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Acute Lymphocytic Leukemia

Acute Lymphocytic Leukemia


Introduction
Epidemiology
Etiology
Clinical Features
Laboratory Features and Diagnostic Workup
Classification
Prognosis
Treatment
Survival
Biologic and Prognostic Investigations
References

Introduction

Acute lymphocytic leukemia (ALL) is a malignant disorder resulting from the clonal proliferation of lymphoid precursors with arrested maturation [1]. The disease can originate in lymphoid cells of different lineages, thus giving rise to B- or T-cell leukemias or sometimes mixed-lineage leukemia.

The disease has historic relevance because it was one of the first malignancies reported to respond to chemotherapy [2] and was later among the first malignancies cured in a majority of children [3]. Since then, much progress has been made, not only in terms of treatment, but, importantly, in deciphering the heterogeneity of ALLs.

As information accumulates about molecular aberrations, immunophenotyping, chromosomal abnormalities, and prognostic factors, more rational therapies have been designed. Because most cases are diagnosed in children [4], our current knowledge has originated from studies in the pediatric population. As differences between childhood and adult ALL become apparent, more research is being conducted and progress is being made in ALL in adults.

Epidemiology

Every year, 3,000 to 5,000 new cases of ALL are diagnosed in the United States [5,6]. The median age at diagnosis is 12 years [4], and nearly two thirds of cases are diagnosed in children, in whom it represents the most common malignancy, accounting for approximately one fourth of all childhood cancers [7]. In adults, ALL represents 20% of all leukemias [4] and 1% to 2% of all cancers [8]. ALL has a bimodal distribution with an initial peak incidence at age 3 to 5 years [4,9], affecting 4.4 of 100,000 children. The incidence gradually decreases and remains low until about age 50, when the incidence increases steadily with age and reaches nearly 2 cases per 100,000 persons older than 65 years [10].

Interestingly, the early age-specific peak is absent in some developing countries [11,12]. In all ages, the incidence is higher in males than in females [4,13] and higher in white than in African-American populations [13]. Although the overall incidence has remained stable over the past 10 to 15 years [13,14], it may be increasing in some subgroups, such as white males [13] and children [15].

Etiology

The etiology of ALL is not known, and although several studies have tried to identify risk factors for leukemic development, definite conclusions cannot be drawn [16]. However, some associations, such as genetic, parental, socioeconomic, and environmental factors, must be considered.

Genetic Factors: Reports have identified families with multiple members affected by leukemia [17]. When an identical twin is diagnosed with ALL, the other twin has a significantly higher risk of developing leukemia; as many as 20% of them will be diagnosed with the disease within 1 year [18], but the risk is age dependent, decreasing from nearly 100% for the twins when the index case is diagnosed before the age of 1 year to a risk no different from that in other siblings when diagnosed after the age of 4 years. Siblings of patients with leukemia have a fourfold higher risk of developing leukemia than the general population [19].

Several genetic syndromes have also been associated with leukemia, with the best characterized being Down's syndrome, which accounts for nearly 2% of all ALL cases in children [20]. Other syndromes, such as Bloom syndrome, ataxia telangiectasia, Wiskott-Aldrich syndrome, and Fanconi's anemia, are also associated with an increased risk of leukemia [21,22].

Parental and Socioeconomic Factors: Maternal reproductive history is also important [23]. Children of mothers older than 35 years of age may have an increased risk of leukemia, only partially explained by the increased risk of having Down's syndrome [24]. A history of prior fetal loss, especially if there have been multiple miscarriages, has been identified as a risk factor for the offspring [25]. The association of increased weight at birth and childhood ALL has been reported consistently [23,26]. Parental occupational exposure to such agents as pesticides and benzene may increase the risk of leukemia in offspring, but most of these cases have been acute myelogenous leukemia (AML) [27]. There may also be a higher risk for children with a better socioeconomic status, but this is not universally accepted [28].

Environmental Factors: Exposure to radiation is associated with a definite risk of ALL. In utero exposure increases the risk of ALL over that of control populations [29]. Exposure to low-dose radiation, such as that used in diagnostic radiology, has not been proven to be leukemogenic, but exposure to high doses (like those used in radiotherapy) may be [30,31]. People exposed to radiation during the atomic disasters at Hiroshima and Nagasaki [32,33], as well as people involved in other nuclear exposures [34-36], may have as much as a 10- to 20-fold higher risk of developing leukemia.

Exposure to different chemicals has also been associated with an increased risk of leukemia. The best characterized association involves benzene, although more than two thirds of these cases are AML [37]. The exposure to electromagnetic fields has been repeatedly linked to an increased risk of ALL [38-41], but the evidence is inconclusive.

Several studies have suggested clustering of cases of childhood leukemia. This clustering usually represents a group of cases occurring within a population, whose incidence is higher than that expected for the general population [42]. This clustering of cases has been attributed to the proximity of environmental hazards, such as nuclear plants. However, evidence of this exposure is lacking in most cases. This and other epidemiologic data, such as the increased incidence of common ALL with higher socioeconomic status and isolation, have led to the hypothesis of an infectious etiology for common ALL in children [43,44]. According to this hypothesis, common ALL at childhood peak ages might arise after unusual patterns of exposure to common infectious agents. In more developed societies with better hygiene and fewer social contacts early in infancy, common infections are frequently delayed beyond the first year of life and until a higher level of social contacts is made [43,44].

Clinical Features

The signs and symptoms of ALL reflect the expansion of the leukemic clone in the bone marrow with impairment of normal hematopoiesis and the infiltration of nonhematopoietic tissues by the leukemic cells. The etiology of the suppression of normal hematopoiesis is not clear. Decreased numbers of normal progenitors, deficient production of normal hematopoietic growth factors, and production of inhibitory cytokines by the malignant clone have all been advocated as causes [45,46].

The most common initial symptoms of ALL are attributable to anemia, neutropenia, and thrombocytopenia. They are manifested by fatigue, weakness, fever, weight loss, and bleeding. Frequently, there is no detectable infectious cause of the fever [47], which may be due to ALL itself [48]. The symptoms usually present abruptly but may be misdiagnosed as being related to an infectious process unless a detailed blood and bone marrow study is performed. Patients, especially children, may have severe pain resulting from an overgrowth of leukemic cells in the bone marrow; this most frequently affects the lower sternum and occasionally large joints [49] and sometimes is due to bone marrow necrosis [50,51].

Almost 80% of patients with ALL have lymphadenopathy [49]. Lymph nodes are usually painless and movable. The spleen and the liver are also frequently enlarged, with up to 70% to 75% of patients presenting with hepatomegaly and/or splenomegaly [49]. Even when the liver is infiltrated, liver function is usually preserved. Lymph node, liver, and spleen enlargement is a representation of tumor burden and, therefore, when extensive, correlates with a poor prognosis [52]. Other organs, such as the kidney cortex (in one third of cases), may be involved but usually without functional impairment [49]. Less frequently, the lungs [53], heart [54], eyes [55], and gastrointestinal tract are involved. Skin involvement is seldom seen and is almost always associated with the pre-B-cell phenotype [56].

Central nervous system (CNS) involvement is seen in 5% of children and in less than 10% of adults with ALL. It is often seen among patients with mature B-cell ALL. However, many patients will eventually develop CNS disease if not adequately treated. Leukemia in the CNS presents with symptoms of increased intracranial pressure in 90% of cases, including headache, papilledema, nausea, vomiting, irritability, and lethargy. Signs of meningismus are common, and cranial nerves may also be affected, most frequently nerves III, IV, VI, and VII.

Testicular involvement is clinically evident in 1% of children with ALL at diagnosis, but it may be occult in as many as 25% [57]. The testicles represent a “sanctuary site,” where disease can persist after systemic therapy. The testicles can be a frequent site of relapse, seen in up to 10% to 15% of children in some series [58-61], but this is rare in adults. Disease in the testes presents as painless enlargement and firmness. Although involvement is usually unilateral, bilateral involvement is frequently diagnosed when a biopsy is performed [62]. The disease is characterized by interstitial involvement, but the seminiferous tubules are affected later [62].

Laboratory Features and Diagnostic Workup

The white blood cell (WBC) count is greater than 10,000/µL in 50% to 60% of patients diagnosed with ALL and may be higher than 100,000/µL in 10%. Another 30% to 40% have WBC counts lower than 10,000/µL [63]. Despite high WBC counts, absolute neutrophil counts are frequently low [63]. The presence of blasts in the peripheral blood suggests the diagnosis of acute leukemia, but they are not always present and are not criteria for diagnosis. Despite very high WBC counts, symptoms of hyperleukocytosis are seldom seen [64]. Thrombocytopenia is the rule, with more than 90% of patients presenting with platelet counts less than 150,000/µL and two thirds with less than 50,000/µL [63]. Coagulopathies, including in situ ductal carcinomas, may be seen with ALL at presentation or during therapy [65,66]. Normocytic, normochromic anemia and reticulocytopenia are nearly universal [63]. Occasionally present at diagnosis is hypereosinophilic syndrome with tissue infiltration by eosinophils, which may lead to death from cardiorespiratory failure [67].

Hyperuricemia and high levels of lactate dehydrogenase are common and reflect a large tumor burden, occasionally accompanied by urate nephropathy. Hypercalcemia is occasionally noted at diagnosis, whereas hypocalcemia, hyperkalemia, and hyperphosphatemia may be seen in association with tumor lysis syndrome. One third of patients have low levels of immunoglobulins (Igs), which may be a poor prognostic factor [68,69].

The diagnosis of ALL requires the presence of at least 30% lymphoblasts [71,72] in bone marrow aspirates. The bone marrow is commonly hypercellular with few normal-appearing myeloid and erythroid precursors; rarely, it is hypoplastic or aplastic [73]. The diagnosis of ALL and its differentiation from AML made only on the basis of the morphologic appearance of the blasts are inaccurate, and additional discriminatory studies are needed. The most common way to determine the lymphoid origin of acute leukemia is by identifying its histochemical characteristics.

Histochemical Characteristics and Techniques

Stains: A combination of myeloperoxidase positivity of less than 3% of the blasts and a strong positive expression of terminal deoxynucleotidyltransferase (TdT)(less than 40% of the blasts) is indicative of a diagnosis of ALL. Positivity for TdT is noted in more than 95% of ALL cases [74]. TdT is a nonreplicative DNA polymerase that can elongate DNA chains on a template-independent basis [74]. TdT usually disappears upon lymphocyte maturation but is expressed on lymphoblasts. Patients with mature B-cell ALL are TdT-negative but express B-cell lineage (CD19 and CD20) and mature B-cell markers (surface Ig [sIg], kappa/lambda). TdT staining is not specific for ALL and is expressed in approximately 10% of patients with AML [75].

A periodic acid-Schiff reaction may be positive in 40% to 70% of patients with ALL and represents liberation and oxidation of carbohydrates. Discrete granules can be seen in normal lymphocytes and megakaryocytes, and there is a diffuse positivity in granulocytes and monocytes. Block positivity for periodic acid-Schiff is seen in ALL, whereas diffuse cytoplasmic positivity for periodic acid-Schiff is noted in erythroleukemia.

Acid phosphatase is present in early T-cells, whereas B-cells have weak activity of this enzyme. Therefore, positivity to acid phosphatase, usually demonstrated as focal paranuclear concentrations, can differentiate T-cell ALL from non-T-cell ALL [76].

Lymphoblasts are characteristically negative for myeloperoxidase, Sudan black B, and chloracetate esterase and may occasionally be faintly positive for nonspecific esterase.

Immunophenotype: The identification of differentiation antigens on leukemic cells by monoclonal antibodies has become an important element in the study of ALL. With this technique, the cell lineage can be determined (ie, B- or T-cell), as well as the state of differentiation within each lineage (Table 1), which may be relevant for therapeutic decisions. Knowledge of the immunophenotype can also aid in lineage determination in patients with acute leukemias that are morphologically undifferentiated and of mixed lineage or in patients with biphenotypic leukemias.

Table 1. Expression of Differentiation Markers That Identify ALL Immunophenotype
B-cell lineage HLA-DR CD19 CD24 CD10 CD20 CD21 CD22 CD23 clg slg
Early pre-B-cell + + + + Cytoplasm
Pre-B-cell + + + + + + + +
Transitional B-cell + + + + + + + +a
Mature B-cell + + + + + + + +
T-cell lineage CD7 CD2 CD5 CD1 CD4 CD8 CD3      
Early + + +      
Intermediate + + + +      
Mature + + + + + +      
ALL = acute lymphocytic leukemia
cIg = cytoplasmic immunoglobulin
sIg = surface immunoglobulin 
a Heavy chains but no light chains

Molecular Techniques: These techniques can assist in identifying the clonality of the disease and the lineage of lymphoblasts [77-81]. They take advantage of the normal rearrangement that occurs among the variable, diverse, joining, and constant regions of the Ig and T-cell receptor (TCR) genes. In normal lymphocyte differentiation, these regions rearrange to produce different molecules (Ig and TCR) specific for the myriad antigens with which they will interact. Because each cell can produce an Ig (B-cells) or TCR (T-cells) that is reactive with only one specific antigen, lymphocytes from the peripheral blood of a normal individual show multiple rearrangements [81]. In patients with ALL, the clonal nature of the disorder results in lymphoblasts with the same rearrangement (ie, a clonal rearrangement) [81,82]. However, the results of these molecular studies have to be interpreted with caution because nonspecificity has been identified [83], with 10% to 20% of patients with T-cell ALL showing Ig gene rearrangement [84,85] and an equivalent proportion of patients with B-cell ALL bearing a TCR-beta gene rearrangement and even more frequently TCR-gamma and TCR-delta gene rearrangements [86,87]. A small percentage of patients with AML may have Ig or TCR gene rearrangements [88]. These cross-lineage rearrangements are frequently nonproductive [77,89], but some Ig gene rearrangements are also nonproductive in B-cell leukemias. Except in a few cases [90], light-chain Ig gene rearrangement appears to be more B-cell specific than does heavy-chain Ig gene rearrangements [91].

Electron Microscopy: Although not a routine element of the ALL workup, electron microscopy is a valuable adjunct in the classification of approximately 5% of leukemias that are otherwise undifferentiated. A small group of patients with ALL has cells that show myeloperoxidase positivity on electron microscopic scans. Such patients form an important subgroup, because 85% of them have high-risk ALL [92]. Although 75% of these patients can achieve a complete response with ALL-type induction chemotherapy, the median duration is only 18 months [92].

Diagnostic Workup

When the diagnosis of ALL is suspected, a complete workup should be initiated. It should include (1) a morphologic evaluation of peripheral blood and bone marrow aspirate and biopsy; (2) a histochemical evaluation of blast cells with stains for TdT, myeloperoxidase, esterase, and, in some cases, periodic acid-Schiff, acid phosphatase, and Sudan black B; (3) cytogenetic analysis; and (4) immunophenotypic analysis using B-lineage markers (CD19, CD20, cytoplasmic and surface Igs), T-lineage markers (CD1, CD2, CD3, CD7, CD5, CD4, and CD8), myeloid markers (CD13, CD33, CD14, CD15), common acute lymphocytic leukemia antigen (CALLA)(ie, CD10), the class II major histocompatibility complex antigen (HLA-DR), and CD34. In some difficult cases, additional studies may be required for diagnostic purposes, including molecular studies to identify Ig or TCR gene rearrangements and electron microscopic scans.

Classification

ALL is a heterogeneous group of disorders comprising several subgroups that have distinct clinical and prognostic features. Several attempts to classify ALL have been made. The two most relevant ones are the morphologic and immunophenotypic classifications.

Morphologic Classification

The morphologic classification follows the guidelines defined by the French-American-British Cooperative Working Group [71,72]. It identifies three subgroups of ALL (Table 2): L1, the most common variety in children (85% of cases), is only found in 30% of adults [93,94]; L2, the predominant variety in adults (60% to 70% of cases), is found in less than 15% of children [93,94]; and L3, which is found in less than 5% of cases. Cytoplasmic vacuoles are a prominent feature but are not pathognomonic of L3 ALL [95]. The original French-American-British classification is not always reproducible, and a scoring system has been added to enhance concordance among observers [72].

Table 2. French-American-British Classification of Acute Lymphocytic Leukemia
Type Incidence in adults (%) Incidence in children (%) Characteristics Response
rate (%)
3-year
survival rate
(%)
L1 31 85 Small, homogeneous cells; round nucleus; scanty cytoplasm 85 40
L2 60 14 Large, heterogeneous cells; irregular nucleus, cleft, nucleolus; more cytoplasm 75 35
L3   9   1 Large, homogeneous; regular nucleus; vacuolated, basophilic cytoplasm; Burkitt's lymphoma; poor prognosis 65 10
Adapted, with permission, from Bennett JM, Catovsky D, Daniel M-T.71,72

Immunophenotypic classification

The immunophenotype is a more clinically relevant classification of ALL and is based on the expression of certain antigens on the surface of leukemic cells. Normal lymphocytes express specific antigens in an orderly fashion through their different stages of differentiation [96]. According to Greaves [91], lymphoblasts represent an interruption at different steps of differentiation of normal lymphocytes. Therefore, expression of antigens on the cell surface indicates the specific step in differentiation where transformation occurred. Several classifications have been proposed for normal [97,98] and leukemic [99,100] lymphocytes. Table 3 presents the current immunophenotypic classification of ALL and the frequency of each subtype.

Table 3. Immunophenotypic Classification of Acute Lymphocytic Leukemia
Type Markers Incidence in children (%) Incidence in adults (%) Observations
Early Pre-B Cytoplasmic Ig– 65–70 50–60 Express at least one B-cell marker,
CALLA + or –
Pre-B-cell Cytoplasmic Ig+ 15–20 15–25 Express at least one B-cell marker,
CALLA + or –, worse prognosis than that for early pre-B-cell
B-cell Surface Ig+ < 5 < 5 Extramedullary lymphomatous masses, CNS involvement, hyperuricemia, acute respiratory failure, Burkitt's leukemia
T-cell CD2
CD3
CD5
CD7
CD4
CD8
10–15 20–25 High WBC count, CNS involvement, thymic mass
ALL = acute lymphocytic leukemia
CALLA = common acute lymphocytic leukemia antigen
CNS = central nervous system
WBC = white blood cell

Although this classification is useful clinically, some cautionary notes must be added. The phenotype of the lymphoblasts may not correlate with any normal phenotype, including some cases with simultaneous expression of antigens normally present at different ends of the differentiation spectrum (ie, asynchronous antigen expression) [101], even though some of these lymphoblasts may actually have a rare normal counterpart [102]. Approximately 5% to 10% of children with ALL [103-105] and 30% of adults with ALL [106-108] express myeloid markers. It is not clear whether these cases represent transformation of a pluripotent cell or an as-yet-unidentified progenitor that coexpresses markers and features from several lineages [109,110]. It is clear that no marker is absolutely lineage-specific; in fact, CD19, CD2, and CD4 can be found in at least 50% of patients who have AML with t(8;21), acute promyelocytic leukemia, and AML with monocytic features, respectively [111-113]. Therefore, it has been suggested that two or more markers corresponding to a different lineage must be present to diagnose a mixed-lineage leukemia [105].

Another cautionary factor is the presence of nonlineage-dependent markers. The most common marker is CD10 (ie, CALLA), which is a membrane-bound neutral endopeptidase [114,115] that can be expressed in both B- and T-cell leukemias [116]. CD34 is a marker of a very early pluripotential cell, including the stem cell [117], and is most frequently expressed in non-T-cell, non-B-cell cases of ALL [118]. Coexpression of CD38 on CD34-positive cells is a marker for lineage commitment [119], is present on 20% of normal bone marrow cells as well as activated plasma cells and T-cells, and is a common marker in both T-cell and B-cell leukemias [120]. CD71, another marker of activation, is more common in patients with T-cell than B-cell leukemias [120].

The immunologic classification of ALL also correlates with clinical characteristics, with certain features associated with specific subtypes of B- and T-cells.

Early Pre-B-Cell ALL: Nearly 70% of children and adults with ALL have the early pre-B-cell type [121]. The immunophenotype is characterized by a lack of expression of cytoplasmic or surface immunoglobulins [122]. Patients are frequently young (1 to 9 years old) and have low WBC counts [114,115]. Nearly 50% of patients younger than 1 year old, 10% of older children, and 10% to 40% of adults do not express CD10 [123-125]. Lack of expression of CD10 is associated with pseudodiploidy, high WBC counts, and poor prognosis. CD10-negative early pre-B-cell ALL probably represents a more immature counterpart of CD10-positive early pre-B-cell ALL [126]. More than three fourths of children with pre-B-cell ALL express CD34, a feature frequently accompanied by hyperdiploidy, a low incidence of CNS involvement at presentation, and good prognosis [127,128].

Pre-B-Cell ALL: Approximately 20% of cases of ALL are pre-B-cell ALL, which is identified by the expression of cytoplasmic Ig heavy chains [122,129]; almost all these patients also express CD10 [121]. This subgroup includes more African-American patients than does the early pre-B-cell subgroup. These patients also have higher levels of lactate dehydrogenase and hemoglobin and higher WBC counts. Cytogenetic analysis often reveals pseudodiploidy, frequently associated with the t(1;19) abnormality and cells that are less likely to be hyperdiploid [130-132]. Poor prognostic characteristics and poor outcome are correlated with the t(1;19) abnormality [133]. Other studies suggest that among patients with the t(1;19) abnormality, a pre-B-cell immunophenotype correlates with a worse prognosis than an early pre-B-cell immunophenotype [134].

Transitional Pre-B-Cell ALL: This newly characterized subtype accounts for approximately 1% of all cases of ALL. The hallmark is the expression of µ heavy chains on the surface with no light chains [135]. These patients have L1 or L2 morphology, low WBC counts, and hyperdiploidy; their outcome is better than that of patients with mature B-cell ALL.

Mature B-Cell ALL: Less than 5% of patients have mature B-cell ALL [121], which represents a leukemic phase of Burkitt's lymphoma [136]. Mature B-cell ALL presents with bulky extramedullary disease, including abdominal lymphadenopathy and frequent CNS involvement [137]. Morphologically, mature B-cell ALL often represents the L3 subtype of the French-American-British classification. Some cases of mature B-cell ALL do not show the L3 morphology but, instead, exhibit lymphoma-like features and particular karyotypic abnormalities, such as 6q-, 14q+, t(11;14), or t(14;18).

T-Cell ALL: Nearly 15% to 20% of children [123] and adults [138] have T-cell ALL, but its incidence may decrease with age [139,140]. T-cell ALL is associated with males, high WBC counts, CNS involvement, and mediastinal masses [123,141]; mediastinal masses are associated with mature thymocyte phenotypes [142]. Patients with T-cell ALL with no expression of CD10 have a poor prognosis [116].

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