Acute Lymphocytic Leukemia


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.

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


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.


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].


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.

B-cell lineageHLA-DRCD19CD24CD10CD20CD21CD22CD23clgslg
Early pre-B-cell++++Cytoplasm
Transitional B-cell++++++++a
Mature B-cell++++++++
T-cell lineageCD7CD2CD5CD1CD4CD8CD3   

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.


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].

TypeIncidence in adults (%)Incidence in children (%)CharacteristicsResponse rate (%)3-year survival rate (%)
L13185Small, homogeneous cells; round nucleus; scanty cytoplasm8540
L26014Large, heterogeneous cells; irregular nucleus, cleft, nucleolus; more cytoplasm7535
L3  9  1Large, homogeneous; regular nucleus; vacuolated, basophilic cytoplasm; Burkitt's lymphoma; poor prognosis6510

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.

TypeMarkersIncidence in children (%)Incidence in adults (%)Observations
Early Pre-BCytoplasmic Ig–65–7050–60Express at least one B-cell marker, CALLA + or –
Pre-B-cellCytoplasmic Ig+15–2015–25Express at least one B-cell marker, CALLA + or –, worse prognosis than that for early pre-B-cell
B-cellSurface Ig+< 5< 5Extramedullary lymphomatous masses, CNS involvement, hyperuricemia, acute respiratory failure, Burkitt's leukemia
T-cellCD2 CD3 CD5 CD7 CD4 CD810–1520–25High WBC count, CNS involvement, thymic mass

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].


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].

 Cytogenetic abnormalityIncidence in children (%)Incidence in adults (%)
Numeric abnormalitiesHyperdiploid40–5010–20
 47 to 50 chromosomes15-205-10
 > 50 chromosomes25-305-10
Structural abnormalitiesPseudodiploid40-5050-60
 t(8;14), t(8;2), and t(8;22)3-55-10
 t(4;11)(q21;q23) (and others involving 11q23)55
 t(1;19)(q23;p13.3)5-7< 5
 4q11 abnormalities< 55-10
 7q35 abnormalities< 5< 5

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].

Risk categoryHoelzer et al [146]Kantarjian et al [155]Gaynor et al [147]
Percentage of all patients27%28%40%
Long-term disease-free survival rate62%70%61%
Percentage of all patients  22%
Long-term disease-free survival rate  43%
Percentage of all patients73%72%38%
Long-term disease-free survival rate28%27%30%
High-risk featuresWBC count >30,000/µL Age > 35 years Null-cell ALL Complete response after > 4 weeksWBC count >5,000/µL B-cell ALL Complete response after > 2 induction courses Ph-positive CNS involvementWBC count >20,000/µL Age > 60 years Null- or B-cell ALL Complete response after > 5 weeks Ph-positive


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.

 Allogeneic BMTAutologous BMT
Number of patients included11695
Number undergoing BMT95 (79%)63 (66%)
3-year survival rate (%)5649
3-year disease-free survival rate (%)4439

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].


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].



1. Sawyers CL, Denny CT, Witte ON: Leukemia and the disruption of normal hematopoiesis. Cell 64:337–350, 1991.

2. Farber S, Diamond LK, Mercer RD, et al: Temporary remissions in acute leukemia in children produced by folic acid antagonist 4-aminopteroylglutamic acid (aminopterin). N Engl J Med 238:787–793, 1948.

3. George SL, Aur RJA, Maurer AM, et al: A reappraisal of the results of stopping therapy in childhood leukemia. N Engl J Med 300:269–273, 1979.

4. Brincker H: Population-based age- and sex-specific incidence rates in the four main types of leukaemia. Scand J Haematol 29:241–249, 1982.

5. Poplack DG: Clinical manifestations of acute lymphoblastic leukemia, in Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice, pp 776–784. New York, Churchill Livingstone, 1991.

6. Lukens JN: Acute lymphocytic leukemia, in Lee GR, Bithell TC, Foerster J, et al (eds): Wintrobe's Clinical Hematology, 9th ed, pp 1892–1919. Philadelphia, Lea & Febiger, 1993.

7. Robinson LL: Epidemiology of childhood leukemia. ASCO Educational Book, pp 120–123, 1994.

8. Boring CC, Squires TT, Ting T, et al: Cancer statistics, 1994. CA Cancer J Clin 44:7–26, 1994.

9. Sather HN: Age at diagnosis in childhood acute lymphoblastic leukemia. Med Pediatr Oncol 14:166–172, 1986.

10. Baranovsky A, Myers MH: Cancer incidence and survival in patients 65 years of age and older. CA Cancer J Clin 36:26–41, 1986.

11. Amsel S, Nabembezi JS: Two-year survey of hematologic malignancies in Uganda. J Natl Cancer Inst 52:1397–1401, 1974.

12. Edington GM, Hendrickse M: Incidence and frequency of lymphoreticular tumors in Ibadan and the Western State of Nigeria. J Natl Cancer Inst 50:1623–1631, 1973.

13. Sandler DP: Epidemiology and etiology of acute leukemia: An update. Leukemia 6(suppl 4):3–5, 1992.

14. Call TG, Noel P, Habermann TM, et al: Incidence of leukemia in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 69:315-322, 1994.

15. Birch JM, Marsden HB, Swindell R: Incidence of malignant disease in childhood: A 24-year review of the Manchester children's tumour registry data. Br J Cancer 42:215–223, 1980.

16. Sandler DP, Collman GW: Cytogenetic and environmental factors in the etiology of the acute leukemias in adults. Am J Epidemiol 126:1017–1032, 1987.

17. Gunz FW, Gunz JP, Vincent PC, et al: Thirteen cases of leukemia in a family. J Natl Cancer Inst 60:1243–1250, 1978.

18. De Oliveira MSP, El Seed FERA, Foroni L, et al: Lymphoblastic leukaemia in Siamese twins: Evidence for identity. Lancet 2:969–970, 1986.

19. Schmitt TA, Degos L: Leucémies familiales. Bull Cancer (Paris) 65:83–88, 1978.

20. Robinson LL, Nesbit ME Jr, Sather HN, et al: Down syndrome and acute leukemia in children: A 10-year retrospective survey from the Children's Cancer Study Group. J Pediatr 105:235–234, 1984.

21. Neglia JP, Robinson LL: Epidemiology of the childhood acute leukemias. Pediatr Clin North Am 35:675–692, 1988.

22. Aurebach AD: Fanconi anemia and leukemia: Tracking the genes. Leukemia 6(suppl 1):1–4, 1992.

23. Kaye SA, Robinson LL, Smithson WA, et al: Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia. Cancer 68:1351–1355, 1991.

24. Stark CHR, Mantel N: Effects of maternal age and birth order on the risk of mongolism and leukemia. J Natl Cancer Inst 37:687–698, 1966.

25. van Steensel-Moll HA, Valkenburg HA, Vandenbroucke JP, et al: Are maternal fertility problems related to childhood leukaemia? Int J Epidemiol 14:555–559, 1985.

26. Dailing JR, Staryk P, Olshan AF, et al: Birth weight and incidence of chilhood cancer. J Natl Cancer Inst 72:1039–1041, 1984.

27. Buckley JD, Robinson LL, Swotinsky R, et al: Occupational exposures of parents of children with acute nonlymphocytic leukemia: A report from the Children's Cancer Study Group. Cancer Res 49:4030–4037, 1989.

28. McWhirter WR: The relationship of incidence of childhood lymphoblastic leukaemia to social class. Br J Cancer 46:640–645, 1982.

29. Stewart A, Kneale GW: Radiation dose effects in relation to obstetric x-rays and childhood cancers. Lancet 1:1185–1188, 1970.

30. Court-Brown WM, Doll R: Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Br Med J 2:1327–1332, 1986.

31. Simpson CL, Hempelmann LH, Fuller LM: Neoplasia in children with x-rays in infancy for thymic enlargement. Radiology 64:840–845, 1955.

32. Ishimaru M, Ishimaru T, Belsky JL: Incidence of leukemia in atomic bomb survivors belonging to a fixed cohort in Hiroshima and Nagasaki, 1950–1971: Radiation dose, years after exposure, age at exposure, and type of leukemia. J Radiat Res (Tokyo) 19:262–282, 1978.

33. Brill AB, Tomonaga M, Heyssel RM: Leukemia in man following exposure to ionizing radiation: A summary of the findings in Hiroshima and Nagasaki and a comparison with other human experience. Ann Intern Med 56:590–609, 1962.

34. Caldwell GG, Kelley DB, Zack M, et al: Mortality and cancer frequency among military nuclear test (Smoky) participants, 1957 through 1959. JAMA 250:620–624, 1984.

35. Land CE, McKay FW, Machado SG: Childhood leukemia and fallout from the Nevada nuclear tests. Science 223:139–144, 1984.

36. Caldwell GG, Kelley DB, Heath CW Jr: Leukemia among participants in military maneuvers at a nuclear bomb test: A preliminary report. JAMA 244:1575–1578, 1980.

37. Rinsky RA, Smith AB, Hornung R, et al: Benzene and leukemia: An epidemiologic risk assessment. N Engl J Med 316:1044–1050, 1987.

38. Savitz DA, Wachtel H, Barnes FA, et al: Case-control study of childhood cancer and exposure to 60-Hz magnetic fields. Am J Epidemiol 128:21–38, l988.

39. London SJ, Thomas DC, Bowman JD, et al: Exposure to residential electric and magnetic fields and risk of childhood leukemia. Am J Epidemiol 134:923–937, 1991.

40. Feychting M, Ahlbom A: Magnetic field and cancer in children residing near Swedish high-voltage power lines. Am J Epidemiol 138:467–481, 1993.

41. Sheikh K: Exposure to electromagnetic fields and the risk of leukemia. Arch Environ Health 41:53–56, 1986.

42. Alexander FE: Viruses, clusters, and clustering of childhood leukemia: A new perspective? Eur J Cancer 29A:1424–1443, 1993.

43. Greaves MF: A natural history of pediatric acute leukemia. Blood 82:1043–1051, 1993.

44. Greaves MF, Alexander FE: An infectious etiology for common acute lymphoblastic leukemia in childhood? Leukemia 7:349–360, 1993.

45. Moore MAS, Williams N, Metcalf D: In vitro formation by normal and leukemic human hematopoietic cells: Interaction between colony-forming and colony-stimulating cells. J Natl Cancer Inst 50:591–602, 1973.

46. Homans AC, Cohen JL, Barker BE, et al: Aplastic presentation of acute lymphoblastic leukemia: Evidence for cellular inhibition of normal hematopoietic progenitors. Am J Pediatr Hematol Oncol 11:456–462, 1989.

47. Peing LH, Keng TH, Sinniah D: Fever in children with acute lymphoblastic leukemia. Cancer 47:583–587, 1981.

48. Freeman AI, Pantazopoulos N, DeCastro L, et al: Infections in children with acute leukemia. Med Pediatr Oncol 1:167–173, 1975.

49. Henderson ES: Acute leukemia: General considerations, in Williams WJ, Beutler E, Erslev AJ, et al (eds): Hematology, 4th ed, pp 236–251. New York, McGraw-Hill, 1990.

50. Bevilacqua G, Abadessa A, Consolini R, et al: Bone marrow necrosis foreshadowing acute lymphoid leukemia. Am J Pediatr Hematol Oncol 7:223–228, 1985.

51. Niebrugge DJ, Benjamin DR: Bone marrow necrosis preceding acute lymphoblastic leukemia in childhood. Cancer 52:2162–2164, 1983.

52. Bakhshi A, Minowada J, Arnold A, et al: Lymphoid blast crises of chronic myelogenous leukemia represent stages in the development of B-cell precursors. N Engl J Med 31:826–831, 1983.

53. Corbaton J, Muñoz A, Madero L, et al: Pulmonary leukemia in a child presenting with infiltrative and nodular lesions. Pediatr Radiol 14:431–432, 1984.

54. Mancuso L, Marchi S, Pietro G, et al: Cardiac tamponade as first manifestation of acute lymphoblastic leukemia in a patient with echographic evidence of mediastinal lymph nodal enlargement. Am Heart J 110:1303–1304, 1985.

55. Taylor D, Day S: The eye as sanctuary in acute lymphoblastic leukemia. Lancet 1:452–453, 1980.

56. Miller DR, Steinherz PG, Feurer D, et al: Unfavorable prognostic significance of hand mirror cells in childhood acute lymphoblastic leukemia. Am J Dis Child 137:346–350, 1983.

57. Kim T, Hargreaves H, Byrnes R, et al: Pretreatment testicular biopsy in childhood acute lymphocytic leukemia. Lancet 2:657–658, 1981.

58. Nesbit ME Jr, Robinson LL, Ortega JA, et al: Testicular relapse in childhood acute lymphoblastic leukemia: Association with pretreatment patient. Cancer 45:2009–2016, 1980.

59. Kuo T-T, Tshang T-P, Chu J-Y: Testicular relapse in childhood acute lymphocytic leukemia during bone marrow remission. Cancer 38:2604–2612, 1976.

60. Land JL, Berry DH, Herson J, et al: Long-term survival in childhood acute leukemia: `Late' relapses. Med Pediatr Oncol 7:19–24, 1979.

61. Eden OB, Hardisty RM, Innes EM, et al: Testicular disease in acute lymphoblastic leukemia in childhood. Br Med J 1:334–338, 1978.

62. Bowman P, Aur RJA, Hustu HA, et al: Isolated testicular relapse in acute lymphocytic leukemia of childhood: Categories and influence on survival. J Clin Oncol 2:924–929, 1984.

63. Boggs DR, Wintrobe MM, Cartwright GE: The acute leukemias. Analysis of 322 cases and review of the literature. Medicine 41:163–225, 1962.

64. Bunin NJ, Pui C-H: Differing complications of hyperleukocytosis in children with acute lymphoblastic or acute nonlymphoblastic leukemia. J Clin Oncol 3:1590–1595, 1985.

65. Sarris AH, Kempin S, Berman E, et al: High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia. Blood 79:1305–1310, 1992.

66. Sarris A, Kantarjian HM, Cortes JE, et al: Successful treatment of the DIC of adult ALL with fresh-frozen plasma, cryoprecipitate, and platelets. Blood 82(suppl 1):253a, 1993.

67. Nelken RP, Stockman JA: The hypereosinophilic syndrome in association with acute lymphoblastic leukemia. J Pediatr 89:771–773, 1976.

68. Leikin S, Miller DR, Sather HN, et al: Immunologic evaluation in the prognosis of acute lymphoblastic leukemia: A report from the Children's Cancer Study Group. Blood 58:501–508, 1981.

69. Hann IM, Jones PHM, Evans DIK, et al: Low IgG or IgA: A further indicator of poor prognosis in childhood acute lymphoblastic leukemia. Br J Cancer 42:317–319, 1980.

70. Hirsch-Ginsberg C, Huh YO, Kagan J, et al: Advances in the diagnosis of acute leukemia. Hematol Oncol Clin North Am 7:1–46, 1993.

71. Bennett JM, Catovsky D, Daniel M-T, et al: Proposals for the classification of the acute leukemias. Br J Haematol 33:451–458, 1976.

72. Bennett JM, Catovsky D, Daniel M-T, et al: The morphological classification of acute lymphoblastic leukaemia: Concordance among observers and clinical correlations. Br J Haematol 47:553–561, 1981.

73. Breatnach F, Chessells JM, Greaves MF: The aplastic presentation of childhood leukaemia: A feature of common ALL. Br J Haematol 49:387–393, 1981.

74. Stass SA, Dean L, Peiper SC, et al: Determination of terminal deoxynucleotidyltransferase on bone marrow smears by immunoperoxidase. Am J Clin Pathol 77:174–176, 1982.

75. Janossy G, Hoffbrand AV, Greaves MF, et al: Terminal transferase enzyme assay and immunological membrane markers in the diagnosis of leukaemia. Br J Haematol 44:221–234, 1980.

76. Catovsky D, Greaves MF, Pain C, et al: Acid-phosphatase reaction in acute lymphoblastic leukaemia. Lancet 1:749–751, 1978.

77. Krolewsky JJ, Dalla-Favera R: Molecular genetic approaches in the diagnosis and classification of lymphoid malignancies. Hematol Pathol 3:45–61, 1989.

78. Adriaansen HJ, Soeting PWC, Wolvers-Tettero ILM, et al: Immunoglobulin and T-cell gene receptor gene rearrangements in acute nonlymphocytic leukemias: Analysis of 54 cases and a review of the literature. Leukemia 9:744–751, 1991.

79. Felix CA, Wright JJ, Poplack DG, et al: T-cell receptor alpha-, beta-, and gamma- genes in T-cell and pre-B cell acute lymphoblastic leukemia. J Clin Invest 80:540–556, 1987.

80. Hara J, Benedict SH, Champagne E, et al: Relationship between rearrangement and transcription of the T-cell receptor alpha, beta, and gamma genes in B-precursor acute lymphoblastic leukemia. Blood 73:500–508, 1989.

81. Lieber MR: The mechanism of V(D)J recombination: a balance of diversity, specificity, and stability. Cell 70:873–876, 1992.

82. Waldmann TA, Davis MM, Bongiovanni KF, et al: Rearrangements of genes for the antigen receptor on T cells as markers of lineage and clonality in human lymphoid neoplasms. N Engl J Med 313:776–783, 1985.

83. Furley AJW, Chan LC, Mizutani S, et al: Lineage specificity of rearrangement and expression of genes encoding the T-cell receptor-T3 complex and immunoglobulin heavy chain in leukemia. Leukemia 1:644–652, 1987.

84. Kitchingam GR, Rovigatti U, Maurer AM, et al: Rearrangement of immunoglobulin heavy chain genes in T cell acute lymphoblastic leukemia. Blood 65:725–729, 1985.

85. Ha K, Minden M, Hozumi N, et al: Immunoglobulin µ chain gene rearrangement in a patient with T cell acute lymphoblastic leukemia. J Clin Invest 73:1232–1236, 1984.

86. Yagi-Yumura K, Hara J, Terada N, et al: Analysis of molecular events in leukemic cells at an early stage of T-cell differentiation. Blood 14:2103–2111, 1989.

87. Pelicci P-G, Knowles D, Dalla-Favera R: Lymphoid tumors displaying rearrangements of both immunoglobulin and T-cell receptor genes. J Exp Med 162:1015–1024, 1985.

88. Seremetis SV, Pelicci P-G, Tabilio A, et al: High frequency of clonal immunoglobulin or T-cell receptor gene rearrangements in acute myelogenous leukemia expressing terminal deoxyribonucleotidyltransferase. J Exp Med 165:1703–1712, 1987.

89. Felix CA, Poplack DG, Reaman GH, et al: Characterization of immunoglobulin and T-cell receptor gene patterns in B-cell precursor acute lymphoblastic leukemia of childhood. J Clin Oncol 8:431–442, 1990.

90. Hanson CA, Thamilarsan M, Ross CW, et al: Kappa light gene rearrangement in T-cell acute lymphoblastic leukemia. Am J Clin Pathol 93:563–568, 1990.

91. Greaves MF: Differentiation-linked leukemogenesis in lymphocytes. Science 234:697–704, 1986.

92. Preti A, Kantarjian HM, Estey EH, et al: Characteristics and outcome of patients with acute lymphocytic leukemia and myeloperoxidase-positive blasts by electron microscopy. Hematol Pathol 8:155–167, 1994.

93. Burns P, Armitage JO, Frey AL, et al: Analysis of the presenting features of adult acute leukemia: The French-American-British classification. Cancer 47:2460–2469, 1981.

94. Miller DR, Leikin S, Albo V, et al: Prognostic importance of morphology (FAB classification) in childhood acute lymphoblastic leukemia (ALL). Br J Haematol 48:199–206, 1981.

95. Lilleyman JS, Hann IM, Stevens RF, et al: Blast cell vacuoles in childhood lymphoblastic leukaemia. Br J Haematol 70:183–186, 1988.

96. Pui C-H, Behm FG, Crist WM: Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia. Blood 82:343–362, 1993.

97. Loken MR, Shah VO, Dattilo KL, et al: Flow cytometric analysis of human bone marrow. II: Normal B-lymphocyte development. Blood 70:1316–1324, 1987.

98. Reinherz EL, Kung PC, Goldstein G, et al: Discrete stages of human intrathymic differentiation: Analysis of normal thymocytes and leukemic lymophoblasts of T-cell lineage. Immunology 77:1588–1562, 1980.

99. Nadler LM, Korsmeyer SJ, Anderson KC, et al: B cell origin of non-T-cell acute lymphoblastic leukemia: A model for discrete stages of neoplastic and normal pre-B-cell differentiation. J Clin Invest 74:332–340, 1984.

100. Foon KA, Tood RF III: Immunologic classification of leukemia and lymphoma. Blood 68:1–31, 1986.

101. Hurwitz CA, Loken MR, Graham ML, et al: Asynchronous antigen expression in B lineage acute lymphoblastic leukemia. Blood 72:299–307, 1988.

102. Hurwitz CA, Gore SD, Stone KD, et al: Flow cytometric detection of rare normal human marrow cells with immunophenotypes characteristic of acute lymphoblastic leukemia cells. Leukemia 6:233–239, 1992.

103. Wiersman SR, Ortega J, Sobol RE, et al: Clinical importance of myeloid-antigen expression in acute lymphoblastic leukemia of childhood. N Engl J Med 324:800–808, 1991.

104. Kurec AS, Belair P, Stefanu C, et al: Significance of aberrant immunophenotypes in childhood acute lymphoid leukemia. Cancer 67:3081–3086, 1991.

105. Pui C-H, Raimondi SC, Head DR, et al: Characterization of childhood acute leukemia with multiple myeloid and lymphoid markers at diagnosis and at relapse. Blood 78:1327–1337, 1991.

106. Davey FR, Mick R, Nelson DA, et al: Morphologic and cytochemical characterization of adult lymphoid leukemias which express myeloid antigen. Leukemia 2:420–426, 1988.

107. Childs CC, Hirsch-Ginsberg C, Walters RS, et al: Myeloid surface antigen-positive acute lymphoblastic leukemia (My+ ALL): Immunophenotypic, ultrastructural, cytogenetic, and molecular characteristics. Leukemia 3:777–783, 1989.

108. Guyotat D, Campos L, Shi Z-H, et al: Myeloid surface antigen expression in adult acute lymphoblastic leukemia. Leukemia 4:664–666, 1990.

109. Greaves MF, Chan LC, Furley AJW, et al: Lineage promiscuity in hemopoietic differentiation and leukemia. Blood 67:1–11, 1986.

110. Smith LJ, Curtis JE, Messner HA, et al: Lineage infidelity in acute leukemia. Blood 61:1138–1145, 1983.

111. Kita K, Nakase K, Miwa H, et al: Phenotypical characteristics of acute myelocytic leukemia associated with the t(8;21) (q22;q22) chromosomal abnormality: Frequent expression of immature B-cell antigen CD19 together with stem-cell antigen CD34. Blood 80:470–477, 1992.

112. Claxton DF, Reading CL, Nagarajan L, et al: Correlation of CD2 expression with PML gene breakpoints in patients with acute promyelocytic leukemia. Blood 80:582–586, 1992.

113. Pui C-H, Schell MJ, Vodian MA, et al: Serum CD4, CD8, and interleukin-2 receptor levels in childhood acute myeloid leukemia. Leukemia 5:249–254, 1991.

114. Letarte M, Vera S, Tran R, et al: Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J Exp Med 168:1247–1252, 1988.

115. LeBien TW, McCormack RT: The common acute lymphoblastic leukemia antigen (CD10)-Emancipation from a functional enigma. Blood 73:625–635, 1989.

116. Pui C-H, Rivera GK, Hancock ML, et al: Clinical significance of CD10 expression in childhood acute lymphoblastic leukemia. Leukemia 7:35–40, 1993.

117. Civin CI, Strauss LC, Brovall C, et al: Antigenic analysis of hematopoiesis. III: A hematopoietic progenitor cell surface antigen defined by monoclonal antibody raised against KG-1a cells. J Immunol 133:157–165, 1984.

118. Batinic D, Tindle R, Boban D, et al: Expression of haematopoietic progenitor cell-associated antigen BI-3C5/CD34 in leukaemia. Leuk Res 13:83–85, 1989.

119. Terstappen LWMM, Huang S, Safford M, et al: Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD34+ CD38- progenitor cells. Blood 77:1218–1227, 1991.

120. Koehler M, Behm FG, Hancock ML, et al: Expression of activation antigens CD38 and CD71 is not clinically important in childhood acute lymphoblastic leukemia. Leukemia 7:41–45, 1993.

121. Bain BJ: Immunological, cytogenetic, and other markers, in Bain BJ (ed): Leukemia Diagnosis: A guide to FAB Classification, p 64. Philadelphia, JB Lippincott, 1990.

122. Crist WM, Grossi CE, Pullen DJ, et al: Immunologic markers in childhood acute lymphocytic leukemia. Semin Oncol 12:105–121, 1985.

123. Coleman J: Carbonic anhydrase: Zinc and the mechanism of catalysis. Ann NY Acad Sci 429:26–48, 1984.

124. Greaves MF, Janossy G, Peto J, et al: Immunologically defined subclasses of acute lymphoblastic leukaemia in children: Their relationship to presentation features and prognosis. Br J Haematol 48:179–197, 1981.

125. Sallan SE, Ritz J, Pesando J, et al: Cell surface antigens: Prognostic implications in childhood acute lymphoblastic leukemia. Blood 55:395–402, 1980.

126. First MIC Cooperative Study Group: Morphologic, immunologic, and cytogenetic (MIC) working classification of acute lymphoblastic leukemias: Report of the workshop held in Leuven, Belgium, April 22–23, 1985. Cancer Genet Cytogenet 23:189–197, 1986.

127. Borowitz MJ, Shuster JJ, Civin CI, et al: Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: A Pediatric Oncology Group study. J Clin Oncol 8:1389–1398, 1990.

128. Pui C-H, Hancock ML, Head DR, et al: Clinical significance of CD34 expression in childhood acute lymphoblastic leukemia. Blood 82:889–894, 1993.

129. Vogler LB, Crist WM, Bockman DE, et al: Pre-B-cell leukemia: A new phenotype of childhood lymphoblastic leukemia. N Engl J Med 298:872–878, 1978.

130. Crist WM, Boyett J, Jackson J, et al: Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: A Pediatric Oncology Group Study. Blood 74:1252–1259, 1989.

131. Pui C-H, Williams DL, Kalwinsky DK, et al: Cytogenetic features and serum lactic dehydrogenase level predict a poor treatment outcome for children with pre-B-cell leukemia. Blood 67:1688–1692, 1986.

132. Raimondi SC, Behm FG, Roberson PK, et al: Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19). J Clin Oncol 8:1380–1388, 1990.

133. Crist WM, Carroll AJ, Shuster JJ, et al: Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19) (q23;p13): A Pediatric Oncology Group study. Blood 76:117–122, 1990.

134. Pui C-H, Raimondi SC, Hancock ML, et al: Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19)(q23;p13) or its derivative. J Clin Oncol 12:2601–2606, 1994.

135. Koehler M, Schell MJ, Behm FG, et al: Expression of a novel surface antigen MKW in childhood acute leukemia has prognostic significance. Leukemia 5:41–48, 1991.

136. Magrath IT, Ziegler JL: Bone marrow involvement in Burkitt's lymphoma and its relationship to acute B-cell leukemia. Leukemia Res 4:33–59, 1979.

137. Sullivan MP, Pullen DJ, Crist WM, et al: Clinical and biological heterogeneity of childhood B cell lymphocytic leukemia: Implications for clinical trials. Leukemia 4:6–11, 1990.

138. Sobol RE, Royston I, LeBien TW, et al: Adult acute lymphoblastic leukemia phenotypes defined by monoclonal antibodies. Blood 65:730, 1985.

139. Taylor PRA, Reid NM, Bown N, et al: Acute lymphoblastic leukemia in patients aged 60 years and over: A population-based study of incidence and outcome. Blood 80:1813–1817, 1992.

140. Zhou M, Findley HW, Ma L, et al: Effect of tumor necrosis factor-alpha on the proliferation of leukemic cells from children with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL): Studies of primary leukemic cells and BCP-ALL cell lines. Blood 77:2002–2007, 1991.

141. Pui C-H, Behm FG, Singh B, et al: Heterogeneity of presenting features and their relation to treatment outcome in 120 children with T-cell acute lymphoblastic leukemia. Blood 75:174–179, 1990.

142. Bernard A, Boumsell L, Reinherz E, et al: Cell surface characterization of malignant T cells from lymphoblastic lymphoma using monoclonal antibodies: Evidence for phenotypic differences between malignant T cells from patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. Blood 57:1105–1110, 1981.

143. Crist WM, Pullen DJ, Boyett J, et al: Clinical and biologic features predict a poor prognosis in acute lymphoid leukemias in infants: A Pediatric Oncology Group study. Blood 67:135–140, 1986.

144. Hammond D, Sather HN, Nesbit ME Jr, et al: Analysis of prognostic factors in acute lymphoblastic leukemia. Med Pediatr Oncol 14:124–134, 1986.

145. Ribeiro RC, Pui C-H: Prognostic factors in childhood acute lymphoblastic leukemia. Hematol Pathol 7:121–142, 1993.

146. Hoelzer D, Thiel E, Löffler H, et al: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71:123–131, 1988.

147. Gaynor J, Chapman D, Little C, et al: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia. J Clin Oncol 6:1014–1030, 1988.

148. Baccarani M, Corbelli G, Amadori S, et al: Adolescent and adult acute lymphoblastic leukemia: Prognostic features and outcome of therapy: A study of 293 patients. Blood 60:677–684, 1982.

149. Sather HN: Age at diagnosis in childhood acute lymphoblastic leukemia. Med Pediatr Oncol 14:166–172, 1986.

150. Cortes J, Kantarjian HM: Leukemia in the elderly. Cancer Bull 1995 (in press).

151. Pui C-H, Raimondi SC, Murphy SB, et al: An analysis of leukemic cell chromosomal features in infants. Blood 69:1289–1293, 1987.

152. Chen C-S, Sorensen PHB, Domer PH, et al: Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 81:2386–2393, 1993.

153. Kaneko Y, Shikano T, Maseki N, et al: Clinical characteristics of infant acute leukemia with or without 11q23 translocations. Leukemia 2:672–676, 1988.

154. Smith M: Towards a more uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia (ALL). ASCO Educational Book, pp 124–130, 1994.

155. Kantarjian HM, Walters RS, Keating MJ, et al: Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia. J Clin Oncol 8:994–1004, 1990.

156. Bloomfield CD, Secker-Walker LM, Goldman AI, et al: Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia. Cancer Genet Cytogenet 40:171–185, 1989.

157. Raimondi SC: Current status of cytogenetic research in childhood acute lymphoblastic leukemia. Blood 81:2237–2251, 1993.

158. Pui C-H, Crist WM, Look TA: Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia. Blood 76:1449–1463, 1990.

159. Trueworthy R, Shuster JJ, Look TA, et al: Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: A Pediatric Oncology Group study. J Clin Oncol 10:606–613, 1992.

160. Look TA, Roberson PK, Williams DL, et al: Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia. Blood 65:1079–1086, 1985.

161. Katz J, Shuster JJ, Schneider N, et al: The significance of ploidy in childhood T-cell acute lymphoblastic leukemia: A Pediatric Oncology Group study. Proc Am Soc Clin Oncol 12:316, 1993.

162. Walker-Secker LM, Lawler SD, Hardisty RM: Prognostic implications of chromosomal findings in acute lymphoblastic leukaemia at diagnosis. Br Med J 2:1529–1530, 1978.

163. Williams DL, Tsiatis A, Brodeur GM, et al: Prognostic importance of chromosome number in 136 untreated children with acute lymphoblastic leukemia. Blood 60:864–871, 1982.

164. Bloomfield CD, Goldman AI, Alimena G, et al: Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia. Blood 67:415–420, 1986.

165. Kaspers GJL, Smets LA, Pieters R, et al: Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: Results of an in vitro study. Blood 85:751–756, 1995.

166. Pui C-H, Raimondi SC, Dodge RK, et al: Prognostic importance of chromosomal abnormalities in children with hyperdiploid (more than 50 chromosomes) acute lymphoblastic leukemia. Blood 73:1963–1967, 1989.

167. Abe R, Raza A, Preisler HD, et al: Chromosomes and causation of human cancer and leukemia: IV. Near tetraploidy in acute leukemia. Cancer Genet Cytogenet 14:45–59, 1985.

168. Heerema NA, Palmer CG, Baehner RL: Karyotypic and clinical findings in a consecutive series of children with acute leukemia. Cancer Genet Cytogenet 17:165–179, 1985.

169. Pui C-H, Carroll AJ, Head DR, et al: Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood. Blood 76:590–596, 1990.

170. Raimondi SC, Roberson PK, Pui C-H, et al: Hyperdiploid (47–50) acute lymphoblastic leukemia in children. Blood 79:3245–3252, 1992.

171. Raimondi SC, Pui C-H, Head DR, et al: Trisomy 21 as the sole acquired chromosomal abnormality in children with acute lymphoblastic leukemia. Leukemia 6:171–175, 1992.

172. Betts DR, Kingston JE, Dorey EL, et al: Monosomy 20: A nonrandom finding in childhood acute lymphoblastic leukemia. Genes Chromosom Cancer 2:182–185, 1990.

173. Pui C-H, Williams DL, Raimondi SC, et al: Hypodiploidy is associated with a poor prognosis in children with acute lymphoblastic leukemia. Blood 70:247–253, 1987.

174. Pui C-H, Carroll AJ, Raimondi SC, et al: Clinical presentation, karyotypic characterization, and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or hypodiploid less than 45 line. Blood 75:1170–1177, 1990.

175. Gibbons B, MacCallum P, Watts E, et al: Near haploid acute lymphoblastic leukemia: Seven new cases and a review of the literature. Leukemia 5:738–743, 1991.

176. Callen DF, Raphael K, Michael PM, et al: Acute lymphoblastic leukemia with a hypodiploid karyotype with less than 40 chromosomes: The basis for division into two subgroups. Leukemia 3:749–753, 1989.

177. Raimondi SC, Behm FG, Roberson PK, et al: Cytogenetics of childhood T-cell leukemia. Blood 72:1560–1566, 1988.

178. Ribeiro RC, Abromowitch M, Raimondi SC, et al: Clinical and biologic hallmarks of the Philadelphia chromosome in childhood acute lymphoblastic leukemia. Blood 70:948–953, 1987.

179. Crist WM, Carroll AJ, Shuster JJ, et al: Philadelphia chromosome-positive childhood acute lymphoblastic leukemia: Clinical and cytogenetic characteristics and treatment outcome: A Pediatric Oncology Group study. Blood 76:489–494, 1990.

180. Fletcher JA, Lynch EA, Kimball VM, et al: Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia. Blood 77:435–439, 1991.

181. Preti HA, O'Brien S, Giralt S, et al: Philadelphia chromosome-positive adult acute lymphocytic leukemia: Characteristics, treatment results, and prognosis in 41 patients. Am J Med 97:60–65, 1994.

182. Westbrook CA, Hooberman AL, Spino C, et al: Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: A Cancer and Leukemia Group B study (8762). Blood 80:2983–2990, 1992.

183. Maurer J, Janssen JWG, Thiel E, et al: Detection of chimeric BCR-ABL genes in acute lymphoblastic leukemia by the polymerase chain reaction. Lancet 337:1055–1058, 1991.

184. Russo C, Carroll AJ, Kohler S, et al: Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 77:1050–1056, 1991.

185. Heisterkamp N, Jenkins R, Thibodeau S, et al: The bcr gene in Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 73:1307–1311, 1989.

186. Kurzrock R, Gutterman JU, Talpaz M: The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 319:999–1005, 1988.

187. Lugo TG, Pendergast A-M, Muller AJ, et al: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247:1079–1081, 1990.

188. Heisterkamp N, Jenster G, ten Hoeve J, et al: Acute leukaemia in bcr/abl transgenic mice. Nature 344:251–253, 1990.

189. McLaughlin J, Chianese E, Witte ON: Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. Mol Cell Biol 9:1866–1874, 1989.

190. Kantarjian HM, Talpaz M, Dhingra K, et al: Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. Blood 78:2411–2418, 1991.

191. Berger R, Bernheim J, Broquet JC, et al: t(8;14) Translocation in a Burkitt's type of lymphoblastic leukaemia (L3). Br J Haematol 43:87–90, 1979.

192. Magrath I: The pathogenesis of Burkitt's lymphoma. Adv Cancer Res 55:133–270, 1990.

193. Croce CM, Nowell PC: Molecular basis of human B-cell neoplasia. Blood 65:1–7, 1985.

194. Rabbitts TH, Forster A, Hamlyn P, et al: Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma. Nature 309:592–597, 1984.

195. Blackwood EM, Eisenman RN: Max: A helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with MYC. Science 251:1211–1217, 1991.

196. Adams JM, Harris AW, Pinkert CA, et al: The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318:533–538, 1985.

197. Fenaux P, Lai JL, Miaux O, et al: Burkitt cell acute leukaemia (L3 ALL) in adults: A report of 18 cases. Br J Haematol 71:371–376, 1989.

198. Kantarjian HM, O'Brien S, Beran M, et al: Modified Burkitt regimen for adult acute lymphocytic leukemia-The hyper-CVAD program. Blood 82:329a, 1993.

199. Hoelzer D: Therapy of acute lymphoblastic leukemia in adults. Leukemia 6(suppl 2):132–135, 1992.

200. Bowman WP, Shuster JJ, Cook B, et al: Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved cell lymphoma. Proc Am Soc Clin Oncol 11:277, 1992.

201. Brecher M, Murphy SB, Bowman WP, et al: Results of Pediatric Oncology Group 8616: A randomized trial of two forms of therapy for stage III diffuse small noncleaved cell lymphoma in children. Proc Am Soc Clin Oncol 11:340, 1992.

202. McMaster ML, Greer JP, Greco A, et al: Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy. J Clin Oncol 9:941–946, 1991.

203. Pui C-H, Behm F, Raimondi SC, et al: Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 321:136–142, 1989.

204. Prieto F, Palau F, Badia L, et al: 11q23 Abnormalities in children with acute nonlymphocytic leukemia (M4-M5): Association with previous chemotherapy. Cancer Genet Cytogenet 45:1–11, 1990.

205. Pedersen-Bjergaard J, Philip P: Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II. Blood 78:1147–1148, 1991.

206. Cortes J, O'Brien S, Kantarjian HM, et al: Abnormalities in the long arm of chromosome 11 (11q) in patients with de novo and secondary acute myelogenous leukemia and myelodysplastic syndromes. Leukemia 8:2174–2178, 1994.

207. Kaneko Y, Maseki N, Takasaki N, et al: Clinical and hematologic characteristics in acute leukemia with 11q23 translocations. Blood 67:484–491, 1986.

208. Raimondi SC, Peiper SC, Kitchingman GR, et al: Childhood acute lymphoblastic leukemia with chromosomal breakpoints at 11q23. Blood 73:1627–1634, 1989.

209. Furley AJW, Chan LC, Mizutani S, et al: Lineage specificity of rearrangement and expression of genes encoding the T-cell receptor-T3 complex and immunoglobulin heavy chain in leukemia. Leukemia 1:644–652, 1987.

210. Pui CH, Raimondi SC, Murphy SB, et al: An analysis of leukemic cell chromosomal features in infants. Blood 69:1289–1293, 1987.

211. Chen C-S, Sorensen PHB, Domer PH, et al: Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 81:2386–2393, 1993.

212. Pui C-H, Behm FG, Downing JR, et al: 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J Clin Oncol 12:909–915, 1994.

213. Kobayashi H, Espinosa R III, Thirman MJ, et al: Heterogeneity of breakpoints of 11q23 rearrangements in hematologic malignancies identified with fluorescence in situ hybridization. Blood 82:547–551, 1993.

214. Nakamura YGT, Alder H, Prasad R, et al: The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71:701–708, 1992.

215. Carroll AJ, Crist WM, Parmley RT, et al: Pre-B cell leukemia associated with chromosome translocation 1;19. Blood 63:721–724, 1984.

216. Michael PM, Levin MD, Garson OM: Translocation 1;19-A new cytogenetic abnormality in acute lymphocytic leukemia. Cancer Genet Cytogenet 12:339–341, 1984.

217. Shikano T, Kaneko Y, Takazawa M, et al: Balanced and unbalanced 1;19 translocation-associated acute lymphoblastic leukemias. Cancer 58:2239–2243, 1986.

218. Crist WM, Boyett J, Jackson J, et al: Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 74:1252–1259, 1989.

219. Nourse J, Melletin JD, Galili N, et al: Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60:535–545, 1990.

220. Kamps MP, Murre C, Sun X-H, et al: A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell 60:547–555, 1990.

221. Erikson J, Williams DL, Finan J, et al: Locus of the alpha-chain of the T-cell receptor is split by chromosome translocation in T-cell leukemias. Science 229:784–786, 1985.

222. Boehm T, Baer R, Lavenir I, et al: The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15. EMBO J 7:385–394, 1988.

223. Champagne E, Takihara Y, Sagman U, et al: The T-cell receptor delta chain locus is disrupted in the T-ALL associated t(11;14) (p13;q11) translocation. Blood 73:1672–1676, 1989.

224. Croce CM, Isobe M, Palumbo A, et al: Gene for alpha-chain of human T-cell receptor: Location on chromosome 14 region involved in T-cell neoplasms. Science 227:1044–1047, 1985.

225. Chapelle A: The 1985 human gene map and human gene mapping in 1985. Cytogenet Cell Genet 40:1–7, 1985.

226. Raimondi SC, Pui C-H, Behm FG, et al: 7q32q36 Translocations in childhood T cell leukemia: Cytogenetic evidence of involvement of the T-cell receptor beta-chain gene. Blood 69:131–134, 1987.

227. Ribeiro RC, Raimondi SC, Behm FG, et al: Clinical and biologic features of childhood T-cell leukemia with the t(11;14). Blood 78:466–470, 1991.

228. Boehm T, Foroni L, Kaneko Y, et al: The rhombotin family of cysteine-rich LIM-domain oncogenes: Distinct members are involved in T-cell translocations to human chromosomes 11q15 and 11p13. Proc Natl Acad Sci U S A 88:4367–4371, 1991.

229. Pokora-Royer B, Loos U, Ludwig WD: TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene 6:1887–1893, 1991.

230. McGuire EA, Hockett RD, Pollock KM, et al: The t(11;14)(p15;q11) in a T-cell acute lymphoblastic leukemia cell line activates multiple transcripts, including Ttg-1, a gene encoding a potential zinc finger protein. Mol Cell Biol 9:2124–2132, 1989.

231. Rabbitts TH: Translocations, master genes, and differences between the origins of acute and chronic leukemias Cell 67:641–644, 1991.

232. Hatano M, Roberts CWM, Minden M, et al: Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253:79–81, 1991.

233. Kennedy MA, Gonzalez-Sarmiento R, Kees UR, et al: HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24. Genetics 88:8900–8904, 1991.

234. Mellentin JD, Smith SD, Cleary ML: IyI-1, a novel gene altered by chromosomal translocation in T-cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif. Cell 58:77–83, 1989.

235. Begley CG, Aplan PD, Davey MP, et al: Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript. Proc Natl Acad Sci U S A 86:2031–2035, 1989.

236. Hsu H-L, Cheng J-T, Chen Q, et al: Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop helix proteins. Mol Cell Biol 11:3037–3042, 1991.

237. Erikson J, Finger L, Sun L, et al: Deregulation of c-myc by translocation of the alpha-locus of the T-cell receptor in T-cell leukemias. Science 232:884–886, 1986.

238. Shima EA, Le Beau MM, McKeithan TW, et al: Gene encoding the alpha-chain of the T-cell receptor is moved immediately downstream of c-myc in a chromosomal 8;14 translocation in a cell line from a human T-cell leukemia. Proc Natl Acad Sci USA 83:3439–3443, 1986.

239. Brito-Babapulle V, Matutes E, Parreira L, et al: Abnormalities of chromosome 7q and Tac expression in T-cell Leukemias. Blood 67:516–521, 1986.

240. Kaneko Y, Maseki N, Homma C, et al: Chromosome translocations involving band 7q35 or 7p15 in childhood T-cell leukemia/lymphoma. Blood 72:534–538, 1988.

241. Xia Y, Brown L, Yang CY-C, et al: TAL2, a helix-loop-helix gene activated by the (7;9)(q34;q32) translocation in human T-cell leukemia. Proc Natl Acad Sci U S A 88:11416–11420, 1991.

242. Ellisen LW, Bird J, West DC, et al: TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T-lymphoblastic neoplasms. Cell 66:649–661, 1991.

243. Chilcote RR, Brown E, Rowley JD: Lymphoblastic leukemia with lymphomatous features associated with abnormalities of the short arm of chromosome 9. N Engl J Med 313:286–291, 1985.

244. Carroll AJ, Castleberry RP, Crist WM: Lack of association between abnormalities of the chromosome 9 short arm and either `lymphomatous' features or T-cell phenotype in childhood acute lymphocytic leukemia. Blood 69:735–738, 1987.

245. Murphy SB, Raimondi SC, Rivera GK, et al: Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: Association with high-risk clinical features. Blood 74:409–415, 1989.

246. Diaz MO, Ziemin S, Le Beau MM, et al: Homozygous deletion of the alpha and beta interferon genes in human leukemia and derived cell lines. Proc Natl Acad Sci U S A 85:5259–5263, 1988.

247. Hayashi Y, Raimondi SC, Look AT, et al: Abnormalities of the long arm of chromosome 6 in childhood acute lymphoblastic leukemia. Blood 76:1626–1630, 1990.

248. Raimondi SC, Williams DL, Callihan T, et al: Nonrandom involvement of the 12p12 breakpoint in chromosome abnormalities of childhood acute lymphoblastic leukemia. Blood 68:69–75, 1986.

249. van der Plas DC, Dekker I, Hagemeijer A, et al: 12p chromosomal aberrations in precursor B cell childhood acute lymphoblastic leukemia predict an increased risk of relapse in the central nervous system and are associated with typical blast cell morphology. Leukemia 8:2041–2046, 1994.

250. Lübert M, Mirro J, Miller CW, et al: N-ras gene point mutations in childhood acute lymphocytic leukemia correlate with poor prognosis. Blood 75:1163–1169, 1990.

251. Distelhorst CW, Lam M, Lisgaris M, et al: Dexamethasone induces increased synthesis of the glucose-regulated protein GRP78 in S49 mouse lymphoma cells. Leukemia 6:162, 1992.

252. Lauer SJ, Pinkel D, Buchanan GR, et al: Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Cancer 60:2366–2371, 1987.

253. Wiley JS, Woodruff RK, Jamieson GP, et al: Cytosine arabinoside in the treatment of T-cell acute lymphoblastic leukemia. Aust N Z J Med 17:379–386, 1987.

254. Patte C, Philip T, Rodary C, et al: High survival rate inadvanced-stage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: Results from the French Pediatric Oncology Society of a randomized trial of 216 children. J Clin Oncol 9:123–132, 1991.

255. Sobol RE, Mick R, Royston I, et al: Clinical importance of myeloid antigen expression in adult acute lymphoblastic leukemia. N Engl J Med 1111–1117, 1987.

256. Preti A, Huh Y, O'Brien S, et al: Prognostic significance of positive myeloid markers in adult acute lymphocytic leukemia. Blood 82(suppl 1): 57a, 1993.

257. Boldt DH, Kopecky K, Head DR, et al: Expression of myeloid antigens in adult acute lymphoblastic leukemia: the Southwest Oncology Group experience. Proc Am Soc Clin Oncol 11:263, 1992.

258. Pui C-H, Hancock ML, Head DR, et al: Clinical significance of CD34 expression in childhood acute lymphoblastic leukemia. Blood 82:889–894, 1993.

259. Goasquen JE, Dossot J-M, Fardel O, et al: Expression of the multidrug resistance-associated P-glycoprotein (P-170) in 59 cases of de novo acute lymphoblastic leukemia: Prognostic implications. Blood 81:2394–2398, 1993.

260. Sather HN: Statistical evaluation of prognostic factors in ALL and treatment results. Med Pediatr Oncol 14:158–165, 1986.

261. Kalwinsky DK, Rivera G, Dahl GV, et al: Variation by race in presenting clinical and biologic features of childhood acute lymphoblastic leukaemia: Implications for treatment outcome. Leuk Res 9:817–823, 1985.

262. Miller DR, Coccia PF, Bleyer WA, et al: Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: A report from the Children's Cancer Study Group. J Clin Oncol 7:1807–1815, 1989.

263. Gaynon PS, Bleyer WA, Steinherz PG, et al: Day 7 marrow response and outcome for children with acute lymphoblastic leukemia and unfavorable presenting features. Med Pediatr Oncol 18:273–279, 1990.

264. Preti A, Kantarjian HM: Management of adult acute lymphocytic leukemia: Present issues and key challenges. J Clin Oncol 12:1312–1322, 1994.

265. Kantarjian HM: Adult acute lymphocytic leukemia: Critical review of current knowledge. Am J Med 97:176–184, 1994.

266. Hoelzer DF: Therapy of the newly diagnosed adult with acute lymphoblastic leukemia. Hematol Oncol Clin North Am 7:139–160, 1993.

267. Amadori S, Montuoro A, Meloni G, et al: Combination chemotherapy for acute lymphocytic leukemia in adults: Results of a retrospective study in 82 patients. Am J Hematol 8:175–183, 1980.

268. Hess CE, Zirkle JW: Results of induction therapy with vincristine and prednisone alone in adult acute lymphoblastic leukemia: Report of 43 patients and review of the literature. Am J Hematol 13:63–71, 1982.

269. Gottlieb AJ, Weinberg V, Ellison RR, et al: Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: A prospective randomized trial by Cancer and Leukemia Group B. Blood 64:267–274, 1984.

270. Stryckmans P, Debusscfer L: Chemotherapy of adult acute lymphoblastic leukaemia. Bailliere's Clin Haematol 4:115–130, 1991.

271. Cuttner J, Mick R, Budman DR, et al: Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: A CALGB study. Leukemia 5:425–431, 1991.

272. Balis FM, Lester CM, Chrousos GP, et al: Differences in cerebrospinal fluid penetration of corticosteroids: Possible relationship in the prevention of meningeal leukemia. J Clin Oncol 5:202–207, 1987.

273. Mandelli F, Annino L, Vegna ML, et al: GIMEMA ALL 0288: A multicenter study on adult acute lymphoblastic leukemia: Preliminary results. Leukemia 6(suppl 2):182–185, 1992.

274. Schiffer CA, Larson RA, Bloomfield CD, for the CALGB: Cancer and Leukemia Group B (CALGB) studies in acute lymphocytic leukemia (ALL). Haematologica 76(suppl 4):106, 1991.

275. Weiss M, Telford P, Kempin S, et al: Severe toxicity limits intensification of induction therapy for acute lymphoblastic leukemia. Leukemia 7:832–837, 1993.

276. Kasparu H, Sreter L, Holowiiecki J, et al: Intensified induction therapy for ALL in adults: A multicenter trial. Onkologie 14(suppl 2):80, 1991.

277. Rohatiner AZS, Bassan R, Battista R, et al: High dose cytosine arabinoside in the initial treatment of adults with acute lymphoblastic leukemia. Br J Cancer 62:454–458, 1990.

278. Schaver P, Arlin ZA, Mertelsman R, et al: Treatment of acute lymphoblastic leukemia in adults: Results of the L-10 and L-10M protocols. J Clin Oncol 1:462–470, 1983.

279. Linker CA, Levitt LJ, O'Donnell M, et al: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: A follow-up report. Blood 78:2814–2822, 1991.

280. Radford JE, Burns CP, Jones MP, et al: Adult acute lymphoblastic leukemia: Results of the Iowa HOP-L protocol. J Clin Oncol 7:58–66, 1989.

281. Clavell LA, Gelber RD, Cohen HJ, et al: Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315:657–663, 1986.

282. Wiernick PH, Dutcher JP, Gucalp R, et al: MOAD therapy for acute lymphocytic leukemia. Proc Am Soc Clin Oncol 9:205, 1990.

283. Dutcher JP, Wiernick PH, Gucalp R: MOAD therapy for adult acute lymphocytic leukemia (ALL). Haematologica 76(suppl 4):66, 1991.

284. Hoelzer D: Acute lymphoblastic leukemia progress in children, less in adults. N Engl J Med 329:1343–1344, 1993.

285. Kantarjian HM, Estey EH, O'Brien S, et al: Intensive chemotherapy with mitoxantrone and high-dose cytosine arabinoside followed by granulocyte-macrophage colony-stimulating factor in the treatment of patients with acute lymphocytic leukemia. Blood 79:876–881, 1992.

286. Kantarjian HM, Estey EH, O'Brien S, et al: Granulocyte colony-stimulating factor supportive treatment following intensive chemotherapy in acute lymphocytic leukemia in first remission. Cancer 72:2950–2955, 1993.

287. Tsuchiya H, Adachi N, Asou N, et al: Responses to granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF in Ph' positive acute lymphoblastic leukemia with myeloid surface markers. Blood 77:411–413, 1991.

288. Pui C-H, Simone JV, Hancock ML, et al: Impact of three methods of treatment intensification on acute lymphoblastic leukemia in children: Long-term results of St. Jude therapy study X. Leukemia 6:150–157, 1992.

289. Abromowitch M, Fairclough D: Contribution of mercaptopurine intensification to improved outcome in patients with lower-risk ALL. J Clin Oncol 8:1442, 1990.

290. Camitta B, Leventhal B, Lauer S, et al: Intermediate-dose intravenous methotrexate and mercaptopurine therapy for non-T, non-B acute lymphocytic leukemia of childhood: A Pediatric Oncology Group study. J Clin Oncol 10:1539–1544, 1989.

291. Rivera GK, Raimondi SC, Hancock ML, et al: Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination. Lancet 337:61–66, 1991.

292. Tubergen DG, Gilchrist GS, O'Brien RT, et al: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: A Children's Cancer Group phase II trial. J Clin Oncol 11:527–537, 1993.

293. Champlin RE, Gale RP: Acute lymphoblastic leukemia: Recent advances in biology and therapy. Blood 8:2051–2066, 1989.

294. Fiere D, Extra JM, David B, et al: Treatment of 218 adult acute lymphoblastic leukemias. Semin Oncol 14(suppl 1):64–66, 1987.

295. Stryckmans P, de Witte TH, Fillet G: Treatment of adult acute lymphoblastic leukemia-ALL-2 and ALL-3 EORTC studies. Haematologica 76(suppl 4):109, 1991.

296. Ellison RR, Mick R, Cuttner J, et al: The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: A prospective randomized clinical trial by Cancer and Leukemia Group B. J Clin Oncol 9:2002–2015, 1991.

297. Hoelzer D, Thiel E, Ludwig WD, et al: The German multicentre trials for treatment of acute lymphoblastic leukemia in adults. Leukemia 6(suppl 2):175–177, 1992.

298. Cassileth PA, Andersen JW, Bennett JM, et al: Adult acute lymphocytic leukemia: The Eastern Cooperative Oncology Group experience Leukemia 6(suppl 2):178–181, 1992.

299. Koren G, Ferrazini G, Sulh H, et al: Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med 323:17–21, 1990.

300. Evans WE, Crom WR, Abromowitch M, et al: Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia: Identification of a relation between concentration and effect. N Engl J Med 314:471–477, 1986.

301. Hussein KK, Dahlberg S, Head DR, et al: Treatment of acute lymphoblastic leukemia in adults with intensive induction, consolidation, and maintenance chemotherapy. Blood 73:57–63, 1989.

302. Mandelli F, Annino L, Giona FMA: ALL 0183: A multicentric study on adult acute lymphoblastic leukemia in Italy, in Gale RP, Hoelzer D (eds): Acute Lymphoblastic Leukemia, pp 205–220. New York, Alan R Liss, 1990.

303. Bleyer WA: Central nervous system leukemia. Pediatr Clin North Am 35:789–814, 1988.

304. Cortes J, O'Brien S, Robertson LE, et al: The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Proc Am Soc Clin Oncol 14:335, 1995.

305. Pinkel D, Woo S: Prevention and treatment of meningeal leukemia in children. Blood 84:355–366, 1994.

306. Law IP, Blom J: Adult acute leukemia: Frequency of central nervous system involvement in long-term survivors. Cancer 40:1304–1306, 1977.

307. Bleyer WA, Coccia PF, Sather HN, et al: Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen. J Clin Oncol 1:317–325, 1983.

308. Bleyer WA: Central nervous system leukemia, in Henderson ES, Lister TA (eds): Leukemia, 5th ed, pp 733–768. Philadelphia, WB Saunders Co, 1990.

309. Balis FM, Poplack DG: Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Oncol Hematol 11:74–86, 1989.

310. Bleyer WA, Poplack DG: Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol 12:131–148, 1985.

311. Bleyer WA: Neurologic sequelae of methotrexate and ionizing radiation: A new classification. Cancer Treat Rep 65(suppl 1):89–98, 1981.

312. Shalet SM, Gibson B, Swindell R, et al: Effect of spinal irradiation on growth. Arch Dis Child 62:461–464, 1987.

313. Price RA, Jamieson PA: The central nervous system in childhood leukemia. II: Subacute leukoencephalopathy. Cancer 35:306–318, 1975.

314. Gilchrist GS, Tubergen DG, Sather HN, et al: Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: A Children's Cancer Group report. J Clin Oncol 12:2594–2600, 1994.

315. Omura GA, Moffitt S, Vogler WR, et al: Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous system prophylaxis. Blood 55:199–204, 1980.

316. Henderson ES, Scharlau C, Cooper MR, et al: Combination chemotherapy and radiotherapy for acute lymphocytic leukemia in adults: Results of CALGB protocol 7113. Leuk Res 3:395–407, 1979.

317. Tucker J, Prior PF, Green CR, et al: Minimal neuropsychological sequelae following prophylactic treatment of the central nervous system in adult leukaemia and lymphoma. Br J Cancer 60:775–780, 1989.

318. Pavlovsky S, Eppinger-Helft M, Muriel FS: Factors that influence the appearance of central nervous system leukemia. Blood 42:935–938, 1973.

319. Kantarjian HM, Walters RS, Smith TL, et al: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72:1784–1789, 1988.

320. Doney K, Fisher LD, Appelbaum FR, et al: Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation: Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival. Bone Marrow Transplant 7:453–459, 1991.

321. 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.

322. Blume KG, Schmidt GM, Chao NJ: Bone marrow transplantation from histocompatible sibling donors for patients with acute lymphoblastic leukemia. Haematol Blood Transfus 33:636–637, 1990.

323. Barrett AJ, Horowitz MM, Gale RP, et al: Marrow transplantation for acute lymphoblastic leukemia: Factors affecting relapse and survival. Blood 74:862–871, 1989.

324. Christiansen NP: Allogeneic bone marrow transplantation for the treatment of adult acute leukemias. Hematol Oncol Clin North Am 7:177–200, 1993.

325. Chao NJ, Forman SJ, Schmidt GM, et al: Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission. Blood 78:1923–1927, 1991.

326. Vernant JP, Marit G, Maraninchi D, et al: Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission. J Clin Oncol 6:227–231, 1988.

327. Mirsic M, Nemet D, Labar B, et al: Chemotherapy versus allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia. Transplant Proc 25:1268–1270, 1993.

328. Horowitz MM, Messerer D, Hoelzer D, et al: Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 115:13–18, 1991.

329. Fiere D, Lepage E, Sebban C, et al: Adult acute lymphoblastic leukemia: A multicenter randomized trial testing bone marrow transplantation as postremission therapy. J Clin Oncol 11:1990–2001, 1993.

330. Sebban C, Lepage E, Vernant JP, et al: Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: A comparative study. J Clin Oncol 12:2580–2587, 1994.

331. Barrett AJ, Horowitz MM, Ash RC, et al: Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 79:3067–3070, 1992.

332. Biggs JC, Horowitz MM, Gale RP, et al: Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80:1090–1093. 1992.

333. Mortimer J, Blinder MA, Schulman S, et al: Relapse of acute leukemia after marrow transplantation: Natural history and results of subsequent therapy. J Clin Oncol 7:50–57, 1989.

334. Sallan SE, Niemeyer CM, Billett AL, et al: Autologous bone marrow transplantation for acute lymphoblastic leukemia. J Clin Oncol 7:1594–1601, 1989.

335. Soiffer RJ, Roy DC, Gonin R, et al: Monoclonal antibody-purged autologous bone marrow transplantation in adults with acute lymphoblastic leukemia at high risk of relapse. Bone Marrow Transplant 12:243–251, 1993.

336. Gilmore MJML, Hamon HG, Prentice F, et al: Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukemia in first complete remission. Bone Marrow Transplant 8:19–26, 1991.

337. Simonsson B, Burnett AK, Prentice HG, et al: Autologous bone marrow transplantation with monoclonal antibody purged marrow for high risk acute lymphoblastic leukemia. Leukemia 3:631–636, 1989.

338. Carella AM, Pollicardo N, Pungolino E, et al: Mobilization of cytogenetically `normal' blood progenitor cells by intensive conventional chemotherapy for chronic myeloid and acute lymphoblastic leukemia. Leuk Lymphoma 9:477–483, 1993.

339. Schauer P, Arlin ZA, Mertelsmann R: Treatment of acute lymphoblastic leukemia in adults-Results of the L-10 and L-10M protocols. J Clin Oncol 1:462–470, 1983.

340. Linker CA, Levitt LJ, O'Donnell M, et al: Improved results of treatment of adult acute lymphoblastic leukemia. Blood 69: 1242–1248, 1987.

341. Potter MN: The detection of minimal residual disease in acute lymphoblastic leukemia. Blood Rev 6:68–82, 1992.

342. Uckun FM, Kersey JH, Haake R, et al: Pretransplantation burden of leukemic progenitor cells as a predictor of relapse after bone marrow transplantation for acute lymphoblastic leukemia. N Engl J Med 329:1296–1301, 1993.

343. Yamada M, Hudson S, Tournay O, et al: Detection of minimal disease in hematopoietic malignancies of the B-cell lineage by using third-complementary-determining region (CDR-III)-specific probes. Proc Natl Acad Sci U S A 86:5123–5127, 1989.

344. Yamada M, Wasserman R, Lange B, et al: Minimal residual disease in childhood B-lineage lymphoblastic leukemia: Persistence of leukemic cells during the first 18 months of treatment. N Engl J Med 323:448–455, 1990.

345. Estrov Z, Grunberger T, Dube ID, et al: Detection of residual acute lymphoblastic leukemia cells in cultures of bone marrow obtained during remission. N Engl J Med 315:538–542, 1986.

346. Chen CJ, Chin JE, Ueda K, et al: Internal duplication and homology with bacterial transport proteins in the MDR1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47:381–389, 1986.

347. Fojo AT, Ueda K, Slamon DJ, et al: Expression of a multidrug resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 84: 265–269, 1987.

348. List A: Multidrug resistance: Clinical relevance in acute leukemia. Oncology 7:23–27, 1993.

349. Goasguen JE, Dossot JM, Fardel O, et al: Expression of the multidrug resistance associated P-glycoprotein (P-170) in 59 cases of acute lymphocytic leukemia-Prognostic implications. Blood 81:2394–2398, 1993.

350. Korsemeyer SJ: Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80:879–886, 1992.

351. Campana D, Coustan-Smith E, Manabe A, et al: Prolonged survival of B-lineage acute lymphoblastic leukemia cells is accompanied by overexpression of bcl-2 protein. Blood 81:1025–1031, 1993.

352. Smets LA, Van den Berg J, Acton D, et al: Bcl-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis. Blood 84:1613–1619, 1994.

353. Gala JL, Vermylen C, Cornu G, et al: High expression of bcl-2 is the rule in acute lymphoblastic leukemia, except in Burkitt subtype at presentation, and is not correlated with prognosis. Ann Hematol 69:17–24, 1994.