a. Leukemia results from the clonal proliferation of white blood cells (WBCs). Leukemias can be classified according to the cell line involved (lymphoid or myeloid) and the maturity of the malignant cell (acute [immature blasts] or chronic [mature cells]).
b. Acute leukemia is considered a hematologic emergency, and patients are commonly hospitalized for initiation of chemotherapy, complications associated with the leukemia itself, or adverse events from chemotherapy.
B. Acute Leukemia. Acute leukemia results from a clonal hematopoietic progenitor cell losing its ability to differentiate, while replicating uncontrollably. It is typically diagnosed when 20% or more blasts (immature hematopoietic cells) are seen in either the peripheral blood or bone marrow.
i. Acute lymphoblastic leukemia (ALL). The progenitor cell is a lymphocyte precursor. ALL can be classified according to:
1. Morphology. This is a rarely used system for classification currently.
a. L1 = small lymphoblastic
b. L2 = large lymphoblastic
c. L3 = undifferentiated
2. Immune subtype:
a. B cell: CD19+ and one or two additional B cell markers: CD79a, cytoplasmic CD22, and/or CD10
b. T cell: CD3+ is expressed on either the surface or in the cytoplasm of the lymphoblast
3. Molecular classification using the World Health Organization (WHO) classification system (Box 71.1):
Source: Derived from Arber D, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391–2405.
ii. Acute myeloid leukemia (AML) is diagnosed when the progenitor cell (blast) is a myeloid precursor. AML can be classified according to the microscopic/cytochemical reactivity of the cells (French-American-British [FAB] classification), or by morphologic/cytogenetic information (WHO classification) (Table 71.1). To demonstrate the myeloid phenotype of the blasts, they must have at least one of the following:
1. Demonstrate the appearance of an Auer rod
2. Demonstrate myeloperoxidase expression (by flow cytometry, immunohistochemistry, or cytochemistry)
3. Demonstrate monocytic differentiation with at least two of the following proteins expressed: nonspecific esterase (NSE), CD11c, CD14, CD64, or lysozyme
Table 71.1 Classification of Acute Myelogenous Leukemia
1. AML with recurrent cytogenetic abnormalities including: t(8;21), t(15;17), inv(16) or t(16;16), t(9;11), t(6;9), inv(3) or t(3;3), t(1;22); mutated NPM or biallelic CEBPA gene
Myeloblastic without maturation
Myeloblastic with maturation
2. AML with multilineage dysplasia
3. Therapy-related AML
4. AML not otherwise categorized3
1 Adapted from Bennett JM, Catovsky D, Daniel M-T, et al. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group. Ann Intern Med 1985;103:626–9.
2 Derived from Arber D, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391–405.
3 The subtypes included in this group revert to the corresponding subtypes in the French-American-British (FAB) classifications (M0–M7).
AML = acute myelogenous leukemia; FAB = French-American-British; WHO = World Health Organization.
i. ALL represents 80% of childhood cases of acute leukemia (peak age: 2–5 years) and approximately 10–20% of adult cases. About 85–90% of cases of childhood ALL have an FAB L1 classification.
ii. AML represents approximately 80% of adult acute leukemias; the average age at onset is 67 years.
iii. Acute leukemia of ambiguous lineage, including mixed phenotype acute leukemia (MPAL) represents another 2–20% of adult cases; this immunophenotype has features of both ALL and AML.
c. Risk factors for acute leukemia include prior radiation or chemotherapy for a malignancy, chemical exposures (e.g., benzene), prior myelodysplastic or myeloproliferative neoplasms, aplastic anemia, congenital chromosomal disorders (e.g., Down’s syndrome, Turner’s syndrome, Klinefelter’s syndrome), and congenital bone marrow failure disorders (e.g., Fanconi’s anemia). In most cases, however, no obvious predisposing condition is found.
d. Clinical manifestations of acute leukemia. Patients usually seek medical attention within days or weeks of the start of their illness. The pathologic processes outlined here (particularly pancytopenia) give rise to the most common findings on presentation.
i. Pancytopenia may result in petechiae, fatigue and pallor, or clinically apparent infections (e.g., cellulitis, pneumonia).
ii. Blast cell proliferation and invasion
1. ALL. Bone pain, arthralgias, lymphadenopathy, and hepatosplenomegaly are common with ALL. Central nervous system (CNS) involvement is more frequent in ALL than in AML, and patients can present with cranial nerve palsies.
2. AML. Bone pain is common; adenopathy is rare. AML subtype M4 or M5 per FAB is associated with gingival, skin, and, less frequently, CNS involvement.
iii. Leukostasis (i.e., vasoocclusion by WBCs) may occur with a leukocyte count as low as 50,000–75,000 cells/μL but is more frequently seen with WBC counts greater than 100,000 cells/μL. Leukostasis is much more common in AML than ALL. CNS disorders (headache, stroke) and pulmonary findings (dyspnea, hypoxemia) are common manifestations of leukostasis.
iv. Disseminated intravascular coagulation (DIC) may occur in all acute leukemias but especially with acute promyelocytic leukemia (APL), also called AML FAB-M3 or [t(15;17)] per WHO.
M3 causes DIC.
e. Approach to the patient
i. Laboratory studies
1. Complete blood count (CBC). Pancytopenia is usually present but may also be found in a variety of other disorders (see Chapter 59). Alternatively, the patient may present with leukocytosis, anemia, and thrombocytopenia.
2. Peripheral blood smear
a. Blasts are usually, but not universally, found on the peripheral blood smear.
b. Auer rods, eosinophilic rods in the cytoplasm of blasts, are pathognomonic for a myeloid neoplasm. FAB-M3 AML often contains multiple Auer rods (an historic term is faggot cell).
3. Coagulation tests. If DIC is present, a prolonged prothrombin time (PT) and partial thromboplastin time (PTT), decreased fibrinogen level, and elevated levels of fibrin degradation products (D-dimer) may be seen.
4. Electrolyte panel. Metabolic abnormalities may result from spontaneous tumor lysis syndrome or, more commonly, with therapy-induced tumor lysis. High cell turnover and lysis can result in hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, and/or acidosis. Daily monitoring for these changes is important in patients with comorbid conditions and at the initiation of chemotherapy.
5. Cerebrospinal fluid (CSF) analysis may show abnormalities in patients with leukemic meningitis, which is most often associated with ALL.
ii. Radiography. A chest radiograph may show an anterior mediastinal mass in patients with ALL (especially T-cell ALL).
iii. Bone marrow biopsy. The diagnosis of acute leukemia relies on the presence of 20% or more blasts in the peripheral blood or bone marrow. Morphology, immunohistochemical stains (e.g., peroxidase, periodic acid–Schiff [PAS]), surface markers (e.g., CD markers), and cytogenetics can all help determine whether the leukemia is ALL or AML, as well as aiding in the choice of treatments and counseling the patients on their prognosis.
1. ALL is divided into B cell or T cell ALL. Most commonly, flow cytometry is used to assess for the expression of lymphoid-associated proteins on the surface or in the cytoplasm of the blasts. T cells must express CD3either inside the cell or on the surface. There is no single B cell lineage marker. CD19 expression is used along with additional B-associated proteins (CD79a, cytoplasmic CD22, and/or CD10) to define this lineage.
2. AML can be defined by the presence of Auer rods, myeloperoxidase (MPO) expression, or evidence of monocytic differentiation by flow cytometry with the expression of at least two of the following proteins: nonspecific esterase (NSE), CD11c, CD14, CD64, or lysozyme.
3. Cytogenetics are critical in determining the prognosis of both AML as well as ALL. Specific translocations can also be identified by fluorescence in situ hybridization (FISH) or occasionally by polymerase chain reaction (PCR) testing.
a. Specific chromosomal changes are associated with individual diagnoses. FAB-M3 AML is associated with the PML-RARα translocation involving chromosomes 15 and 17 [t(15;17)], and the translocations t(8;21) and inv(16) are pathognomonic for AML.
b. Poorer responses to therapy and higher risks for relapse occur with specific chromosomal alterations.
c. Additionally, specific changes alter treatment decisions:
i. t(15;17) in AML often warrants addition of all-trans retinoic acid (ATRA) and potentially arsenic trioxide to the patient’s therapy.
ii. t(9;22) in ALL or AML often leads to addition of an oral tyrosine kinase inhibitor like imatinib (Gleevec).
i. Types of therapy
1. Induction chemotherapy is intensive, usually kills more than 99.9% of leukemic cells, and is meant to induce a complete remission (CR). A patient is in CR if there are fewer than 5% blasts in the bone marrow, no blasts in the peripheral blood, no evidence of extramedullary disease, normal cytogenetics, and normalization of the blood counts (neutrophil count >1000 cells/µL and a platelet count >100,000 cells/µL).
2. Consolidation therapy is usually needed to prevent relapse.
3. Maintenance therapy, which entails lower doses of antimetabolites, may be indicated and is often continued for several years (only in ALL).
ii. General approaches to therapy
i. Induction chemotherapy (usually a combination of daunorubicin vincristine, and prednisone) can induce a CR in most patients with ALL.
iii. CNS prophylaxis with cranial irradiation and/or intrathecal chemotherapy is usually administered after remission because leukemic meningitis is a common site of relapse in up to 30–50% of patients who do not receive prophylactic therapy. This rate is reduced to less than 5% for those receiving prophylactic therapy.
iv. Late intensification/maintenance therapy is often given for 2–3 years.
b. Bone marrow transplantation. With standard therapy, approximately 70–95% of children and 50% of adults will be cured. These rates are comparable to those observed with allogenic transplantation during the first remission, so bone marrow transplantation is usually reserved for patients with poor prognostic features (high-risk cytogenetics or primary refractory disease) or for relapsed patients who achieve a second remission.
i. Induction chemotherapy, with an anthracycline (e.g., daunorubicin or idarubicin) and cytarabine, given over 3 days and 7 days, respectively (the “3 + 7” regimen) produces a CR in approximately two-thirds of patients, but less than one-half are cured.
ii. CNS prophylaxis. Patients with symptoms suggestive of leukemic meningitis undergo a CSF evaluation to rule out leukemic meningitis. The use of prophylactic CNS therapy varies but is rare.
iii. Consolidation therapy is required to prevent systemic relapse. This typically involves abbreviated cycles with the same agents used in induction or high-dose cytarabine alone. Individuals older than 60 years may not benefit from consolidative therapy because of higher risk for complications from the therapy. In contrast to the management of ALL, maintenance therapy is not indicated except in acute promyelocytic leukemia (FAB M3).
iv. ATRA is used for FAB M3 AML. These leukemic cells bear a characteristic translocation [t(15:17)] involving the retinoic acid receptor α gene. ATRA induces differentiation in M3 AML and improves both initial remission rates and overall survival. Likewise, arsenic trioxide also induces terminal differentiation of promyelocytic blasts. Arsenic and ATRA are often used together in the treatment of APL.
b. Allogeneic bone marrow transplantation may be preferable after the first remission in patients with poor-risk AML because cure rates may be increased.
C. Complications Associated with Acute Leukemia
a. Leukostasis with symptoms is more common in patients with AML than those with ALL and may necessitate emergent leukapheresis.
b. Tumor lysis syndrome may occur de novo or with the initiation of therapy. Preventive and therapeutic measures usually include aggressive IV hydration and allopurinol therapy (to facilitate the excretion of uric acid). Rasburicase can be given to acutely lower uric acid levels in those with a high risk for TLS or in those with acute renal injury requiring rapid correction.
d. DIC is frequently seen in acute promyelocytic leukemia. Close monitoring of fibrinogen levels, coagulation parameters (PT and PTT), and platelet levels along with strict blood product replacement is required.
e. Fever and neutropenia. The risks associated with neutropenia are highest when the absolute neutrophil count is less than 500 cells/μL. Neutropenic precautions should be taken (see Chapter 59). Patients should be thoroughly evaluated for the source of their fever (see Chapter 48), and broad-spectrum anti-pseudomonal beta-lactam intravenous antibiotics that cover gram-positive and gram-negative bacteria should be instituted as soon as blood cultures are drawn.
f. Complications associated with bone marrow transplant
i. Graft-versus-host disease (GVHD) may accompany an allogenic bone marrow transplantation. The perceived benefit of an allogeneic transplantation is likely due to a graft-versus-leukemia effect, but there is no way to quantify this effect.
1. Acute GVHD is typically seen within the first 100 days after transplantation and may be manifested by a rash, diarrhea, shortness of breath, or liver enzyme abnormalities. Immunosuppression with various combinations of medications, including methotrexate, cyclosporine, tacrolimus, and/or mycophenolate, is used to suppress acute GVHD.
2. Chronic GVHD can be manifested by skin changes, joint changes, dry eyes and mouth, and chronic shortness of breath. This is often treated with prolonged immunosuppression.
ii. Pneumocystis jiroveci pneumonia (PCP) is usually treated with trimethoprim/sulfamethoxazole (TMP/SMX).
iii. Cytomegalovirus (CMV) infections are increasingly recognized as complications of chemotherapy-induced immunosuppression and are actively screened for by reverse transcriptase PCR in previously exposed patients. Treatment is commonly with valganciclovir.
iv. Herpesvirus infections, including herpes simplex virus and varicella-zoster virus reactivations, may be prevented and/or treated with either oral or intravenous acyclovir or oral valacyclovir.
v. Fungal infections, including aspergillosis and candidiasis, confer an especially poor prognosis. Infections may be prevented or treated with fluconazole, itraconazole, voriconazole, or posaconazole.
Suggested Further Readings
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391.Find this resource:
Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013;381:1943–55.Find this resource:
Litzow MR, Ferrando AA. How I treat T-cell acute lymphoblastic leukemia in adults. Blood 2015;126:833.Find this resource:
Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–21.Find this resource: