with specific affinity for the
CD52 antigen, may be effective therapy for this subset of patients.
Infections, especially viral infections, are common. The use of corticosteroids to
treat ALL increases the patient’s susceptibility to infection. Patients with ALL
tend to have a better response to treatment than do patients with AML. BMT or
PBSCT offers a chance for prolonged remission, or even cure, if the illness
recurs after therapy
Pathophysiology
CLL is typically derived from a malignant clone of B lymphocytes (T-lymphocyte
CLL is rare). In contrast to the acute forms of leukemia, most of the leukemia
cells in CLL are fully mature. It was initially hypothesized that these cells can
escape apoptosis (programmed cell death), resulting in an excessive
accumulation of the cells in the marrow and circulation. However, this
hypothesis is now being questioned (Chiorazzi & Ferrarini, 2006). The disease is
classified into three or four stages (two classification systems are in use). In the
early stage, an elevated lymphocyte count is seen; it can exceed 100,000/mm3 .
Because the lymphocytes are small, they can easily travel through the small
capillaries within the circulation, and the pulmonary and cerebral
complications of leukocytosis (as seen with myeloid leukemias) typically are not
found in CLL. Lymphadenopathy occurs as the lymphocytes are trapped within
the lymph nodes. The nodes can become very large and are sometimes painful.
Hepatomegaly and splenomegaly then develop.
In later stages, anemia and thrombocytopenia may develop. Autoimmune
complications can also occur at any stage, as either autoimmune hemolytic
anemia or idiopathic thrombocytopenic purpura. In the autoimmune process,
the RES destroys the body’s own erythrocytes or platelets.
More sophisticated prognostic markers have recently been identified
(Montserrat, 2006). Beta2-microglobulin, a protein found on the surface of
lymphocytes, can be measured in the serum; an elevated level correlates with
more advanced clinical stage and poorer prognosis. Cytogenetic analysis is also
useful.
Clinical Manifestations
Many patients are asymptomatic and are diagnosed incidentally during routine
physical examinations or during treatment for another disease. An increased
lymphocyte count (lymphocytosis) is always present. The erythrocyte and
platelet counts may be normal or, in later stages of the illness, decreased.
Enlargement of lymph nodes (lymphadenopathy) is common; this can be severe
and sometimes painful. The spleen can also be enlarged (splenomegaly).
Patients with CLL can develop “B symptoms,” a constellation of symptoms
including fevers, drenching sweats (especially at night), and unintentional
weight loss. Patients with CLL have defects in their humoral and cell-mediated
immune systems; therefore, infections are common. The defect in cellular
immunity is evidenced by an absent or decreased reaction to skin sensitivity
tests (eg, Candida, mumps), which is known as anergy. Life-threatening
infections are common, particularly with advanced disease. Viral infections,
such as herpes zoster, can become widely disseminated. Defects in the
complement system are also seen, which results in increased risk of developing
infection with encapsulated organisms (eg, Haemophilus influenzae) (Moran,
Browning, Buckby, et al., 2007).
Medical Management
A major paradigm shift has occurred in CLL therapy. For years, there appeared
to be no survival advantage in treating CLL in its early stages. However, with
the advent of more sensitive means of assessing therapeutic response, it has
been demonstrated that achieving a complete remission and eradicating even
minimal residual disease results in improved survival (Tam & Keating, 2007).
Even if treatment is not initiated early in the course of the illness, it typically
begins when symptoms are severe (drenching night sweats, painful
lymphadenopathy) or when the disease progresses to later stages (with
resultant anemia and thrombocytopenia).
The chemotherapy agents fludarabine (Fludara) and cyclophosphamide
(Cytoxan) are often given in combination with the monoclonal antibody
rituximab (Rituxan). This regimen can result in remission that lasts for 5 years
in 70% of patients. The major side effect of fludarabine is prolonged bone
marrow suppression, manifested by prolonged periods of neutropenia,
lymphopenia, and thrombocytopenia, which puts patients at risk for such
infections as Pneumocystis jiroveci, Listeria, mycobacteria, herpes viruses, and
cytomegalovirus (CMV). The monoclonal antibody alemtuzumab (Campath) is
often used in combination with other chemotherapeutic agents when the
disease is refractory to fludarabine, the patient has very poor prognostic
markers, or it is necessary to eradicate residual disease after initial treatment
(Tam & Keating, 2007). Alemtuzumab targets the CD52 antigen commonly
found on CLL cells, and it is effective in clearing the marrow and circulation of
these cells without affecting the stem cells. Because CD52 is present on both B
and T lymphocytes, patients receiving alemtuzumab are at significant risk for
infection; prophylactic use of antiviral agents and antibiotics (eg,
trimethoprim/sulfamethoxazole [Bactrim, Septra]) is important and needs to
continue for several months after treatment ends. Bacterial infections are
common in patients with CLL, and IV treatment with immunoglobulin may be
given to selected patients with recurrent infection.
Reference: Medical-Surgical nursing (Critical Thinking in Patient Care) 5 th Edition
Brunner & Suddarth’s Textbook of Medical-Surgical Nursing Volume 1