Susan Brighton, Elizabeth Kimtis
Leukemias
Referral to a hematologist is indicated for all suspected cases of leukemia.
Definition and Epidemiology
Some of the most challenging and complex cancers to manage in the community setting are the leukemias, hematologic malignant neoplasms that affect the bone marrow and lymphatic tissue. There are four different types of leukemia, two acute and two chronic forms. The acute forms of leukemia are acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL). Chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) are the two chronic forms of leukemia, with CLL being the most common form of leukemia.1 Acute leukemias are distinguished by an abnormal production of immature white blood cells (WBCs), called blasts, and rapid disease progression over approximately 6 months, which results in limited life expectancy if left untreated. Chronic leukemias reveal an overabundance of more mature-appearing but ineffective WBCs. Disease progression is usually slower, over several years as opposed to months. The overproduction of leukemia cells displaces normal cells in the bone marrow and thus crowds out normal hematopoiesis, resulting in granulocytopenia, anemia, and thrombocytopenia. Depending on the type of leukemia, treatment may be as conservative as observation or as aggressive as bone marrow or peripheral blood stem cell transplantation. Consequences of the disease state and side effects of treatment represent a true challenge to the health care provider.
In 2015, there were estimated to be approximately 54,270 new cases of leukemia in the United States, with a slightly higher incidence of acute compared with chronic leukemia. The estimated number of deaths from leukemia in 2015 was approximately 24,450.2,3 The exact cause of leukemia is unknown. Causes and risk factors for consideration are genetic factors and disorders, exposure to radiation, environmental factors, occupational exposures, drugs, viruses, and other bone marrow disorders.
Children with genetic disorders such as Down syndrome have an increased risk for the development of acute leukemia. Other conditions that are associated with a higher risk for developing leukemia include Ellis–van Creveld syndrome, Fanconi anemia, Klinefelter syndrome, Bloom syndrome, and ataxia-telangiectasia.
Exposure to ionizing radiation is the most conclusive predisposing factor associated with the development of leukemia. This became evident after World War II, when a large number of Japanese survivors of the atomic bomb demonstrated an increased incidence of AML and CML, usually 5 to 9 years after exposure.2 Pioneer radiologists who were exposed to massive radiation also exhibited a high incidence of leukemia.4
Environmental factors such as hair dye, cigarette smoking, and sunbathing may also increase the risk for development of leukemia, although studies have been inconclusive.5
Occupational exposure to certain chemicals increases the risk for development of leukemia. Workers exposed to benzene (a hydrocarbon used in industry, such as rubber and shoe-making plants, and in unleaded gasoline), rubber cement, and cleaning solvents are at risk. Other occupations in which workers are at risk of contracting leukemia are those that expose workers to explosives, dyes, or paints including distilleries, pesticide manufacturing, and leather tanning industries.5 Although the relationship between leukemia and viruses remains unclear, there does appear to be a correlation between retroviruses and T-cell leukemia and hairy cell leukemia.6
Antecedent hematologic disorders, such as polycythemia vera, aplastic anemia, myelodysplastic syndromes (MDSs), and other diseases of the bone marrow also appear to predispose individuals to leukemia. Intensive combination chemotherapy for patients with cancer has led to increased survival rates overall. However, these survivors must be continually evaluated for complications of the long-term cytotoxic treatment. One serious consequence is the development of a second cancer, especially myeloid leukemia. Therapy-related leukemia is typically a fatal disease. Treatment-related myelodysplastic syndrome (t-MDS) and treatment-related AML (t-AML) are the terms used to describe a clinical syndrome that is arguably the most serious unpredictable long-term complication of cancer treatment. In total, therapy-related myeloid neoplasms represent 10% to 20% of acute leukemias, MDSs, and myelodysplastic or myeloproliferative neoplasms.7
Pathophysiology
All blood cells—WBCs, red blood cells and platelets—originate from the stem cell, which is predominantly found in the bone marrow. The stem cell’s unique ability for self-renewal and differentiation is necessary to meet the body’s requirements throughout a lifetime.8
Leukemia is a malignant disorder of the blood and blood-forming organs—the spleen, lymphatic system, and bone marrow. It is identified as acute or chronic by the onset of symptoms and the maturity of the blood cell. Leukemic cells are designated either myeloid or lymphoid, according to the type of cell that predominates, as identified by morphology of the cells in combination with flow cytometry, cytogenetics, and molecular markers.
There is a maturational arrest of immature leukocytes, or blasts, in acute leukemia. These blasts proliferate or accumulate uncontrollably, inhibiting normal hematopoiesis and contributing to organomegaly. In chronic leukemia, there is an accumulation of mature-appearing leukocytes that have lost their ability to function efficiently and to undergo apoptosis, or programmed cell death.
The accumulation of abnormal blood cells in the bone marrow and lymphatic tissue can result in organomegaly as well as abnormal hematopoiesis, causing anemia, neutropenia, and thrombocytopenia, as well as an impaired immune response.
Clinical Presentation and Physical Examination
Acute Leukemias
The presenting signs and symptoms of AML and ALL can be nonspecific, along with associated cytopenias. The patient may have fevers and/or recurrent infection owing to a low WBC count. Increasing weakness, progressive fatigue, pallor, or dyspnea, all related to anemia, is not uncommon. Unexplained or spontaneous bruising, oral bleeding, epistaxis, heavy menstrual periods, and excessive bleeding after minor dental or surgical procedures are all caused by thrombocytopenia. Rarely, patients may have chloromas, the collection of blast cells in the subcutaneous tissues. In addition, with AML, some patients have oral involvement manifesting with gum hypertrophy; therefore an oral examination may be helpful.
If leukemia infiltrates lymph nodes, spleen, and liver, diffuse lymphadenopathy and hepatosplenomegaly may be present on examination. Patients may also have bone pain as a result of a packed, expanding bone marrow. Younger patients may experience joint pain and swelling that resembles rheumatoid arthritis.
Ocular involvement is seen in both childhood and adult leukemia patients. Not all ocular lesions cause symptoms; therefore it is important to consider an ophthalmic examination at the time of diagnosis.9
Approximately 5% to 8% of patients have central nervous system (CNS) involvement at the time of initial diagnosis. Common signs and symptoms of leukemia that has invaded the CNS are headache, papilledema, vision changes such as diplopia, vomiting, mental status changes, and cranial nerve palsy. In AML, leukostasis occurs when the blast count exceeds 100,000 cells/mm3, and the patient is at risk for a fatal cerebral hemorrhage.10
Physical examination findings such as lymphadenopathy, hepatosplenomegaly, and testicular involvement are more common in ALL than in AML.
Chronic Leukemias
Patients with CML and CLL are usually asymptomatic in the early stages of disease. There may be subtle changes in the WBC count and differential early in the course of disease. A cardinal finding on physical examination of patients with chronic leukemia is splenomegaly. The patient may report a mild sensation of fullness in the left upper quadrant or may have an obvious mass. Severe splenomegaly can compress surrounding organs, causing early satiety, weight loss, and peripheral leg edema related to compression of the splenic vein. As the disease progresses, other symptoms occur, such as bone pain, bleeding problems, infection, fatigue, pallor, adenopathy, fevers, and night sweats.11
Diagnostics and Differential Diagnosis
Acute Leukemias
The key in making the diagnosis of acute leukemia lies with the evaluation of a complete blood count and bone marrow aspirate with biopsy, to study the morphology of the cells. Additional studies on these specimens should include immunophenotyping and cytogenetic analysis. Most patients initially have a combination of cytopenias, with striking abnormalities noted in the WBC count and differential. The parameters of the WBC count vary within a wide range, from 1000 to 100,000 cells/mm3. Most patients have counts between 5000 and 30,000 cells/mm3.12
Careful examination of the blood smear is essential. The significant finding on the blood smear is an increased population of blast cells and a decrease of granulocytes, red blood cells, and platelets. However, as many as 10% of all patients have normal blood counts even when the marrow has been replaced by leukemic cells; therefore bone marrow aspiration and biopsy are required for a definitive diagnosis. Auer rods (rod-shaped granules incorporated within the blast cells) are pathognomonic of AML.12
Additional laboratory studies should be performed to identify a wide range of metabolic and electrolyte abnormalities that can be seen in acute leukemia. Biochemical studies may reveal hyperuricemia. Hyperuricemia occurs because of the high turnover rate of proliferating leukemia cells resulting in rapid purine catabolism and elevations in serum uric acid. Electrolyte abnormalities are common, and an elevated lactate dehydrogenase (LDH) level can be seen in patients without change in other liver function test (LFT) parameters. The presence of any or all of these abnormalities is a reflection of the rate of growth and turnover of the leukemia cells.
Patients with excessive bruising or bleeding should undergo a coagulation panel to look for disseminated intravascular coagulation (DIC) or other coagulopathies. Any patient with an increased myeloblast count may be at risk for leukostasis. This condition primarily affects the lungs and brain, but any organ can be involved. Lowering of the blast count in a rapid fashion is necessary, usually with chemotherapy or leukapheresis. The differential diagnosis for ALL and AML includes lymphoma, although other infiltrative processes, such as solid tumors (e.g., breast cancer or small cell lung cancer), must be excluded. Some patients with fever and cytopenia who have a small number of circulating blast cells must be differentiated from those with reactions to tuberculosis, systemic lupus erythematosus, megaloblastic anemia, or aplastic anemia. Surface antigen and serologic studies can exclude viral infections such as infectious mononucleosis. AML needs to be distinguished from MDS or a myeloproliferative disorder, such as the transformation of CML in blast crisis.
Chronic Leukemias
At diagnosis, the WBC count in chronic leukemias may range from fewer than 10,000 to more than 200,000 cells/mm3, with mature and predominantly myelocytic cells. In general, the red blood cell count is normal, but a slight degree of anemia may occur. Hypereosinophilia and hyperbasophilia are common. Increased levels of uric acid in the blood and urine are also found in patients with CML. Bone marrow biopsy reveals hyperplastic myeloid cells and storage cells similar to Gaucher cells scattered throughout the marrow. The striking biochemical abnormality in CML is the reduction or absence of leukocyte alkaline phosphatase. This, along with the positive test result for Philadelphia chromosome (Ph1), the hallmark of CML, confirms the diagnosis. CML is the first cancer shown to be associated with a chromosomal abnormality.11
CLL is often discovered on a routine office visit when a CBC is ordered. The physical examination findings may be normal, but some patients have nontender adenopathy or splenomegaly. Patients may report fatigue, night sweats, occasional fever, or malaise. The majority of patients consult their health care provider because of a painless cervical lymph node that waxes and wanes but does not disappear completely.11
CLL is suspected whenever an absolute lymphocytosis in the peripheral blood occurs in an adult and is sustained over time. Lymphocytosis also occurs in infectious mononucleosis, pertussis, and toxoplasmosis; but in these conditions, the lymphocyte count returns to normal after a few weeks.
A peripheral smear may be adequate for the diagnosis of CLL; a bone marrow biopsy will always reveal lymphocytosis in cases of CLL. The lymphocyte count ranges from 10,000 to 150,000/mm3. Because there may be a decrease in immunoglobulin (Ig) levels, serum protein electrophoresis should be performed; this test may reveal a marked decrease in levels of IgG and slight decreases in IgA and IgM levels.12 A chest x-ray study may be helpful in detecting hilar and mediastinal adenopathy.
The differential diagnosis for CLL includes non-Hodgkin lymphoma, hairy cell leukemia, and a variety of other lymphoproliferative disorders.
Management
Acute Leukemias
Patients diagnosed with ALL and AML require aggressive chemotherapy to restore normal hematopoiesis. Given the abrupt onset, prompt evaluation and intervention are required in order to successfully eradicate the disease and improve the chance of survival. Treatment of AML involves two phases of therapy: induction therapy to induce a complete remission and consolidation therapy to secure the remission. Induction therapy usually requires a 1-month hospitalization during which patients are supported with blood product support and antibiotic therapy while normal hematopoiesis is restored. Treatment for ALL involves long-term use of chemotherapy in three phases: induction, consolidation, and maintenance therapy. The total time of therapy usually takes about 2 years.
Patients with AML may also undergo hematopoietic stem cell transplantation (HSCT). The increasing use of both autologous and allogeneic HSCTs will have a profound effect on the outcome of AML. The impact of these approaches continues to be researched. Management of these patients requires a multidisciplinary approach. Expertise in transfusion management, infectious disease, care of indwelling catheters, nutrition, chemotherapy and its side effects, and psychosocial counseling is required.13
Approximately 50% of patients with ALL who are younger than 15 years achieve a long-term, leukemia-free survival. Approximately 70% of all patients with AML who are younger than 60 years achieve a complete but short-lived remission; only 15% remain disease free for 5 years or more. The major cause of failure to achieve remission during induction therapy is death from hemorrhage and infection.1
Age, health, and other factors need to be taken into consideration when assessing treatment options. Older individuals or those in poor health may not do as well with intensive therapy.
Chronic Leukemias
CML has three phases: chronic phase, accelerated phase, and terminal blast crisis phase. The chronic phase has a duration of approximately 3 to 5 years; the durations of the other phases vary. In contrast, CLL is usually a long-term disease, with reported cases lasting 1 to 15 years.
Chronic leukemias are managed differently from acute leukemias. CML is treated initially with imatinib mesylate (Gleevec). The U.S. Food and Drug Administration approved Gleevec for CML treatment in May 2001. The translocation between chromosomes 9 and 22, or Ph1, disappears in 75% of patients taking Gleevec by 18 months of therapy. Alternative treatments include the second-generation tyrosine kinase inhibitors dasatinib and nilotinib.14 Allogeneic stem cell transplantation and clinical trials remain an option for patients who are intolerant of or refractory to tyrosine kinase inhibitors. Allogeneic stem cell transplant remains the only known cure for CML.
CLL and small lymphocytic lymphoma are the same disease, manifesting differently. They are treated identically, and the terms are commonly used interchangeably. Initiation of treatment should be individualized and based on prognostic information, including cytogenetic aberrations and stage of disease. Various treatment options exist, including enrollment in a clinical trial, purine analogs such as fludarabine, alkylating agents such as chlorambucil and bendamustine, and corticosteroids. Many of these drugs will be given in combination with other agents including monoclonal antibodies such as rituximab. For patients who have progressed in spite of having received first-line therapies, ibrutinib is the newest medication designed for treatment of patients with CLL. The drug is taken daily by mouth.
Patients diagnosed with leukemia who have undergone chemotherapy or perhaps HSCT are at risk for infection (bacterial, fungal, viral) and other long-term side effects of aggressive treatment. Patients with CLL are predisposed to several infectious complications that are related to the humoral immunocompromise associated with the disease process as well as to further immunosuppression from steroid therapy and cytotoxic therapy.15 These patients benefit from monitoring of IgG levels and infusions of IVIG to replete their IgG levels and decrease their risk of infection. Periodic visits to the health care provider and the hematologist or oncologist are essential for close monitoring and support.
Patients who have undergone HSCT need close follow-up monitoring, which usually occurs in collaboration with the tertiary center that performed the HSCT. These patients are immunocompromised, and intervention in a timely fashion with antibiotics and antifungal agents when indicated will improve survival and quality of life. Continuing with routine health maintenance is also important when caring for this patient population.
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