Acute leukemia occurs when a hematopoietic stem cell undergoes malignant transformation into a primitive, undifferentiated cell with abnormal longevity. These lymphoid cells (acute lymphocytic leukemia [ALL]) or myeloid cells (acute myelocytic leukemia [AML]) proliferate abnormally, replacing normal marrow tissue and hematopoietic cells and inducing anemia, thrombocytopenia, and granulocytopenia. Because they are bloodborne, they can infiltrate various organs and sites, including the liver, spleen, lymph nodes, CNS, kidneys, and gonads.
Symptoms and Signs
Symptoms may be present for only days to weeks before diagnosis. Disrupted hematopoiesis leads to the most common presenting symptoms (anemia, infection, easy bruising and bleeding). Other presenting symptoms and signs are usually nonspecific (eg, pallor, fatigue, fever, malaise, weight loss, tachycardia, chest pain) and are attributable to anemia and a hypermetabolic state. The cause of fever often is not found, although granulocytopenia may lead to a rapidly progressing and potentially life-threatening bacterial infection. Bleeding is usually manifested by petechiae, easy bruising, epistaxis, bleeding gums, or menstrual irregularity. Hematuria and GI bleeding are uncommon. Bone marrow and periosteal infiltration may cause bone and joint pain, especially in children with ALL. Initial CNS involvement or leukemic meningitis (manifesting as headaches, vomiting, irritability, cranial nerve palsies, seizures, and papilledema) is uncommon. Extramedullary infiltration by leukemic cells may cause lymphadenopathy, splenomegaly, hepatomegaly, and leukemia cutis (a raised, nonpruritic rash). Gum hyperplasia may be prominent, particularly in AML.
CBC and peripheral smear are the first tests done; pancytopenia and peripheral blasts suggest acute leukemia. Blast cells in the peripheral smear may approach 90% of WBC count. Although the diagnosis can usually be made from the peripheral smear, bone marrow examination (aspiration or needle biopsy) is routinely done. Blast cells in the bone marrow are classically between 25 and 95%. Aplastic anemia, viral infections such as infectious mononucleosis, and vitamin B12 and folate deficiency should be considered in the differential diagnosis of severe pancytopenia. Leukemoid reactions to infectious disease (such as TB) can rarely manifest with high blast counts.
Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies help distinguish the blasts of ALL from those of AML or other disease processes. Specific B-cell, T-cell, and myeloid-antigen monoclonal antibodies, together with flow cytometry, are essential in classifying the acute leukemias, which is critical for treatment.
Other laboratory findings may include hyperuricemia, hyperphosphatemia, hyperkalemia or hypokalemia, hypocalcemia, elevated serum hepatic transaminases or LDH, hypoglycemia, and hypoxia. CT of the head is done in patients with CNS symptoms. Chest x-ray should be done to detect mediastinal masses, especially before the patient is given anesthesia. CT, MRI, or abdominal ultrasonography may help assess splenomegaly or leukemic infiltration of other organs.
Cure is a realistic goal for both ALL and AML, especially in younger patients. Prognosis is worse in infants and the elderly and in those with hepatic or renal dysfunction, CNS involvement, myelodysplasia, or a high WBC count (> 25,000/μL). Survival in untreated acute leukemia generally is 3 to 6 mo. Prognosis varies according to multiple variables including karyotype, response to therapy, and performance status.
The goal of treatment is complete remission, including resolution of abnormal clinical features, restoration of normal blood counts and normal hematopoiesis with < 5% blast cells in the bone marrow, and elimination of the leukemic clone. Although basic principles in treating ALL and AML are similar, the drug regimens differ. The complex nature of patients' clinical situations and the available treatment protocols necessitate an experienced team. Whenever possible, patients should be treated at specialized medical centers, particularly during critical phases (eg, remission induction).
Supportive care is similar in the acute leukemias and may include
Transfusions of platelets, RBCs, and granulocytes are administered as needed to patients with bleeding, anemia, and neutropenia, respectively. Prophylactic platelet transfusion is done when platelets fall to < 10,000/μL; a higher threshold (20,000/μL) is used for patients with the triad of fever, disseminated intravascular coagulation, and mucositis secondary to chemotherapy. Anemia (Hb < 8 g/dL) is treated with transfusions of packed RBCs. Granulocyte transfusions may help neutropenic patients with gram-negative or other serious infections but have no proven benefit as prophylaxis.
Antimicrobials are often needed because patients are neutropenic and immunosuppressed; in such patients, infections can progress quickly with little clinical prodrome. After appropriate studies and cultures have been done, febrile patients with neutrophil counts < 500/μL should begin treatment with a broad-spectrum bactericidal antibiotic that is effective against gram-positive and gram-negative organisms (eg, ceftazidime, imipenem, cilastatin). Fungal infections, especially pneumonias, are becoming more common and are difficult to diagnose; empiric antifungal therapy should be given if antibacterial therapy is not effective within 72 h. In patients with refractory pneumonitis, Pneumocystis jirovecii infection or a viral infection should be suspected and confirmed by bronchoscopy and bronchoalveolar lavage and treated appropriately. Empiric therapy with trimethoprim/sulfamethoxazole (TMP/SMX), amphotericin B, and acyclovir or other analogs, often with granulocyte transfusions, is often necessary. In patients with drug-induced immunosuppression at risk of opportunistic infections, TMP/SMX is given to prevent P. jirovecii pneumonia.
Hydration (twice the daily maintenance volume), urine alkalinization (pH 7 to 8), and electrolyte monitoring can prevent the hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia (tumor lysis syndrome—see Principles of Cancer Therapy: Tumor Lysis Syndrome) caused by the rapid lysis of leukemic cells during initial therapy (particularly in ALL). Hyperuricemia can be minimized by giving allopurinol (a xanthine oxidase inhibitor) or rasburicase (a recombinant urate-oxidase enzyme) before starting chemotherapy to reduce the conversion of xanthine to uric acid.
Psychologic support may help patients and their families weather the shock of illness and the rigors of treatment for a potentially life-threatening condition.
Acute Lymphocytic Leukemia (ALL)
(Acute Lymphoblastic Leukemia)
ALL is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived hematopoietic progenitor cell results in a high circulating number of blasts, replacement of normal marrow by malignant cells, and the potential for leukemic infiltration of the CNS and abdominal organs. Symptoms include fatigue, pallor, infection, bone pain, and easy bruising and bleeding. Examination of peripheral blood smear and bone marrow is usually diagnostic. Treatment typically includes combination chemotherapy to achieve remission, intrathecal chemotherapy for CNS prophylaxis and/or cerebral irradiation for intracerebral leukemic infiltration, consolidation chemotherapy with or without stem cell transplantation, and maintenance chemotherapy for up to 3 yr to avoid relapse.
Two thirds of all ALL cases occur in children, with a peak incidence at age 2 to 5 yr; ALL is the most common cancer in children and the 2nd most common cause of death in children < 15 yr. A 2nd rise in incidence occurs after age 45.
Prognostic factors help determine treatment protocol and intensity.
Favorable prognostic factors are
Unfavorable factors are
Regardless of prognostic factors, the likelihood of initial remission is ≥ 95% in children and 70 to 90% in adults. Of children, 75% or more have continuous disease-free survival for 5 yr and appear cured. Of adults, 30 to 40% have continuous disease-free survival for 5 yr. Imatinib improves outcome in adults and children with Ph chromosome–positive ALL. Most investigatory protocols select patients with poor prognostic factors for more intense therapy, because the increased risk of and toxicity from treatment are outweighed by the greater risk of treatment failure leading to death.
The 4 general phases of chemotherapy for ALL include
The goal is to induce remission. Several regimens emphasize early introduction of an intensive multidrug regimen. Remission can be induced with daily oral prednisone and weekly IV vincristine with the addition of an anthracycline or asparaginase. Other drugs and combinations that may be introduced early in treatment are cytarabine and etoposide as well as cyclophosphamide. In some regimens, intermediate-dose or high-dose IV methotrexate is given with leucovorin rescue. The combinations and their dosages are modified according to the presence of risk factors. Imatinib can be added to the drug regimen in patients with Ph chromosome–positive ALL.
An important site of leukemic infiltration is the meninges; prophylaxis and treatment may include intrathecal methotrexate, cytarabine, and corticosteroids in combination or methotrexate and cytarabine singly. Cranial nerve or whole-brain irradiation may be necessary and is often used for patients at high risk of CNS disease (eg, high WBC count, high serum LDH, B-cell phenotype), but its use has been decreasing in recent years.
The goal of consolidation is to prevent leukemic regrowth. Consolidation therapy usually lasts a few months and combines drugs that have different mechanisms of action than drugs used in induction regimens. Allogeneic stem cell transplantation is recommended as consolidation therapy for Ph chromosome–positive ALL in adults or for 2nd or later relapses or remissions.
Most regimens include maintenance therapy with methotrexate and mercaptopurine. Therapy duration is usually 2½ to 3 yr but may be shorter when regimens that are more intensive in earlier phases are used.
Therapy is usually short and intensive for Burkitt's leukemia or ALL with mature B-cells (FAB L3 morphology). For patients in continuous complete remission for 1 yr after therapy stops, the risk of relapse is small.
Leukemic cells may reappear in the bone marrow, the CNS, the testes, or other sites. Bone marrow relapse is particularly ominous. Although a new round of chemotherapy may induce a 2nd remission in 80 to 90% of children (30 to 40% of adults), subsequent remissions tend to be brief. Chemotherapy causes only a few patients with early bone marrow relapse to achieve long disease-free 2nd remissions or cure.
If an HLA-matched sibling is available, stem cell transplantation offers the greatest hope of long-term remission or cure (see Transplantation: Hematopoietic Stem Cell Transplantation). Cells from other relatives or from matched, unrelated donors are sometimes used. Transplantation is rarely used for patients > 65 yr because it is much less likely to be successful and because adverse effects are much more likely to be fatal.
When relapse involves the CNS, treatment includes intrathecal methotrexate (with or without cytarabine or corticosteroids) twice weekly until all signs disappear. Most regimens include systemic reinduction chemotherapy because of the likelihood of systemic spread of blast cells. The role of continued intrathecal drug use or CNS irradiation is unclear.
Testicular relapse may be evidenced clinically by painless firm swelling of a testis or may be identified on biopsy. If unilateral testicular involvement is clinically evident, the apparently uninvolved testis should undergo biopsy. Treatment is radiation therapy of the involved testis and administration of systemic reinduction therapy as for isolated CNS relapse.
Acute Myelocytic Leukemia (AML)
(Acute Myelogenous Leukemia; Acute Myeloid Leukemia)
In AML, malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers of immature blood forms and replacement of normal marrow by malignant cells. Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and infection; symptoms of extramedullary leukemic infiltration are present in only about 5% of patients (often as skin manifestations). Examination of peripheral blood smear and bone marrow is diagnostic. Treatment includes induction chemotherapy to achieve remission and postremission chemotherapy (with or without stem cell transplantation) to avoid relapse.
The incidence of AML increases with age; it is the more common acute leukemia in adults, with a median age of onset of 50 yr. AML may occur as a secondary cancer after chemotherapy or radiation therapy for a different type of cancer.
AML has a number of subtypes that are distinguished from each other by morphology, immunophenotype, and cytochemistry. Five classes are described, based on predominant cell type, including myeloid, myeloid-monocytic, monocytic, erythroid, and megakaryocytic.
Acute promyelocytic leukemia (APL) is a particularly important subtype, representing 10 to 15% of all cases of AML, striking a younger age group (median age 31 yr) and particular ethnicity (Hispanics), in which the patient commonly presents with a coagulation disorder.
Remission induction rates range from 50 to 85%. Long-term disease-free survival occurs in 20 to 40% of patients and increases to 40 to 50% in younger patients treated with intensive chemotherapy or stem cell transplantation.
Prognostic factors help determine treatment protocol and intensity; patients with strongly negative prognostic features are usually given more intense forms of therapy, because the potential benefits are thought to justify the increased treatment toxicity. An important prognostic factor is the leukemia cell karyotype. The specific chromosomal rearrangements of the different forms of AML affect the outcome. Three clinical groups have been identified: favorable, intermediate, and poor. Patients who have the cytogenetics t(8;21), t(15;17), and inv(16) typically have a favorable response to therapy, durable remission, and improved survival. Patients with a normal karyotype have an intermediate prognosis, and patients with a poor prognosis are those with a deletion of chromosome 5 or 7, trisomy 8, or a karyotype with > 3 abnormalities. Molecular genetic abnormalities are becoming more important in refining prognosis and therapy in AML. Mutations in Flt3 kinase in particular effect prognosis and are targets for additional therapy. Other negative factors include increasing age, a preceding myelodysplastic phase, secondary leukemia, high WBC count, and absence of Auer rods. The FAB or WHO classification alone does not predict response.
Initial therapy attempts to induce remission and differs most from ALL in that AML responds to fewer drugs. The basic induction regimen includes cytarabine by continuous IV infusion or high doses for 5 to 7 days; daunorubicin or idarubicin is given IV for 3 days during this time. Some regimens include 6-thioguanine, etoposide, vincristine, and prednisone, but their contribution is unclear. Treatment usually results in significant myelosuppression, with infection or bleeding. There is significant latency before marrow recovery. During this time, meticulous preventive and supportive care is vital (see Leukemias: Supportive care).
In APL and some other cases of AML, disseminated intravascular coagulation (DIC) may be present when leukemia is diagnosed and may worsen as leukemic cell lysis releases procoagulant. In APL with the translocation t(15;17), all-trans retinoic acid (tretinoin) corrects the DIC in 2 to 5 days; combined with daunorubicin or idarubicin, this regimen can induce remission in 80 to 90% of patients and bring about long-term survival in 65 to 70%. Arsenic trioxide is also very active in APL.
After remission, many regimens involve a phase of intensification with the same drugs used for induction or with other drugs. High-dose cytarabine regimens may lengthen remission duration, particularly when given for consolidation in patients < 60 yr. CNS prophylaxis usually is not given to adult patients because with better systemic disease control, CNS leukemia is a less frequent complication. In AML patients who have completed consolidation, maintenance therapy has no demonstrated role.
Patients who have not responded to treatment and younger patients who are in remission but who are at high risk of relapse (generally identified by certain chromosomal abnormalities) may be given high-dose chemotherapy and stem cell transplantation. Extramedullary sites are infrequently involved in isolated relapse. When relapse occurs, additional chemotherapy for patients unable to undergo stem cell transplantation is less effective and often poorly tolerated. Another course of chemotherapy is most effective in younger patients and in patients whose initial remission lasted > 1 yr.
Last full review/revision July 2012 by Michael E. Rytting