Acute Lymphocytic Leukemia

Introduction Epidemiology Etiology Clinical FeaturesLaboratory Features and Diagnostic Workup ClassificationPrognosisTreatmentSurvivalBiologic and Prognostic InvestigationsReferences

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.

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].

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.

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].

Prognosis

Several prognostic factors have been identified for children [143-145] and adults [146-148] with ALL, and risk categories have been defined to guide therapy. Some of the better-defined prognostic factors include age, WBC count, and cytogenetic characteristics and abnormalities.

Age: Infants younger than age 1 and children older than age 10 have a worse prognosis than patients 1 to 9 years old [143,145,149]. Adults have a worse prognosis than children, with the worst outcome associated with patients older than age 60 [146,147,150]. The poor outcome in infants may be related to the frequent occurrence of other poor prognostic features in this group, including higher WBC counts; higher incidences of hepatomegaly, splenomegaly, and CNS involvement at diagnosis; CD10-negative disease [143]; and abnormalities in band 23 of the long arm of chromosome 11 in approximately 70% of patients [151-153]. Infants without 11q23 rearrangements may have an outcome comparable to that of children 1 year old or older [152].

WBC Count: The WBC count at presentation is a highly significant prognostic variable. Patients with counts higher than 10,000/µL have a worse prognosis [145]. The cutoff at which a good prognosis is defined in children varies in different centers [154], but WBC counts higher than 50,000/µL are clearly associated with a poor outcome [126,154], and this value has been proposed by a National Cancer Institute (NCI)-sponsored workshop as the value with which to identify pediatric patients with a poor prognosis [154]. In adults, WBC counts are also an important prognostic factor for both the achievement [147] and duration [146,147,155] of a complete remission. The cutoff value for adults is not clear but is probably lower than that for children, ranging from 5,000 to 50,000/µL [155].

Cytogenetic Characteristics: Cytogenetic characteristics are probably the most important prognostic factor for ALL [156]. Cytogenetic abnormalities can be numeric or structural [157,158], as shown in Table 4. In children, ploidy is the most important prognostic factor [159-161]. Patients with hyperdiploid ALL, in particular those with more than 50 chromosomes, have the best prognosis [162-164]. When analyzed by DNA index (ie, DNA content in leukemic cells vs that in normal cells), patients with an index higher than 1.16, which corresponds approximately to more than 50 chromosomes, have a better prognosis, with almost 90% of patients' having an event-free survival duration of 4 years [159]. The favorable outcome in patients with hyperdiploid common ALL may be due to an increased sensitivity to drugs, such as asparaginase (Elspar), mercaptopurine (Purinethol), cytarabine, and methotrexate [165].

Hyperdiploidy is present in 25% to 30% of children with ALL [145] but in only 10% to 20% of adults. The index classification should be accompanied by regular cytogenetic analysis, because hyperdiploidy alone does not provide information on additional structural abnormalities and when they are present (as in 60% of hyperdiploid cases), the prognosis is not as good as when only the numeric abnormality is present [166]. Patients with a DNA index higher than 1.16 usually present with good prognostic features (ie, age 1 to 9 years, low WBC counts, early pre-B-cell phenotype).

Patients with high-risk features should be treated as good risks if hyperdiploid [154]. Hyperdiploid patients with nearly tetraploid cells (approximately 1% of all cases) [145,167,168] and patients with 47 to 50 chromosomes (ie, a DNA index between 1 and 1.16)(15% of all cases) [145] have an intermediate prognosis [163]. Patients with near tetraploidy are older and have a T-cell phenotype [169]. Patients with 47 to 50 chromosomes often have additional chromosomes 21, X, 8, and 10 and in 76% of cases also have additional structural abnormalities [170]. When trisomy 21 is the sole chromosomal abnormality, patients may have a particularly good prognosis, in part because of the association with other good prognostic features [171].

Hypodiploid cases, most frequently from loss of chromosome 20 [172,173], represent 6% of all cases of ALL [145]. Although these patients commonly present with good prognostic features, they have an intermediate prognosis [173]. Patients with near-haploid ALL (less than 1% of all cases [145]) have a very poor prognosis [174-176]. Of all patients, 8% to 10% have a normal diploid karyotype [145], but the frequency is as high as 30% in patients with T-cell ALL [177]. The prognosis of disease with a normal karyotype is intermediate [163]. Numeric chromosomal abnormalities (hyper- and hypodiploid) are less common in adults and have much less impact on outcome in adults than they do in children [164]. Adults with diploid ALL may have the best prognosis [164].

A large percentage of patients have pseudodiploid ALL [145,164]. Overall, these patients have a poor prognosis. Some of the specific abnormalities observed in patients with pseudodiploid ALL are discussed.

Chromosomal Abnormalities: Translocation t(9;22)(q34;q11) or Philadelphia (Ph) chromosome is present in less than 5% of children with ALL [178-180] but is found in 15% to 30% of adults with ALL [147,164,181]. The incidence may be higher with more sensitive techniques; molecular studies for Ph-related abnormalities are positive in up to 30% of adults with ALL [182,183]. Ph-positive ALL is associated with older age, high WBC counts, and L2 morphology [179,181]; in adults, it is also associated with a higher frequency of expression of CD10 and CD34 [181]. Nearly one half of all patients with Ph-positive ALL may have additional chromosomal abnormalities, particularly monosomy 7 [184].

At the molecular level, the Ph chromosome in ALL may be different from the one seen in patients with chronic myelogenous leukemia (CML). In ALL, it involves band 34 of the long arm of chromosome 9, splicing the proto-oncogene c-abl to band 11 of the long arm of chromosome 22 in the bcr gene [185]. In 50% to 80% of cases of ALL, the breakpoint in 22q11 falls between exons b1 and b2 of the major breakpoint cluster region [186], as opposed to between b2 and b3 or b3 and b4 in CML [185]. This translates into a different protein product of only 190 kDa (p190BCR/ABL) compared with that of CML (210 kDa, p210BCR/ABL) [185,186]. Both proteins have increased tyrosine kinase activity [187]. Protein p190BCR/ABL can induce acute leukemia in transgenic mice [188] and may have a comparatively higher transforming potential than p210BCR/ABL [189]. Of adults with Ph-positive ALL, 20% to 50% express p210 rather than p190 [183]; some of these patients may have a blastic phase of a previously unrecognized CML [190].

The outcome of patients with Ph-positive ALL is poor, with significantly low complete remission rates (75% in children and 50% to 70% in adults) [179,180], and long-term disease-free survival rates (less than 10%) [179,181,182].

Translocations t(8;14), t(8;2), and t(8;22) are present in most cases of mature B-cell ALL [191] and Burkitt's lymphoma [192]. The proto-oncogene c-myc present in band 24 of the long arm of chromosome 8 is juxtaposed to an Ig locus, most frequently the heavy chain (chromosome 14q32), but sometimes to the light chains kappa (2p12) or lambda (22q11) [193]. This results in overexpression of MYC [194], a transcription factor that interacts with other proteins (MAX and MAZ) and binds to DNA [195]. In transgenic mice, overexpression of c-myc driven by Ig enhancers induces lymphoid malignancies [196]. As previously mentioned, mature B-cell leukemia represents less than 5% of all cases of ALL [121], is characterized by early CNS involvement and extramedullary disease, and carries a poor prognosis with conventional chemotherapy [137]. However, recent short-term dose-intensive regimens have significantly improved the outcome for patients with mature B-cell ALL [197-202].

Translocation t(4;11) and other abnormalities in band 23 of the long arm of chromosome 11 (11q23) have become a focus of attention because an increasing number of patients being treated for ALL and other malignancies are developing the 11q23 abnormality that causes AML [203-206]. ALL with 11q23 abnormalities may present de novo and is seen in approximately 5% of children with ALL and less often in adults [207]. Patients with 11q23 abnormalities are frequently young and African-American, have high WBC counts [207-208], are CD10 negative, and have early pre-B-cell disease [209], and myeloid features. It is the most common chromosomal abnormality in infants with ALL [210], affecting more than 70% of cases at the molecular level [211]. Translocation t(4;11) carries a poor prognosis, but infants who do not have this chromosomal abnormality may have an outcome comparable to that of intermediate-risk childhood ALL; infants with 11q23 rearrangements have a 3-year event-free survival rate of 13%, compared with 67% for infants without this rearrangement [212]. The 11q23 abnormality codes for a gene called MLL or ALL-1 [213-214]. It has an unknown function, but the fact that it is frequently involved in mixed-lineage and myeloid leukemias suggests that it plays a role in lineage differentiation.

Translocation t(1;19) is the most common (5% of cases) translocation in children with ALL [215-217] but is uncommon in adults. This translocation is frequently associated with a pre-B-cell immunophenotype [132,218]. Patients with this abnormality exhibit other poor prognostic factors (high WBC count and high lactate dehydrogenase level) and have a poor prognosis [132]. At the molecular level, translocation t(1;19) results in the fusion of E2A, an immunoglobulin enhancer-binding protein coded for in chromosome 19p13, with PBX, a homeobox protein that binds to DNA and is probably a transcription activation factor, coded for in chromosome 1q23 [219,220]. This results in the constitutional expression in pre-B-cells of a gene (PBX) that is normally not expressed in these cells.

Regions 14q11 and 7q35 contain the loci for the alpha/delta and beta TCR gene, respectively. They are rearranged in patients with T-cell ALL [221-226]. The most common of these abnormalities is t(11;14)(p13;q11)(present in 7% of patients with T-cell ALL) [177,229], which fuses the TCR alpha/delta to a gene called rhombotin 2 (Ttg2) [227,228]. A less common translocation, t(11;14)(p15;q11), present in only 1% of patients with T-cell ALL [229], affects rhombotin 1 (Ttg1) [230]. The rhombotin (Ttg) family of genes is involved in transcription regulation by means of a LIM-domain-mediated protein interaction, which, in turn, could prevent transcription activation by LIM-domain protein partners [231]. Other partner genes for TCR alpha/delta include HOX11 in t(10;14), a homeobox gene [232,233] that binds DNA and activates gene expression; TAL1/SCL in t(1;14), a basic helix-loop-helix protein that binds DNA and can control transcription either directly or by dimerization with other DNA-binding proteins [234-236]; and c-myc in a t(8;14) [237-238]. Translocations affecting TCR beta are less common [237,238,240]. Partner genes involved in these translocations include TAL2, similar to TAL1/SCL, in t(7;9)(q34;q32) [241]; LYL1 in t(7;19), analogous to TAL2 [234-236]; Ttg2 in t(7;11); and TAN1 in t(7;9) [242].

Another abnormality found in the short arm of chromosome 9 occurs in 7% to 12% of children [243,244] and adults with ALL. This abnormality identifies a group of patients with high WBC counts, older age, T-cell immunophenotype, a high rate of extramedullary relapse [245], and poor outcome. It affects 9p21-22, which contains the alpha and beta interferon (IFN-alfa and -beta) genes [246]. Abnormalities in 6q occur in 6% of cases [164], and their clinical and prognostic significance is uncertain [247]. The short arm of chromosome 12 is affected in 10% of cases of ALL in children [248], usually of B-cell lineage, but there is great heterogeneity of the specific change. Patients with this abnormality may have a high incidence of CNS relapse [249]. Mutations of N-ras have been detected in 6% of children with ALL, clustered in codons 12 and 13, and may be a poor prognostic feature [250].

Immunophenotype: Patients with T-cell ALL have a historically poor outcome, with a 5-year event-free survival rate of 50% in children [251] and 10% to 20% in adults. Recent studies have shown a similar or better outcome compared with that of other immunophenotypes [146,147], probably from the inclusion of cyclophosphamide (Cytoxan, Neosar) and cytarabine in the treatment of this subgroup of patients [252,253]. Within the T-cell phenotype, patients with the pre-T-cell phenotype (CD7+, CD2–, CD1–, CD4–, CD8–) have a worse prognosis. CD10– T-cell ALL also carries a poor prognosis [233].

Mature B-cell ALL is also associated with a poor prognosis. The introduction of hyperfractionated cyclophosphamide, high-dose methotrexate, and cytarabine has significantly improved the results, both in children [137,254] and in adults [197]. The best prognosis among B-cell-lineage ALL is associated with the early pre-B-cell phenotype, particularly when it is associated with CD10 [122,123].

The expression of myeloid markers has been difficult to evaluate as a prognostic factor, mostly because of different diagnostic criteria. Wide variations in the incidence of myeloid markers (from less than 20% to more than 40%) have been reported, most commonly in adults. Some investigators have reported an associated poor prognosis [255], especially when adjusted for other poor prognostic factors [108], but others have not [256,257].

Other Prognostic Factors: CD34 expression has been correlated with a favorable outcome in children with the pre-B-cell phenotype [258] but has not in adults [256]. Expression of MDR (multidrug resistance)-associated protein P170 has also been reported to confer a poor prognosis for both children and adults [259]. Patients with MDR-positive ALL at diagnosis had lower complete response rates, higher relapse rates, and shorter survival than MDR-negative patients [259]. Males and African-Americans may have a worse prognosis [260,261]. Although not a feature that can be evaluated at diagnosis, a late response to therapy is a poor prognostic feature for all age groups [146,147,262,263].

Prognostic Models: With all these risk factors, several prognostic models have been proposed. In children, an NCI-sponsored workshop has used age and WBC counts to define risk [154]. Patients aged 1 to 9 years with a WBC count lower than 50,000/µL represent 68% of all children with B-cell-precursor ALL, and they have a 4-year event-free survival rate of approximately 80%. Patients older than age 10 or who have WBC counts higher than 50,000/µL have a 4-year event-free survival rate of approximately 64% [154]. Moreover, there is a strong correlation between age and WBC counts. Almost 50% of infants have WBC counts of at least 50,000/µL, whereas less than 20% of older children have WBC counts this high [143], and 50% have counts lower than 10,000/µL [143,144]. Twenty-five percent of all adults have WBC counts higher than 50,000/µL.

Several prognostic models with similarities have been proposed for adults with ALL and are summarized in Table 5. High risk is associated with the majority of cases of adults with ALL. Hoelzer et al identified a time to complete response of longer than 4 weeks, age older than 35 years, WBC count higher than 30,000/µL, and a null ALL phenotype as poor prognostic features [146]. Patients with none of these features (27% of cases) have a 5-year remission rate of 62%, compared with 28% for patients with at least 1 of these features [146]. Ph-positive ALL identifies a definitely poor prognostic group, whereas the prognosis of mature B-cell ALL is changing; favorable outcomes (complete response rates of 80% to 90% and long-term disease-free survival rates of 40% to 60%) have been reported with the use of recent short-term, dose-intensive regimens. The cutoff for WBC count depends on whether the particular model incorporates older age as a poor prognostic factor, because an inverse correlation is noted between age and WBC count. In the model by Hoelzer et al, age older than 35 years (more than 50% of patients) is a poor prognostic factor; thus, the cutoff for WBC count is high (30,000/µL). In a model from the University of Texas M.D. Anderson Cancer Center (Table 5), age is not a poor prognostic factor, and so the cutoff for WBC count is lower (5,000/µL) [155].

Treatment

Modern therapy has changed the outcome for patients with ALL. In children, ALL is now a highly curable disease, with cure rates ranging from 60% to 85%. Therapy for ALL in adults has followed the lead of that for children. Approximately 75% of adults with ALL (range, 65% to 90%) achieve a complete remission, but despite significant progress in the past 30 years, only 20% to 40% are cured [264-266]. Therapy for ALL includes induction, consolidation, maintenance, and CNS prophylaxis. The different phases are discussed separately, because modifications in each phase have been attempted and have resulted in improved outcome.

Induction Therapy

The first combination successfully used for induction chemotherapy in adults with ALL included vincristine (Oncovin) and corticosteroids, most frequently prednisone [267-268]. With this combination, 40% to 60% of patients achieved a complete response, but the median remission duration was only 3 to 7 months. Anthracyclines were then incorporated into this combination, and the complete response rate improved to 85% (range, 70% to 85%) compared with 47% without anthracyclines (P = .003) [269]. This triple combination has become standard for induction of remission in adults with ALL. Doxorubicin (Adriamycin, Rubex) and daunorubicin (Cerubidine) are the commonly used anthracyclines and have produced similar results [269,270]. Mitoxantrone (Novantrone) may also be effective [271]. Among the corticosteroids, prednisone and methylprednisolone are the most frequently used agents; dexamethasone penetrates the CNS-blood barrier better and exhibits better in vitro antileukemic activity [272]. This triple-drug induction combination chemotherapy is associated with a low induction mortality rate of approximately 10% or less.

Other chemotherapeutic agents, including cyclophosphamide, asparaginase, cytarabine, and, less frequently, etoposide (VePesid), teniposide (Vumon), and amsacrine, have been incorporated into induction regimens in an attempt to improve the rate and duration of complete response. The benefit from these modifications is difficult to determine, but overall results seem equivalent to those with vincristine, anthracyclines, and corticosteroids.

In one study, half of the patients who received induction therapy with vincristine, asparaginase, daunorubicin, and corticosteroids were randomized to receive additional cyclophosphamide induction. The complete response rate was 84% for both arms, and the continuous complete response rates at 3 years were also similar (47% vs 43%) [273]. In another study, the addition of cyclophosphamide may have improved the outcome for patients with T-cell ALL [274]. The addition of high-dose cytarabine to the induction regimen has not improved the results and has been associated with increased toxicity and induction mortality rate [275]. Cytarabine at lower doses, together with thioguanine and daunorubicin, has been added to vincristine and prednisone, resulting in a complete response rate of 91%, but the median remission duration was only 15 months [276]. Cytarabine during induction therapy may selectively improve the outcome in T-cell ALL [277]. Asparaginase has been added to induction therapy with no improvement in complete response rates [277-280], but remission duration may be prolonged in children [281]. In one study, asparaginase replaced anthracyclines in the induction regimen, resulting in a similar outcome but with the potential benefit of decreased cardiotoxicity [282]. Using methotrexate instead of anthracycline produced equivalent results [283].

More intensive regimens with growth factor support may induce rapid reductions in tumor burden and a potentially better outcome [284]. Preliminary results with such an approach are encouraging [198,285]. The duration of neutropenia may be shortened by using growth factors [285,286], but there is the potential risk of growth factors stimulating the growth of leukemic cells [287].

Some subsets of patients require a different induction approach. The improved outcome with cytarabine and cyclophosphamide for patients with T-cell ALL has been mentioned [146,147,274,277]. In patients with mature B-cell ALL, the use of hyperfractionated cyclophosphamide alternating with high-dose methotrexate and cytarabine has resulted in cure rates of 50% to 60% in children and in small series of adults [197-202].

Consolidation Therapy

The use of intensive consolidation has demonstrated its value in children with ALL. High-dose methotrexate [288], sometimes in combination with mercaptopurine [289,290] or teniposide and cytarabine [291], and asparaginase [281] have significantly contributed to increasing the cure rate to 70% to 80% in children with ALL. Delayed intensification has also improved the outcome in children with ALL [292], but it is difficult to demonstrate this benefit in adults. Some studies have failed to demonstrate that consolidation improves results [293], whereas others conclude that it does improve outcome [266]. This discordance may be due to the difficulty in assessing the specific value of individual components or phases of overall treatment.

Some of the most effective regimens reported in the literature have included some form of consolidation, but its intensity varied from asparaginase alone [280], to combinations including cyclophosphamide, cytarabine, mercaptopurine, and methotrexate [146,147,156]. These studies have resulted in median remission durations of 20 to 24 months and 3-year survival rates of 35% to 45%. One study randomized 61 patients to receive 3 monthly consolidation courses with doxorubicin, cytarabine, and asparaginase vs no consolidation and documented a 3-year disease-free survival rate of 38% and 0%, respectively [294].

Other studies raised questions as to the benefit of this approach. The European Organization for Research and Treatment of Cancer randomized patients to receive a 3-month consolidation schedule with methotrexate, cytarabine, and thioguanine vs maintenance therapy after the induction of complete remission. No difference in the disease-free survival rate between the two groups was found [295]. Similarly, the Cancer and Leukemia Group B randomized patients after induction to receive two courses of cytarabine and daunorubicin vs maintenance with mercaptopurine and methotrexate. The duration of complete remission and the overall survival rate were similar for both arms [296]. There are important limitations in these studies, including (1) the limited time and intensity of the consolidation drugs used in these patients and (2) the use of schedules that did not include some of the most effective agents for consolidation in children with ALL, such as high-dose methotrexate and mercaptopurine, high-dose asparaginase, and cyclophosphamide with cytarabine.

High-dose cytarabine may be beneficial in some patients. Rohatiner et al found a trend for improved remission duration using high-dose cytarabine consolidation in patients with high blast-cell counts or T-cell morphology [277]. A German multicenter study used high-dose cytarabine with mitoxantrone for intensification in high-risk patients and found a continuous complete response rate at 4 years of 43%, compared with 23% for patients not receiving this therapy [297]. However, older patients were frequently not offered the high-dose therapy, and the difference in results may be at least partially explained by the presence of higher-risk patients in the control arm [297]. The Eastern Cooperative Oncology Group used high-dose cytarabine consolidation without improvement in outcome. However, some patients received very short induction regimens, and no patients received maintenance with mercaptopurine and methotrexate [298].

Therefore, consolidation may be beneficial when adequate drugs at adequate doses are used. Some subsets of patients may benefit from specific agents (ie, patients with T-cell ALL from cyclophosphamide and cytarabine and patients with Ph-positive ALL or patients in high-risk groups from high-dose cytarabine).

Maintenance Therapy

Studies in children with ALL have established the value of maintenance therapy. This usually consists of mercaptopurine and methotrexate and is continued for 2 years. There is evidence that when adequate levels of these drugs are not achieved, the outcome may be as poor as when no maintenance is attempted [299-300]. Maintenance therapy with mercaptopurine and methotrexate-based regimens has also been used in adults with ALL [146,147,155,280,301], but the schedules have varied. Some schedules have used relatively intensive maintenance, with regimens including high-dose methotrexate, daunorubicin, mercaptopurine, and prednisone [155] or with vincristine, prednisone, doxorubicin, mercaptopurine, oral methotrexate, dactinomycin (Cosmegen), cyclophosphamide, and carmustine (BiCNU) [301]. Others have used simpler regimens with oral mercaptopurine and methotrexate reinforced by monthly doses of vincristine and prednisone and occasionally the addition of doxorubicin, or carmustine and cyclophosphamide [147,280].

A few studies have omitted maintenance therapy altogether. The Cancer and Leukemia Group B used four intensification courses with several agents, including cytarabine, mercaptopurine, methotrexate, and asparaginase, but used no drugs for maintenance [272]. The median remission duration for these patients was only 11.2 months [271]. The Eastern Cooperative Oncology Group used consolidation therapy with high-dose cytarabine and methotrexate, asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone without maintenance therapy and showed a 4-year disease-free survival rate of only 13%, with a median remission duration of 9.6 months [298]. One study from Italy randomized patients to receive conventional maintenance therapy or a more intensive schedule with mercaptopurine and methotrexate, alternating with the same drugs for consolidation therapy. No difference in disease-free survival was observed [302]. Therefore, conventional maintenance therapy with mercaptopurine and methotrexate could be as effective as more intensive regimens.

Maintenance therapy with mercaptopurine and methotrexate is not needed in patients with mature B-cell ALL, who are usually treated with dose-intensive therapy for 3 to 8 months, which results in disease-free survival rates of 40% to 60%. Patients with Ph-positive ALL probably do not benefit from maintenance therapy with mercaptopurine and methotrexate. Alternative investigations studying the use of IFN-alfa, high-dose cytarabine, immunomodulation, dose-intensive chemotherapy with autologous stem-cell transplantation with or without purging, and gene-targeted therapy are warranted in patients for whom allogeneic bone marrow transplantation (BMT) is not feasible in first complete remission.

CNS Prophylaxis and Treatment

Disease involving the CNS is present at diagnosis in only 5% of children and adults [303,304]. Without adequate prophylaxis, disease in 50% to 75% of patients with ALL will eventually involve the CNS [305,306]. CNS prophylaxis has reduced the incidence of relapses in the CNS to less than 10% [212].

Different approaches have been used as prophylaxis for CNS disease, including cranial irradiation and intrathecal (IT) chemotherapy with methotrexate and cytarabine [307-309], and are now standard for children with ALL [305,310]. These approaches can result in neurologic sequelae, including intellectual dysfunction, seizures, and dementia [311], as well as extraneural complications, particularly slow growth in children [312]. Complications may be more common in patients receiving cranial irradiation [311,313], and prophylaxis without cranial irradiation may be as effective, at least in patients who are at intermediate risk [314].

Adults with ALL frequently receive CNS prophylaxis with IT chemotherapy and cranial irradiation in a manner similar to that for children. This has resulted in a lower incidence of relapse in the CNS [315,316]. The incidence of complications associated with CNS prophylaxis is similar to that in children, but the abnormalities observed are frequently asymptomatic and are detected only on electroencephalograms or computed tomography scans [317]. In a randomized study allocating patients to receive cranial irradiation and IT methotrexate or no CNS prophylaxis, the 3-year CNS relapse rate significantly decreased from 45% to 20% with prophylaxis. However, this did not translate into an improved survival rate [315]. In our studies, early intervention with IT chemotherapy and high-dose systemic chemotherapy without cranial irradiation is highly effective prophylactically in adults with ALL, particularly for patients at high risk for CNS relapse [304]. More recent studies have emphasized IT therapy plus high-dose systemic chemotherapy over cranial irradiation as CNS prophylaxis in both children and adults with ALL.

Several reports have identified risk factors for the development of CNS leukemia in children, including high WBC counts, T-cell or B-cell disease, young age, lymphadenopathy, thrombocytopenia, hepatomegaly, and splenomegaly [305,318]. In adults, a multivariate analysis identified a mature B-cell phenotype, high serum levels of lactate dehydrogenase, and a high proliferative index (ie, cells in S+G2M compartments greater than or equal to 14%) as risk factors for CNS disease [319]. Among patients with none of these factors (40%), the incidence of CNS leukemia at 1 year was 5%, compared with more than 50% in patients with high levels of lactate dehydrogenase and a high proliferative index [319]. The intensity of CNS prophylaxis could be adjusted to the risk of CNS disease according to this model [304].

Patients who present with leukemia in the CNS should receive more aggressive therapy. One proposed therapeutic scheme includes IT methotrexate alternating with IT cytarabine twice weekly until the cerebrospinal fluid clears, then weekly for 1 month and once monthly thereafter for 2 years [296]. Cranial irradiation may be indicated in these patients [201,296]. For patients with a WBC count lower than 5,000/µL and 15 WBC/µL in the cerebrospinal fluid together with blasts, prophylaxis as used for patients whose cerebrospinal fluid is blast-negative may be equally effective [314]. Patients with cranial nerve root involvement may benefit from selective irradiation to the base of the skull.

Allogeneic BMT

Allogeneic BMT is an effective alternative therapy for patients with ALL. The timing of the transplantation is controversial. Some groups have performed allogeneic BMT in patients who are in first remission and have reported long-term disease-free survivals in 22% to 60% of patients [320-322]. This wide range derives from the variability in patient selection because factors such as age, phenotype of the disease, WBC count, gender mismatch, and the type of prophylaxis used to prevent graft-vs-host disease significantly influence the outcome [323].

The International Bone Marrow Transplant Registry reported a 5-year actuarial rate of leukemia-free survival of 44% for patients who received BMT during their first remission [324]. Several other studies have reported long-term disease-free survival for 40% to 70% of patients [325-327]. Patients undergoing allogeneic BMT usually represent a highly select population of young patients with no organ dysfunction.

To clarify the value of allogeneic BMT in patients in first remission, Horowitz et al conducted a retrospective analysis of patients who received intensive consolidation and maintenance therapies with the Berlin-Frankfurt-Munster regimen vs patients undergoing allogeneic BMT in first remission [328]. After accounting for age and lead time bias to BMT, the 5-year leukemia-free survival rate was 38% in patients who received chemotherapy and 44% in patients who underwent allogeneic BMT [328]. The causes of failure differed with these approaches. With chemotherapy, the 5-year probability of relapse was 59% and the probability of treatment-related death 4%; for patients treated with BMT, the probabilities were 26% and 39%, respectively [328]. The investigators were not able to identify subgroups of patients who benefited from BMT [320].

In a prospective study by Fire et al, patients who had an HLA-identical sibling and who achieved remission were assigned to undergo allogeneic BMT if they were younger than 40 years; if older than 50 years, patients received consolidation with chemotherapy, and all others were randomized to autologous BMT or consolidation with chemotherapy alone [329]. The estimated 3-year disease-free survival rate was 43% for patients undergoing allogeneic BMT, 39% for patients undergoing autologous BMT, and 32% for patients receiving chemotherapy (statistical difference not significant). The older patients had a significantly shorter 3-year disease free survival rate of only 24% [329].

In a recent update of this study, the 5-year disease-free survival rate was 45% for the allogeneic BMT group and 31% for the control group, which combined the autologous BMT and chemotherapy groups (P = .1, Table 6) [330]. When patients at high risk (ie, Ph-positive ALL, null or undifferentiated ALL, age older than 35 years, WBC count higher than 30 ,000/µL, or time to complete response longer than 4 weeks) were analyzed separately, the 5-year disease-free survival rate was 39% for patients who underwent allogeneic BMT and 14% for patients who received other therapies (P = .01). For patients at standard-risk (62.5% of the total patient population), the 5-year disease-free survival rates were 48% and 43% for patients who underwent allogeneic BMT and patients who did not, respectively (nonsignificant difference). This study also showed the bias inherent in selecting patients for BMT: 62.5% of patients included had standard-risk ALL, whereas in most studies (Table 5), patients with standard-risk ALL comprise less than 30% of patients.

Adapted, with permission, from Gratwohl A, Hermans J, Zwaan F: Bone marrow transplantation for ALL in Europe, in Gale RP, Hoelzer D (eds): Acute Lymphoblastic Leukemia, pp 271–278. New York, Alan R. Liss, 1990.

Barrett et al reported a 2-year disease-free survival rate of 38% in patients with Ph-positive ALL who underwent allogeneic BMT during their first remission [331]. These patients had a cure rate of less than 10% when treated with chemotherapy alone. Therefore, patients at high risk are likely to benefit from allogeneic BMT performed during first remission. However, this population must be selected carefully, because treatment-related mortality is still significant with BMT, and because the sequence of chemotherapy during the first complete response and BMT at the first relapse or subsequently may yield the best cumulative cure rate.

For patients with disease refractory to conventional therapy or in relapse or second remission, allogeneic BMT is the treatment of choice. In patients refractory to chemotherapy, the actuarial 3-year disease-free survival rate with allogeneic BMT was 23% in 1 study [332], which is more than can be expected with salvage chemotherapy. For patients in second remission, several studies have reported long-term disease-free survival rates ranging from 18% to 45% (average, 30%) [320-323].

Patients experiencing relapse after allogeneic BMT may still respond to salvage chemotherapy. The outcome depends on the time from BMT to relapse: patients who experience relapse less than 100 days after BMT have a complete response rate of 18%, compared with 71% if the relapse occurs more than 1 year after BMT [333]. Remissions are usually short.

Autologous BMT

Two large studies have failed to demonstrate an advantage in disease-free survival for patients undergoing autologous BMT compared with chemotherapy alone [323,339]. A study from M.D. Anderson Cancer Center planned an intensive consolidation regimen that included autologous BMT for patients in complete remission [155]. Of 79 patients achieving complete remission, 32 experienced relapse before the time of BMT. Among the other 47 patients, 21 could not undergo BMT because of age, medical contraindications, or socioeconomic reasons. When the 26 patients who underwent BMT were compared with the 21 patients who did not, no significant difference in 3-year complete response rates (60% vs 49%, respectively) or survival rates (58% vs 62%, respectively) was evident. In the series from the French Group on Therapy for ALL, chemotherapy and autologous BMT produced comparable disease-free survival rates at 3 years (39% vs 32%; P = .8). However, late relapses (ie, after 3 years) were seen mainly in patients in the chemotherapy arm [329].

These studies suggest that autologous BMT is not more effective than consolidation chemotherapy but may produce a plateau in disease-free survival after 3 years. Some patients, particularly those who are noncompliant or who are not willing to receive long-term therapy, may benefit from this one-time procedure. Several studies with autologous BMT also exemplify the problems with patient selection. Only 20% to 50% of patients for whom autologous BMT is planned can actually receive the transplant [155,330].

For patients with refractory ALL or patients who experience relapse, autologous BMT can result in a long-term disease-free survival rate of 20% to 30% [334-337]. The best results (a disease-free survival rate of 40% to 50%) are achieved in patients who remain in first complete remission for longer than 1 year [334]. These patients may therefore benefit from autologous BMT. However, better methods of bone marrow purging are needed to reduce relapse rates to make this therapy a better alternative. One promising approach is in vivo purging by means of mobilization of normal hematopoietic precursors, which can be collected and later reinfused, after intensive chemotherapy [338].

Survival

Long-term prognosis is excellent in children. More than 90% achieve a complete response and 60% to 70% will eventually be cured. In adults, the results are worse. When analyzing the outcome in adults with ALL, it is important to consider studies that have a long follow-up and the study inclusion criteria. The initial studies from Memorial Sloan-Kettering Cancer Center using the L2 to L10-M programs projected a long-term disease-free survival rate of more than 50% [339]. Linker et al initially reported long-term complete response and survival rates of 50% to 60% in patients younger than 50 years [340]. Both studies [339,340] excluded patients with Ph-positive disease. The follow-up from Memorial Sloan-Kettering, with less stringent inclusion criteria, indicated a long-term complete response rate of approximately 25% [145], and the follow-up study from Linker et al demonstrated a long-term disease-free survival rate of 35% [279]. These and several other studies report a cure rate for adult ALL of 20% to 35%. Although a major improvement from results 3 decades ago, these findings pose a challenge for improving outcome toward what is now achievable in children with ALL.

Biologic and Prognostic Investigations

Minimal Residual Disease

The availability of immunologic and molecular techniques has increased our ability to detect residual disease at levels below the sensitivity of morphologic evaluation. These techniques include flow cytometric sorting and immunophenotyping, clonogenic assays, and detection of leukemia-specific DNA or RNA sequences by Southern blot or polymerase chain reaction [341]. With these techniques, the presence of residual clonal cells may predict survival. In one study of patients treated with autologous BMT, all 42 patients with more than 51 malignant cells per 10 million total cells (as measured by multiparameter flow cytometry and cell-sorting with assays for leukemic progenitor cells) experienced relapse within 1 year, but only 41% of patients with lower levels of residual disease experienced relapse [342].

One approach for detecting minimal residual disease is to identify the rearrangement of Ig or TCR genes. As mentioned previously, the clonal nature of ALL is manifested by a specific and unique rearrangement of these genes in all malignant cells, whereas normal cells have a germline configuration [81,82]. Amplification of such a leukemia-specific marker by polymerase chain reaction can identify one leukemic cell among 1 million normal cells [343]. The principle of this technique is based on amplifying and identifying the specific rearrangement that occurs during the differentiation of B- and T-cells in the Ig heavy chain (the hypervariable sequence known as the complementary determinant region III) and the TCR, respectively.

During induction chemotherapy, there is a 3- to 4-log reduction in the number of leukemic cells, but even after a complete response is achieved, some residual disease can be documented [344]. In some patients, an increase in leukemic cells can be demonstrated by polymerase chain reaction months before it becomes clinically evident [344]. The major limitation of this technique is that, because the specific rearrangement is unique for each clone, specific probes must be generated for each patient.

An alternative approach is the blast-colony assay, described by Estrov et al [345]. With this assay, in vitro growth of lymphoblastic colonies during complete remission was observed in patients who later experienced relapse. The presence of disease as detected by this method is not always associated with relapse, and a threshold for prediction of adverse outcome has not been established.

Multidrug Resistance Detection

The multidrug resistance (MDR) gene encodes for a membrane glycoprotein, p170, that is thought to function as an efflux pump [346]. The expression of this gene confers resistance to some chemotherapeutic agents, including vinca alkaloids, taxoids, anthracyclines, and epipodophylotoxins [347]. Of patients with ALL, 10% to 50% express MDR at diagnosis, and 15% to 60% express MDR at relapse [348]. In adults, the incidence of MDR positivity increases markedly after relapse (10% at diagnosis, 50% after relapse) [349]. The expression of MDR is associated with a lower complete response rate (56% for MDR-positive patients vs 93% for MDR-negative patients; P = .05) and a higher relapse rate (100% vs 46%, respectively; P = .05). This results in a survival advantage for MDR-negative patients [349].

Expression of bcl-2

Oncogene bcl-2 is involved in the regulation of cell death. Overexpression of bcl-2 results in an inhibition of programmed cell death of hematopoietic cells [350]. B-cell precursor ALL cells overexpress bcl-2, and this results in prolonged survival of leukemic cells [351]. An association between bcl-2 overexpression and glucocorticoid resistance has been reported [352]. Overexpression of bcl-2 was documented in all patients with ALL, children and adults, studied by Gala et al, except in patients with Burkitt's phenotype [353]. The overexpression, however, was not associated with a poor prognosis [353].

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