Hematopoietic malignancies account for 6% to 8% of new cancers diagnosed annually. In 2016, an estimated 60,140 new cases of leukemia will be diagnosed, and 24,400 deaths will be attributable to leukemias of all types. Nearly half of all new cases of leukemias are acute lymphoblastic leukemia (ALL; 6,590) and acute myelogenous leukemia (AML; 19,950). The total age-adjusted incidence of leukemia, including both the acute and chronic forms, is 12.5 per 100,000 population; the incidence of ALL is 1.6 per 100,000 and of AML, 3.6 per 100,000 population.
The incidence of both ALL and AML is slightly higher in males than in females.
The age-specific incidence of AML is similar to that of solid tumors in adults, with an exponential rise after age 40. With regard to ALL, 60% of cases are seen in children, with a peak incidence in the first 5 years of life and a subsequent drop in incidence until age 60, when a second peak emerges.
Race and Ethnicity
The incidence of acute leukemia is slightly higher in populations of European descent. Also, a report from the University of Southern California indicates that acute promyelocytic leukemia (APL) is more common in Hispanic populations than in other ethnic groups.
There is wide diversity in the behavior of the various subsets of acute leukemias. Thus, it is unlikely that there is one common cause for these aberrant cellular proliferations. There are, however, some accepted risk factors for leukemogenesis.
The increased incidence of AML and myelodysplasia (pre-leukemia) has been reported in persons with prolonged exposure to benzene and petroleum products. The interval between exposure and the onset of leukemia is long (10 to 30 years). Chromosomal damage is common.
Pesticide exposure also has been linked to some forms of AML. The incidence of AML is beginning to rise in developing countries, as industrialization and pollution increase.
Other Environmental Exposures
Exposure to hair dyes, smoking, and nonionic radiation may also increase the risk of leukemia.
Prior Chemotherapy or Irradiation
Use of alkylating agents, such as cyclophosphamide and melphalan, in the treatment of lymphomas, myelomas, and breast and ovarian cancers has been associated with the development of AML, usually within 3 to 5 years of exposure and often preceded by a myelodysplastic phase. Cytogenetic abnormalities, particularly monosomy 5 or 7 as well as mutations of 11q23 (MLL gene rearrangement), and deletion 17p causing a p53 mutation are common. Concurrent radiation exposure slightly increases the risk of leukemogenesis posed by alkylating agents.
Topoisomerase II inhibitors (etoposide, teniposide); doxorubicin and its derivatives; mitoxantrone, used to treat ALL, lymphomas, testicular cancer, and sarcomas; and taxanes, used to treat breast cancer, have also been implicated in leukemogenesis. These agents, in contrast to alkylators, are associated with a short latency period without antecedent myelodysplasia and with cytogenetic abnormalities involving chromosome 11q23 or 21q22 in the malignant clone.
An increased incidence of AML is seen in patients with Down syndrome, Bloom syndrome, or Fanconi anemia, as well as in individuals with ataxia-telangiectasia or Wiskott-Aldrich syndrome. In identical twins younger than 10 years, if one twin develops leukemia (usually ALL), there is a 20% chance that the other twin will develop leukemia within a year; subsequently, the risk falls off rapidly and joins that of nonidentical siblings, which is three to five times that of the general population.
Effects on Hematopoiesis
Leukemia manifests symptomatically by its impact on normal hematopoiesis. Thus, easy fatigability, bruising, bleeding from mucosal surfaces, fever, and persistent infection are all reflections of the anemia, thrombocytopenia, and decrease in functional neutrophils associated with marrow replacement by malignant cells. Bone pain is common in children with ALL (occurring in 40% to 50%) but is less common in adults (5% to 10%).
Whereas a marked elevation in white blood cell (WBC) count is the classic hallmark of leukemia, pancytopenia is more common, particularly in patients of all ages with ALL or in older patients with AML, who may have had preexisting marrow dysfunction (myelodysplasia). Only 10% of patients with newly diagnosed AML or ALL present with leukocyte counts greater than 100,000/μL. These patients, however, constitute a poor prognostic group and are at increased risk for central nervous system (CNS) disease, tumor lysis syndrome, and leukostasis caused by impedance of blood flow due to intravascular sludging of blasts, which are “stickier” than mature myeloid or lymphoid cells.
Leukostasis may manifest as an alteration in mental status; intermittent or persistent cranial nerve palsies, particularly those involving extraocular muscles; priapism; dyspnea; or pleuritic chest pain caused by small leukemic emboli in the pulmonary vasculature.
Physical findings in AML are usually minimal. Pallor, increased ecchymoses or petechiae, retinal hemorrhage, gingival hypertrophy, and cutaneous involvement are more common with monocytic (M4 or M5) variants of AML than with other variants of AML.
Mild hepatosplenomegaly and lymphadenopathy are seen in many cases, particularly in childhood ALL. Massive hepatosplenomegaly occurs infrequently and should raise the suspicion of a leukemia evolving from a prior hematologic disorder, such as chronic myelogenous leukemia (CML) or myelodysplasia/myeloproliferative disorders. Mediastinal adenopathy is seen in 80% of cases of T-cell ALL, but is less common in pre-B ALLs and is rare in AML.
Visceral involvement is also rare, occurring as an initial manifestation of AML in fewer than 5% of cases, but it may be more frequent during subsequent relapses. These focal collections of blasts, called chloromas or granulocytic sarcomas, can present as soft tissue masses, infiltrative lesions of the small bowel and mesentery, or obstructing lesions of the hepatobiliary or genitourinary system.
CNS involvement is uncommon at presentation in adult AML (< 1%) and adult ALL (3% to 5%). In most instances, CNS involvement is detected by screening lumbar puncture in high-risk patients who are asymptomatic at the time of the procedure. Symptoms, when they do occur, include headache, diplopia, cranial nerve palsies, radicular pain, and/or weakness in a particular nerve root distribution. CNS involvement usually is restricted to leptomeninges; parenchymal mass lesions are uncommon.
Like the CNS, the testes appear to be a “sanctuary” for isolated relapses in pediatric ALL, but rarely in adult ALL. Signs of testicular involvement include painless, asymmetric enlargement.
Metabolic effects of acute leukemia relate primarily to the rate of cell death.
Hyperuricemia with possible interstitial or ureteral obstruction is seen predominantly in AML with moderate leukocytosis and in ALL with bulky adenopathy. This condition may be exacerbated by a rapid response to chemotherapy and the “tumor lysis syndrome” (hyperuricemia with renal insufficiency, acidosis, hyperphosphatemia, and hypocalcemia), which may occur within the first 24 to 48 hours after initiating chemotherapy. To prevent this complication, all patients should receive allopurinol and urine alkalinization before marrow-ablative chemotherapy is initiated. For patients who are intolerant to allopurinol and do not have rapidly risng blast counts, febuxostat is another option. In patients with a high tumor burden, renal insufficiency, or acidosis before initiation of chemotherapy, rasburicase may offer a more rapid treatment for hyperuricemia.
Coagulopathies can also complicate the hemostatic defects associated with thrombocytopenia. Disseminated intravascular coagulation (DIC) is most often seen in acute promyelocytic leukemia (APL) because of the release of procoagulants from the abnormal primary granules, which activates the coagulation cascade, leading to decreased levels of factors II, V, VIII, and X, and fibrinogen, as well as rapid platelet consumption. Lysozyme released from monoblasts in M4 and M5 subtypes of AML with monocytic differentiation can also trigger the clotting cascade. Finally, DIC can occur following L-asparaginase chemotherapy for ALL. Fibrinogen and antithrombin III need to be monitored for 10 to 14 days following asparaginase therapy so that adequate replacement of these factors can be provided.