Acute Leukemias
Accumulation of neoplastic, immature lymphoid or immature myeloid cells in the bone marrow and peripheral blood; tissue invasion by these cells; and associated bone marrow failure.
Acute leukemias are categorized as acute lymphoblastic (lymphocytic) leukemia (ALL) or acute myelogenous (myelocytic, myeloblastic) leukemia (AML), according to the morphologic characteristics of leukemic cells in peripheral blood and bone marrow smears and to the cells' histochemical staining and immunologic markers. The French-American-British (FAB) Cooperative Group classification, the system most widely used to facilitate clinical studies, allows some degree of prognostication.
Acute leukemia is primarily a disease of children and the elderly. In the USA, acute leukemia has an incidence of about 15/100,000 across all age groups. However, the incidence begins rising at age 40 and by age 80 is about 160/100,000. About 80% of adults with acute leukemia have AML.
Etiology and Pathophysiology
In most cases of acute leukemia, the etiology is unknown. Radiation exposure has been causally implicated in some cases. Atomic bomb survivors from Hiroshima and Nagasaki have a 10 to 20% increase in the incidence of AML. Likewise, the risk of developing AML is 2.5 times greater in diagnostic radiologists and 14 times greater in patients who received radiation therapy for ankylosing spondylitis earlier this century. High-level benzene exposure in the workplace has been strongly implicated as a risk factor for AML. Also, long-term low-dose therapy with virtually any chemotherapeutic alkylating agent can cause acute leukemia, usually the myelogenous type. Combining a chemotherapeutic agent with radiation therapy increases the risk.
Chronic bone marrow disorders (eg, myelodysplasia, polycythemia vera, aplastic anemia) are sometimes followed by a rapidly progressive leukemic phase in patients of all ages.
Viruses have long been suspected as the cause of some acute leukemias, particularly the lymphocytic varieties. Oncogenes appear to have a role in inducing and maintaining malignancy. In some cases, specific oncogenes are involved in particular chromosome translocations or in chromosome deletion or reduplication.
In acute promyelocytic leukemia (FAB M3 classification), the t(15;17) translocation, which involves the retinoic acid receptor gene on chromosome 17, is present as a unique feature in virtually all cases, which may explain the response to treatment with all-trans-retinoic acid.
In acute leukemia, primitive lymphoblasts and myeloblasts accumulate rapidly in the bone marrow and invade many tissues, including the liver, spleen, lymph nodes, and central nervous system (CNS). Normal bone marrow and normal leukocytes are replaced by these blasts, resulting in severe anemia, thrombocytopenia with marked bleeding, and great susceptibility to infection.
Symptoms and Signs
Acute leukemia frequently presents as an apparent infection with an acute onset of malaise and high fever. An associated thrombocytopenia usually produces petechiae, ecchymoses, and bleeding from the nose, mouth, and gastrointestinal and genitourinary tracts. Often, the liver, spleen, and lymph nodes are enlarged. In the elderly, the disease can present insidiously with progressive weakness, pallor, an altered sense of well-being, and delirium.
Diagnosis
The total peripheral white blood cell (WBC) count may be low, normal, or elevated. Blasts are usually present in the peripheral blood smear, but a bone marrow aspiration should be performed to confirm the diagnosis. The bone marrow in acute leukemia contains excessive blast cells and an absence or decreased number of normal erythrocytic, granulocytic, and megakaryocytic cells. Histochemical stains, immunophenotype, and chromosome abnormalities help identify the type of acute leukemia.
Elderly patients with ALL often have one or more of the following: a WBC count > 20,000/µL, mediastinal mass, L2 to L3 morphologic changes, T-cell or B-cell leukemia, and meningitis.
Prognosis
Without treatment, death usually occurs within 4 to 6 months of clinical onset. Some patients die within days. Indicators of a poor prognosis include advanced age, infection, bleeding, high blast counts, and chromosomal abnormalities (the elderly have more complex karyotypic abnormalities than do younger patients). Auer rods (in AML) have been reported to be an indicator of a good prognosis. A prior bone marrow disorder (eg, polycythemia vera, myelodysplasia) or leukemia secondary to previous therapy with an alkylating agent seems to indicate a poor prognosis. However, data regarding all prognostic signs are contradictory.
Advanced age has typically been considered an unfavorable prognostic factor. The major problem in treating the elderly is their relative inability to tolerate the prolonged pancytopenia that accompanies aggressive chemotherapy. Of patients with ALL, the elderly have a much worse prognosis than do children, who have an excellent prognosis. T-cell leukemia has a slightly better prognosis than does B-cell leukemia.
Treatment
Acute lymphoblastic leukemia: Therapy traditionally consists of a combination of drugs, including vincristine, prednisone, an anthracycline, and asparaginase (which is tolerated poorly by elderly patients). Most elderly patients experience relapse within the first year of treatment, and no accepted standard salvage therapy exists. Bone marrow transplantation is rarely used for patients > 65. Patients with true B-cell ALL (FAB L3 classification) are treated with regimens for small noncleaved cell non-Hodgkin's lymphoma (high-grade non-Hodgkin's lymphoma).
Acute myelogenous leukemia: The initial aim is to induce a complete remission, ie, to reduce leukemic blasts to an undetectable level (in practice, < 5% marrow blasts). In the induction phase of treatment, comprehensive care is critical, because the patient is often infected and bleeding and has a large tumor burden with little normal hematopoiesis. Many induction regimens are being used; the standard combination is cytarabine 100 to 200 mg/m2/day as a continuous IV infusion for 5 to 7 days and daunorubicin 45 mg/m2/day IV for the first 3 days. A low-dose cytarabine regimen of 50 to 100 mg/m2/day lowers the mortality rate during induction but does not improve the complete remission rate. With the use of fresh, frozen, and packed red blood cells (RBCs), platelets, antibiotics, and growth factors, the complete remission rate in patients > 60 ranges from 40 to 76%. Median survival is 1 to 2 years. The value of maintenance and consolidation chemotherapeutic regimens is under study. As in ALL, bone marrow transplantation is rarely used for patients > 65.
In acute promyelocytic leukemia, oral administration of all-trans-retinoic acid can induce differentiation of the leukemic cells and produce a histologic and cytogenetic remission; however, this regimen has not been studied specifically in the elderly. Moreover, the remissions are temporary, and standard chemotherapy is also required.
Complications of treatment: Infections are the major cause of morbidity and mortality in patients with acute leukemia. Infections result from the severe leukopenia (with polymorphonuclear leukocytes often < 500 to 1000/µL) and destruction of normal cutaneous and mucosal barriers. In many patients, endogenous bowel flora is the source of infection, but the pharynx, lungs, perirectal area, and skin are also common sources. The genitourinary tract and CNS are rare sources. Because the source of infection is usually internal, isolation has limited value. Viruses, protozoa, and anaerobic bacteria are uncommon pathogens early in therapy. Fungal infections usually occur after 7 to 14 days of antibiotic therapy in neutropenic patients.
The initial choice of antibiotics depends on the predominant organisms causing infection in a given hospital. In most hospitals the most common organisms are Pseudomonas and Escherichia coli; therefore, an aminoglycoside plus a semisynthetic penicillin or a cephalosporin is usually the combination of choice. Trimethoprim-sulfamethoxazole has been suggested as prophylaxis, particularly in patients who have been admitted frequently with fever and neutropenia.
Metabolic problems are common during induction therapy. Hyperuricemia should be treated prophylactically with allopurinol 300 mg/day. Oliguric renal failure will develop from uric acid nephropathy unless the patient is vigorously hydrated, is treated with allopurinol, and undergoes urine alkalinization. Natriuresis and hyponatremia often develop from increased osmolar clearance as a result of electrolytes, water, and urea released from dead blasts. Hypokalemia can occur from natriuresis, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), physiologic hypervasopressinemia, or proximal renal tubular dysfunction. A renal tubular acidosis-like syndrome, with hypokalemia, aminoaciduria, and hyperphosphaturia, occurs but is probably not related to lysozyme, because it occurs when the leukemic cells are not releasing large amounts of this enzyme, and the serum and urinary lysozyme levels are not elevated. Metabolic alkalosis, metabolic acidosis, hypocalcemia, and hyperphosphatemia are also common complications.
Aggregates of blasts and thrombi may occlude small blood vessels throughout the body, particularly in the brain and lungs. Therapy consists of hydration and rapid reduction of the blast count by promptly initiating chemotherapy. Leukapheresis may be palliative.
The CNS is the most common site of extramedullary relapse in acute leukemia; patients present with headache, vomiting, and irritability. The need for prophylactic meningeal therapy with cranial irradiation and intrathecal methotrexate and/or cytarabine has not been formally addressed in the elderly. Therefore, these treatments must be used with extreme caution, if at all. Spinal cord compression with resulting motor and sensory deficits may occur; it usually responds to local radiation. The acute T-cell lymphocytic leukemias are most likely to cause either CNS or gonadal invasion. However, the role of prophylactic testicular irradiation in the elderly is unclear.
Disseminated intravascular coagulation (DIC) is an uncommon complication occurring mainly in promyeloblastic leukemia. The patient presents either with massive sudden bleeding (acute DIC) or, more commonly, with slow bleeding (chronic DIC). Generally, DIC is self-limited and is most problematic during the rapid cell lysis of induction chemotherapy. Use of prophylactic heparin to treat this condition is controversial.
End-of-Life Issues
Acute leukemia in elderly patients is most often fatal within 1 to 2 years. Patients and family members should understand that, even with aggressive treatment, the best that can usually be hoped for is a short prolongation of life. The patient must weigh this prognosis against the unpleasant side effects of chemotherapy. Often, older patients decide not to undergo chemotherapy. Hospice care, palliative care (including pain relief), and patient comfort are the goals.
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