1337

The Biology and Therapy of Adult Acute Lymphoblastic Leukemia

Stefan Faderl, M.D. Sima Jeha, M.D. Hagop M. Kantarjian,
BACKGROUND. Much progress has been made in understanding the biology of
M.D.

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

acute lymphoblastic leukemia (ALL). This has translated into the recognition of several subgroups of ALL and the institution of risk-adapted therapies. New therapies are emerging based on the denition of specic cytogenetic-molecular abnormalities. METHODS. A review from the English literature, including original articles and related reviews from Medline (Pubmed) and abstracts based on publication of meeting material, was performed.

RESULTS. Changes in the pathologic classication of ALL have led to therapeutic consequences. Adaptation of successful treatment strategies in children with ALL has resulted in similar complete response rates in adults. Prognosis has especially improved in matureB-cell and T-lineage ALL. The role of tyrosine kinase inhibitors in Philadelphia chromosomepositive ALL was evaluated in the current study. However, regardless of the ALL subgroup, long-term survival of adults is still inferior to that in children. CONCLUSIONS. Intense clinical and laboratory research is attempting to close the gap in outcome between children and adults with ALL. Investigations are focusing on 1) renement of the basic treatment stratagem of induction, consolidation, and maintenance; 2) expansion of risk-based, subgroup-oriented therapies; 3) assessment of minimal residual disease, its impact on disease recurrence, and its practical implications in clinical practice; 4) salvage strategies; 5) the role of stem cell transplantation in ALL; and 6) the development of new drugs based on a better understanding of disease biology. Cancer 2003;98:133754. 2003 American Cancer Society. KEYWORDS: acute lymphoblastic leukemia, adult acute leukemias, Philadelphia chromosome, risk-adapted therapies.

Address for reprints: Stefan Faderl, M.D., Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, P.O. Box 428, 1515 Holcombe Blvd., Houston, TX 77030; Fax: (713) 7944297; E-mail: sfaderl@mdanderson.org Received April 3, 2003; revision received June 11, 2003; accepted June 30, 2003. 2003 American Cancer Society DOI 10.1002/cncr.11664

uch progress has been made in understanding the biology of acute lymphoblastic leukemia (ALL), which is now recognized as an expanding group of heterogeneous entities. Recognition of distinct gene expression patterns may identify patient subgroups with unique responses to therapy and prognosis. Accurate denition of prognostic subgroups based on cytogenetic-molecular markers has allowed institution of risk-oriented therapies. Adaptation of successful pediatric ALL treatment strategies into the therapeutic algorithms of adult ALL has resulted in complete response (CR) rates similar to those achieved in children. Improvement is particularly evident in subgroups such as matureB-cell or T-lineage ALL. However, whereas almost 80% of children are cured from ALL, only about 30 40% of adults achieve long-term disease-free survival (DFS). With further molecular dissection of ALL subtypes, and with the development of new and targeted drugs, signicant progress will hopefully occur soon in adult ALL.

1338

CANCER October 1, 2003 / Volume 98 / Number 7

EPIDEMIOLOGY
About 5000 patients with ALL are diagnosed annually in the United States.1,2 ALL is the most frequently diagnosed childhood acute leukemia, constituting 25% of childhood malignancies. It represents only 20% of adult acute leukemias. ALL has a bimodal distribution. The incidence is 4 5 per 100,000 population between the ages of 2 4, which decreases during later childhood, adolescence, and young adulthood before a second, smaller peak occurs in patients older than 50 years (incidence 1 per 100,000 population).3 Among children, white children are affected more frequently than African-American children. There is little difference in incidence rates by gender among children, but in older age groups, ALL is more predominant in males. The incidence of ALL has remained stable worldwide for decades. An unexplained small increase in the number of cases has been observed recently.4

with higher socioeconomic status, which may relate to better hygiene, less social contact in early infancy, and thus a differing exposure to infectious agents.27 EBV, a DNA virus causing infectious mononucleosis, is associated with Burkitt lymphoma and matureB-cell ALL including many HIV-related lymphoproliferative disorders.28 A link between the onset of ALL and seasonality has been described and also may be related to infectious etiologies.29,30 Few cases of ALL after chemotherapy exposure have been described. Translocation t(4;11)(q21;q23) has been demonstrated in ALL up to 2 years after treatment with topoisomerase II inhibitors.31

CLINICAL PRESENTATION
Symptoms arise from expansion of leukemic cells in the bone marrow, peripheral blood, and extramedullary sites. Fatigue, lack of energy, dyspnea, dizziness, bleeding, easy bruising, and infections are common. Extremity and joint pain may be the presenting symptom in children. Physical examination may reveal pallor, ecchymoses, or petechiae. Lymphadenopathy and hepatosplenomegaly are infrequent and rarely symptomatic.32 Involvement of skin, testicles, kidneys, joints, and bones is uncommon in adults.33,34 Central nervous system (CNS) involvement is uncommon at diagnosis, except in patients with matureB-cell ALL. These patients may present with cranial nerve deciencies (especially cranial nerves VI, III, IV, and VII), leading to double vision, abnormal ocular movements, facial dysesthesia, and facial droop.35 Chin numbness due to mental nerve involvement may be subtle and can be overlooked easily. Patients with T-lineage ALL present with a mediastinal mass on chest X-ray. If the mass is sufciently large, it results in stridor, wheezing, pericardial effusions, and superior vena cava syndrome.36,37 B-cell ALL is a rapidly proliferating tumor. Patients present with signs and symptoms of metabolic hyperactivity, including profound constitutional symptoms, weight loss, and often large abdominal and (especially in children) testicular masses that can lead to obstructive hydronephrosis with renal insufciency.38,39 Involvement of the gastrointestinal tract is frequent and may cause bleeding or rupture.

ETIOLOGY
Associations with environmental, socioeconomic, infectious, and genetic events are being studied extensively. Few causal links have been established and the etiology of ALL remains obscure in most cases.5 The strongest associations to date exist with genetic factors and the role of Epstein-Barr virus (EBV) and human immunodeciency virus (HIV) in patients with matureB-cell ALL. The role of genetic factors is suggested by several observations. ALL in a monozygotic twin has a 20 25% likelihood of developing in the second twin within 1 year.6 Among dizygotic siblings, there is a fourfold higher risk of leukemia compared with the general population.7,8 Patients with trisomy 21 (Down syndrome) have a 20-fold higher risk of developing ALL compared with the general population.9 12 Klinefelter syndrome and inherited diseases with excessive chromosomal fragility (Fanconi anemia, Bloom syndrome, ataxia-telangiectasia) also have been associated with the development of ALL.13, 14 16 An increased number of ALL cases have been recorded after the atomic bomb explosions,17 other nuclear exposures such as the Chernobyl accident,18 exposure to therapeutic radiotherapy,19 and in utero exposure.20 Increased incidence of ALL also has been associated with residence close to industrial sites; exposure to gasoline, diesel and motor exhausts, smoking, and hair dyes;2124 parental use of amphetamines, diet pills, and mind-altering drugs before and during the pregnancy;25 and exposure to electromagnetic elds.26 An increased incidence of ALL has been described

CLASSIFICATION
FrenchAmericanBritish Classication
Morphology and cytochemical stains are essential in the initial workup. The bone marrow is usually hypercellular and replaced with a homogenous population of leukemic blasts. Bone marrow hypocellularity with increased numbers of lymphoblasts or a necrotic bone marrow at presentation is rare.40 43

Adult ALL/Faderl et al. TABLE 1 FrenchAmericanBritish Classication of Acute Lymphoblastic Leukemia

FAB L1 Morphology Size N/C ratio Nucleoli Vacuolization Basophilia Cytochemistry MPO NSE PAS AP Frequency (%) Adults Children FAB L2

1339

FAB L3 (Burkitt lymphoma)

Small and homogenous Higher in 75% of cells Inconspicuous, 01 Not prominent Moderate 30 85

Larger and pleomorphic Lower in 25% of cells Prominent, 1 Not prominent Moderate 60 14

Medium and homogenous Variable Multiple and prominent Sharply dened Deep 10 1

FAB: FrenchAmericanBritish classication; N/C: nuclear-to-cytoplasmic; MPO: myeloperoxidase; NSE: nonspecic esterase; PAS: periodic acid-Schiff; AP: acid phosphatase.

The FrenchAmericanBritish (FAB) Group described three types of ALL (L1, L2, and L3), which are distinguished by cell size, amount of cytoplasm, prominence of nucleoli, degree of cytoplasmic basophilia, and vacuolation (Table 1).44 46 By denition, ALL blasts are negative for myeloperoxidase (MPO). Low-level MPO positivity (35%) has been described in rare cases that otherwise lack expression of myeloid markers by ow cytometry.47,48 The World Health Organization (WHO) proposed new diagnostic guidelines for neoplastic diseases of hematopoietic and lymphoid tissues or lymphomas.49 The WHO classication suggested that 20% or a greater amount of blasts are sufcient for the diagnosis of ALL. The WHO classication also suggested that the distinction of L1, L2, and L3 morphologies be abandoned because L1 and L2 morphologies do not predict immunophenotype, genetic aberrations, or clinical behavior.

Immunophenotype
Immunophenotyping has contributed to a prognostically relevant view of the leukemic blasts in ALL. Due to the ease of application, accuracy in diagnosis, and quantiability of results, ow cytometry has become the preferred method for lineage assignment.50 A distinct lineage determination is possible in greater than 98% of the leukemic blasts (Fig. 1). ALL blasts are divided into precursorB-cell types, matureB-cell ALL, and T-lineage ALL (Table 2).51,52 PrecursorB-cell ALL includes prepre-B ALL (pro-B ALL), common ALL (cALL), and pre-B ALL. Pro-B ALL blasts express CD19, CD79a, or CD22, but no other B-cell differentiation antigens. CD19-posi-

FIGURE 1. Diagnostic approach to patients with acute lymphoblastic leukemia (ALL). EST: Esterase stain; PAS: periodic acidSchiff stain; AML: acute myelogenous leukemia; Ph: Philadelphia chromosome; TdT: terminal deoxynucleotidyl transferase; NK: natural killer; cALL; common ALL; cyIg: cytoplasmic immunoglobulin; sIg: surface immunoglobulin; MPO: myeloperoxidase.

tive, CD10-negative, cytoplasmic immunoglobulinnegative B-lineage ALL with myeloid marker coexpression is common among infants with ALL and translocation t(4;11) and MLL gene rearrangements.53 cALL (early pre-B ALL), the most common immunophenotype in adults and children, is positive for CD10 (common ALL antigen). It is found frequently in Philadelphia chromosome (Ph)-positive ALL (i.e., in 50% of cases), accounting for the worse prognosis of CD10-

1340

CANCER October 1, 2003 / Volume 98 / Number 7

TABLE 2 Immunophenotype of Adult Acute Lymphoblastic Leukemia

Lineage PrecursorB-cell ALL Pro-B ALL cALL Pre-B ALL Transitional precursorB-cell ALL MatureB-cell ALL T-lineage ALL Pro-T ALL Pre-T ALL Cortical-T ALL Mature-T ALL TdT HLA-DR CD34 CD19 CD22 CD79a CD10 cy cy/ slgH/L cyCD3 CD7 CD1a CD2 CD5 sCD3 Frequency (%) 510 4050 10 1 1 5 5 1015 510

TdT: terminal deoxynucleotidyl transferase; cy: cytoplasmic; s: surface; IgH: immunoglobulin heavy chain; IgL: immunoglobulin light chain; ALL: acute lymphoblastic leukemia; cALL: common acute lymphoblastic leukemia. a Usually no surface light chain (L) expression.

positive ALL in adults versus children. Finally, pre-B ALL blasts express cytoplasmic immunoglobulins (Ig). The blasts are more differentiated than in early pre-B ALL and more cases have translocation t(1;19).54,55 In children, but not in adults, identication of this cytogenetic abnormality has been linked to a worse prognosis in pre-B ALL than in early pre-B ALL.56 MatureB-cell ALL is distinguished by the expression of surface Ig, usually IgM, and by the absence of staining for the enzyme terminal deoxynucleotidyl transferase (TdT). MatureB-cell ALL is associated with the FAB L3 subtype. In some cases, L1 or L2 morphology has been described.57 Translocations between the c-myc locus on chromosome 8q24 and one of the loci for the Ig heavy (IgH) or light chain genes (14q32, 2p12, and 22q11) are characteristic.58 The T ALL subtypes are distinguished according to the stage of normal thymocyte development.59 Cytoplasmic CD3 (cCD3) is the most T-lineagespecic marker. Although early subtypes do not express surface CD3 (sCD3), they are positive for cCD3. CD4 and CD8 are either double-positive or double-negative. CD2 is negative. The more mature subtypes of T ALL are positive for both sCD3 and cCD3, CD2, and either CD4 or CD8 but not both.60 Although it is the most sensitive T-cell marker, CD7 lacks specicity, as cases of acute myelogenous leukemia (AML) or natural killer (NK) cell leukemia can express CD7 too.61 ALL blasts coexpress myeloid markers in 1550% of adults and in 535% of children.51,62 65 The most frequently coexpressed myeloid markers are CD13 and CD33.66 68 No association exists between myeloid marker expression and FAB group or karyotype, except for a higher incidence with translocations t(9;

FIGURE 2. Cytogenetic abnormalities in adult acute lymphoblastic leukemia.

22) and t(4;11).69 Although earlier studies had shown a worse outcome with coexpression of myeloid markers, recent studies did not show any prognostic signicance.63,70 75

Cytogenetic-Molecular Markers
Recurrent cytogenetic-molecular abnormalities occur in about 80% of children and 60 70% of adults (Fig. 2).76 Distinct subsets of ALL can now be identied based on molecular abnormalities with implications on prognosis and on the choice of therapy.77

The Philadelphia chromosome

Ph results from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11). With a frequency of 1530%, it is the most common cytogenetic abnormality in adult ALL.76 A segment of the ABL gene

Adult ALL/Faderl et al.

1341

(9q34) is moved into one of several breakpoint cluster regions of the BCR gene (22q11). The chimeric BCRABL gene is translated into BCR-ABL oncoproteins of different molecular weights, depending on the location of the breakpoint in the BCR gene.78 Whereas p210BCR-ABL is characteristic for chronic myeloid leukemia, a shorter version, p190BCR-ABL, predominates in Ph-positive ALL. The abnormal fusion proteins have deregulated and abnormally increased tyrosine kinase activity, leading to the involvement of downstream signaling pathways. Patients with t(9;22) typically are older and frequently have higher leukocyte and blast counts at diagnosis than patients with normal karyotypes.79 A preB-cell immunophenotype and expression of CD10 and myeloid markers typically are associated with Ph.

Chromosome 19p13
The two known translocations involving 19p13 are t(1;19)(q23;p13) and its rare variant, t(17;19)(q21;p13). Translocation t(1;19) has a strong association with cytoplasmic Ig-positive pre-B ALL.89 Its overall frequency in childhood ALL and pre-B ALL is 5% and 25%, respectively. The translocation juxtaposes the E2A gene on chromosome 19 with the homeoboxcontaining gene, PBX1, to generate the E2A-PBX1 fusion gene. It functions as a potent transcriptional activator and transforms in vitro several cell types including broblasts, myeloid progenitors, and lymphoblasts.90 Patients with E2A-PBX1 expressing ALL do poorly with standard therapy, but have a better prognosis with more aggressive approaches. In contrast to the unfavorable prognosis of patients with pre-B ALL and t(1;19), patients with pro-B ALL and t(1;19) do better.91

Chromosome 9p21 abnormalities

Chromosome 9p21 abnormalities occur in about 15% of patients.80 The cyclin-dependent kinase inhibitors (CDKI), p16INK4a/p14ARF and p15INK4b, are localized on chromosome 9p21 and deletions of these genes, more so than silencing of gene expression by hypermethylation, are their major mode of inactivation.81 Using uorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), deletions of p16INK4a are present in 80% of children with T-ALL and 20% of children with pre-B ALL. Patients with 9p21 abnormalities are prognostically heterogeneous. Deletions of 9p are an adverse risk factor in B-lineage, but not T-cell, ALL, although homozygous deletions are associated with a signicantly poorer survival in T-ALL as well.82 Prognostic associations are stronger in children than in adults with ALL.83 85

Translocation t(12;21)
Using PCR, this otherwise cryptic translocation now can be identied in up to 30% of children with ALL, making it the most frequent recurring cytogeneticmolecular abnormality in pediatric ALL. It is rare in adults (i.e., it occurs in 13% of adults).92,93 The translocation involves TEL (ETV6), a transcription-regulating gene of the Ets family of transcription factors on 12p11, and AML1 on 21q22.94 The outcome of patients with a TEL-AML1 fusion is favorable in children with pre-B ALL, independent of age or leukocyte count at presentation. One study suggested that the favorable outcome was from exclusion of patients with other poor-risk cytogenetic abnormalities and the younger age of these patients compared with patients with normal karyotypes.78 Translocation t(12;21) may be associated with late disease recurrences.95,96 Its prognostic signicance is undetermined in adults.

11q23 rearrangements
The common denominator among 11q23 abnormalities is the involvement of the mixed lineage leukemia gene, MLL (previously ALL-1, HRX, or HTRX1). More than 20 chromosomal loci participate in reciprocal rearrangements with 11q23, including 4q21, 9p22, 19p13, and 1p32.86,87 The most common translocation is t(4;11)(q21;23). It is specically associated with ALL in infants (85% of the cases) and it is found in 3 8% of adults.77,86 Adults with this translocation tend to be older and more frequently have higher leukocyte counts, organomegaly, and CNS involvement. The pro-B ALL immunophenotype is positive for TdT, HLA-DR, and CD19 and is variably negative for CD10. Myeloid antigen coexpression is common. Prognosis with 11q23 rearrangements is poor. Allogeneic stem cell transplantation (SCT) for patients with their rst disease remission is currently the treatment of choice.88

Translocation t(8;14) and its variants

Translocation t(8;14)(q24;q32), and its less common variants, t(8;22)(q24;q11) and t(2;8)(p12;q24), are characteristic of matureB-cell ALL. All three translocations result in deregulation, increased transcription, and overexpression of c-MYC. In 80% of patients, 8q24 is juxtaposed to the IgH gene locus on 14q32, whereas the Ig lamba gene locus on 22q11 is involved in 15% of patients and the Ig kappa gene locus on 2p12 is involved in 5% of patients.97 MatureB-cell ALL and Burkitt lymphoma typically are associated with 8q24 rearrangements.

T-cell receptor gene rearrangements

T-cell receptor (TCR) gene rearrangements are the most common genetic abnormalities in T-ALL.76 Al-

1342

CANCER October 1, 2003 / Volume 98 / Number 7

because within the same recurrent translocation (e.g., Ph abnormality), adults fare much worse than children. New therapies targeting newly identied specic molecular abnormalities may increase the effectiveness of current therapies.

PROGNOSIS
Advances in ALL therapy have changed the risk assignment of some subgroups such as T-lineage ALL and matureB-cell ALL. Some believed to be previously useful prognostic, clinical, laboratory, or biologic predictors have now little value as the treatment has improved dramatically over the last two decades.102104 Other prognostic factors can be explained by superceding genetic-molecular abnormalities that are being recognized increasingly as powerful predictors of outcome.76 Persistent adverse prognostic features include older age, leukocytosis, delayed response to therapy, specic cytogenetic abnormalities, and immunophenotype, with some limitations (Table 3).105112 Up to 75% of adults with ALL are considered to be poor-risk patients, with an expected DFS rate of 25%. Only 25% of adults with ALL constitute standard-risk patients, with a projected DFS rate of greater than 50%. Recently, other factors were identied to predict prognosis. The dynamics of blast clearance in response to steroids, assessed within 12 weeks, have prognostic value in adults.113 Markers of drug resistance, such as expression of MDR-1, were reported to be prognostic factors by the Italian GIMEMA group.114 Finally, assessment of minimal residual disease (MRD) is emerging as important for determining the risk of disease recurrence.

FIGURE 3.

Comparison of the incidence of prognostically relevant cytogenetic abnormalities between adults and children.

though no specic cytogenetic abnormality can be linked to a specic clinical subtype of T-ALL, a number of distinct chromosomal translocations have been identied (Fig. 3).

Gene Expression Proling

Success in ALL therapy is achieved partly from recognizing ALL as heterogeneous and using risk-adapted therapies.98 Assignment of risk is based on a number of clinical and laboratory parameters in ALL, but cytogenetic-molecular alterations are emerging as the dening prognostic features.99 Oligonucleotide microarray technology simultaneously quanties the expression of thousands of individual genes and therefore establishes gene expression proles for well dened ALL subgroups. The goals of gene expression proling are 1) denition of lineage afliation and distinct molecular subtypes that may defy current classication schemes; 2) association of gene expression with chromosomal abnormalities including the possibility to identify cases with cryptic translocations; 3) identication of genetic alterations that underlie the pathogenesis of individual leukemia subtypes; 4) detection of gene expression clusters that characterize patients with distinct responses to therapy, providing prognostic information; and 5) establishment of gene expression clusters in disease recurrence. Oligonucleotide or cDNA microarray technology is being established as an alternative and extension to conventional karyotyping and FISH in the diagnosis of leukemia subtypes and as a method to dene previously unrecognized molecular subtypes of ALL.98 101 Further applications will include comparisons of gene expression proles of adults versus children with ALL

PRIMARY THERAPY
Chemotherapy
Treatment programs incorporate multiple drugs into regimen-specic sequences of dose intensity and time intensity (Table 4).104,113,115125 The goal is rapid restoration of normal hematopoiesis, prevention of the emergence of resistant subclones, adequate prophylaxis of sanctuary sites such as the CNS, and elimination of MRD through postremission consolidation. Therefore, therapy is divided into several phases: induction, consolidation and intensication, and maintenance. CNS prophylaxis is essential in ALL and is usually delivered during induction and consolidation.

Induction
Vincristine plus corticosteroids achieve CR rates of 40 65%, but the median duration of disease remission is only 37 months. Adding anthracyclines has increased the CR rate to 7292% and the median dura-

Adult ALL/Faderl et al. TABLE 3 Prognostic Factors in Adult Acute Lymphoblastic Leukemia
Characteristic Patient-related Age Performance status Gender Race Plasma albumin levels Treatment-related Late response Response to steroids Dose intensity Pharmacodynamics Disease-related Leukocytosis Cytogenetics Immunophenotype Other characteristics P-glcyoprotein p53 p15INK4b Glutathione Caspase 2 and 3 High-risk factor(s)

1343

Standard-risk factor(s)

50 yrs Poor Male Black Low Time to CR 4 weeks Persistence of blasts in PB at Day 7 and BM at Day 14 Delayed, incomplete Decreased Nontherapeutic levels of 6-MP, MTX 30 109/L (B-lineage) 100 109/L (T-lineage) t(9;22), t(4;11) Early- and mature-T ALL, pro-B ALL (null type) Greater expression Aberrant expression Greater methylation High levels High levels

35 yrs Good

Normal Time to CR 4 weeks Timely clearance of blasts Fast, complete Therapeutic levels of drugs 30 109/L t(12;21), hyperdiploid Cortical-T ALL

ALL: acute lymphoblastic leukemia; CR: complete response; PB: peripheral blood; BM: bone marrow; 6-MP: 6-mercaptopurine; MTX: methotrexate.

tion of disease remission to approximately 18 months.125127 Dexamethasone has been substituted for prednisone because of better in vitro antileukemic activity and achievement of higher drug levels in the cerebrospinal uid (CSF).128 130 It has been difcult to demonstrate further improvement of CR rates with the addition of asparaginase, cyclophosphamide, cytarabine, and other agents. Intensication of induction may, however, positively inuence the duration of disease remission and survival (e.g. in T-lineage ALL with cytarabine [ara-C] and cyclophosphamide and in matureB-cell ALL with fractionated doses of cyclophosphamide and high doses of methotrexate).104,113,118,131133 Other approaches to induction therapy include high-dose ara-C and mitoxantrone without vincristine-steroids,134 high doses of daunorubicin (total of 270 mg/m2) and ara-C during induction-consolidation,124 and high doses of liposomal daunorubicin during induction. The use of growth factors during induction may alleviate profound myelosuppression and its complications and allow timely administration of dose-intensive treatment regimens.135137 In a double-blind, randomized trial (Cancer and Leukemia Group B [CALGB] 9111), granulocyte colony-stimulating factor (G-CSF) during induction was associated with faster recovery

of neutrophils to greater than 1 109/L (P 0.0001), platelet recovery, and reduction of the duration of the hospital stay (P 0.02).137 The CR rate was higher with G-CSF (90% vs. 81%; P 0.10), which was more pronounced in elderly patients. A higher rate of induction deaths was observed in the placebo group compared with the G-CSFtreated group (11% vs. 4%, P 0.04) and in patients age 60 years or older (25% vs. 10%, P 0.24).

Consolidation
Consolidation may include a modied induction treatment, rotational consolidation programs, and SCT. It is difcult to assess the value of individual components of the treatment because the number, schedule, and combination of cytostatic drugs vary considerably among studies. Current strategies address the subtype and risk-oriented approaches of consolidation programs. Hyper-CVAD is a dose-intensive regimen with alternating hyperfractionated cyclophosphamide and high doses of ara-C and methotrexate.118 Compared with the earlier and less intensive regimen of vincristine, doxorubicin, and dexamethasone (VAD), CR rates (91% vs. 75%, P 0.01) and survival (P 0.01) were superior with hyper-CVAD. In the CALGB 8811 study, patients underwent

1344

CANCER October 1, 2003 / Volume 98 / Number 7

TABLE 4 Results of Chemotherapy Studies in Adult Acute Lymphoblastic Leukemia

Study Annino et al., 2002113 Linker et al., 2002122 Goekbuget et al., 2001138 Bassan R et al., 2001196 Dekker et al., 2001197 Rowe et al., 2001161 Kantarjian et al., 2000118 Thiebaut et al., 2000160 Hallbook et al., 1999198 Todeschini et al., 1998124 Ribera et al., 1998139 Larson et al., 1998137 Durrant et al., 1997123 Larson et al., 1995104 Go kbuget et al., 2000115 Hussein et al., 1989120 GIMEMA, 1989121 n 794 84 1200 121 193 871 203 572 120 60 108 198 618 197 569 168 358 Median age (range) (yrs) 27.5 (1259.9) 27 (1859) 35 (1565) 35 (NA) 33 (1560) 30 (1460) 39.5 (1679) 33 (1560) 44 (1682) 34 (1471) 28 (1574) 35 (1683) 15 32 (1680) 27 (1565) 28 (1585) 31 (1564) CR (%) 82 93 86 84 82 89 91 76 85 93 86 82 88 85 75 68 79 Induction mortality (%) 7 NI 5 NI NI 5 6 9 5 5 5 8 9 9 10 17 7 LTS (%) (yrs) NI 48 (5) 47 (5) 49 (3) 35 (5) 34 (5) 39 (5) 27 (10) 36 (3) 55 (6) 41 (5) 23 mosa 28 (5) 36 mosa 39 (7) 17.7 mosa 21.7 mosa

CR: complete response; LTS: long-term survival; NI: no information; GIMENA: Grupo Italiano Malattie Ematologische dellAdulto. a Median survival.

early and late intensication courses with eight drugs following a ve-drug induction regimen.104 Maintenance therapy was given for 2 years after diagnosis. The median duration of disease remission was 29 months, and the median survival period was 36 months; these results were considerably better than those from earlier, less intensive trials. In the Medical Research Council (MRC) UKALL XA, patients were randomized to receive early intensication at 5 weeks, late intensication at 20 weeks, both, or neither.123 The early block of intensive treatment prevented disease recurrence although the DFS at 5 years was increased only slightly. The German multicenter trial 05/93 intensied the consolidation in a subtype-specic manner.138 In that study, patients received high-dose methotrexate for standard-risk B-lineage ALL, cyclophosphamide and ara-C for T-lineage ALL, and high-dose methotrexate and high-dose ara-C for high-risk B-lineage ALL. Induction was intensied with high-dose ara-C (4 doses of 3 g/m2) and mitoxantrone instead of the Phase II induction in high-risk patients. The CR rate was 87% for standard-risk patients, with a median duration of disease remission of 57 months and a 5-year survival rate of 55%. Intensied induction/consolidation did not improve the CR rate and DFS in high-risk patients, with the exception of pro-B ALL. Patients with pro-B ALL achieved a continuous CR rate of 41% compared with 19% in other high-risk patients.

The GIMEMA ALL 0288 study randomized patients to receive an early post-CR intensication versus maintenance therapy.113 Of 388 patients, 201 had maintenance alone whereas 187 received consolidation followed by maintenance. Intensication of postCR treatment did not inuence the continuous CR rate. At 8 years, 36% of patients who received consolidation-maintenance and 37% of patients who received maintenance remained in CR. Only 35% of patients randomized to the intensied consolidation completed their treatment in the expected time frame because of toxicities and compliance problems. In the PETHEMA ALL-89 trial, patients in disease remission at the end of the rst year were randomized to receive 1 6-week cycle of late intensication therapy.139 There was no difference in survival and DFS between patients who did or did not receive late intensication.

Maintenance
The maintenance regimen consists of daily doses of 6-mercaptopurine, weekly doses of methotrexate, and monthly pulses of vincristine and prednisone given over 23 years. Extension of the maintenance regimen beyond 3 years has not shown additional benets. Omission of maintenance therapy has been associated with shorter DFS rates.140 142 No clear advantage has been demonstrated with intensied versus conventional maintenance doses,143 leading some investigators to revisit shorter maintenance strategies. In T-cell ALL, the benet of maintenance chemotherapy has

Adult ALL/Faderl et al.

1345

been questioned. No maintenance therapy is given to patients with matureB-cell ALL. These patients respond well to short-term dose-intensive regimens and disease recurrences beyond the rst year in remission are rare.

remains to be determined whether any particular group of patients may benet from this approach. CNS prophylaxis remains essential. Omission of craniospinal XRT in favor of IT therapy, possibly combined with high-dose systemic therapy, may be possible, particulary in adult patients.

Central nervous system prophylaxis

CNS disease is rare at diagnosis (i.e., in 10% of patients), but may be diagnosed in 50 75% of patients at 1 year in the absence of CNS-directed therapy.108,118,144 146 The diagnosis of CNS leukemia requires the presence of more than ve leukocytes per microliter in the CSF and the identication of lymphoblasts in the CSF differential.147 The presence of blasts in a CSF sample with less than ve leukocytes per microliter may still signify CNS disease.148 False-negative CSF results may occur in patients with predominantly cranial nerve involvement. CNS prophylaxis clearly reduced the incidence of CNS disease.149 Measures of CNS prophylaxis include intrathecal (IT) chemotherapy (methotrexate, ara-C, steroids), high-dose systemic chemotherapy (methotrexate, ara-C, L-asparaginase), and craniospinal irradiation (XRT).35 The role of cranial XRT has become controversial. It can result in neurologic adverse events including seizures, dementia, intellectual dysfunction, growth retardation in children, and other complications. Risk factors for CNS leukemia in children include an age of 1 year or younger, excessive leukocytosis, T-lineage and matureB-cell ALL, lymphadenopathy, thrombocytopenia, hepatomegaly, and splenomegaly.150,151 MatureB-cell ALL, serum lactate dehydrogenase levels, and a high proportion of bone marrow cells in a proliferative state ( 14% of cells in the SG2M phase of the cell cycle) have been associated with a higher risk of CNS disease in adults compared with adults without these risk factors.152 Recent studies suggested that effective CNS prophylaxis can be achieved with a combination of IT and high-dose systemic chemotherapy without cranial XRT, even in patients at high risk for developing CNS disease.146,152 Based on the experience with hyperCVAD, CNS prophylaxis consists of 4 IT treatments in the low-risk category, 8 IT treatments with high-risk disease, and 16 IT treatments for matureB-cell ALL or Burkitt disease. Patients with cranial nerve root involvement may benet from selective XRT to the base of the skull. The backbone of chemotherapy for ALL remains the sequence of induction, consolidation, and a prolonged maintenance of at least 2 years. Attempts to intensify treatment during the consolidation phase have been met with mixed results. Whereas the compliance rate has been questioned in some trials, it

Stem Cell Transplantation Allogeneic sibling stem cell transplantation

The survival rate for adult patients with ALL with matched related allogeneic SCT in rst CR is about 50% (range, 20 81%).153155 Several studies have tried to compare the outcome of SCT versus chemotherapy in ALL in rst CR. As 70% of adults with ALL cannot be allocated to SCT because of a lack of a matched related sibling, comorbidities, or severe infections, an objective and unbiased comparison among treatments is difcult.156 The International Bone Marrow Transplant Registry compared 251 patients who received intensive postremission chemotherapy with 484 patients who received matched related sibling allogeneic SCT. After adjustments for differences in disease characteristics and time to treatment, the 9-year DFS rates were 32% for chemotherapy and 34% for allogeneic SCT.157 The causes of treatment failure were different, i.e., the actuarial disease recurrence rates at 9 years were 66% with chemotherapy and 30% with transplantation. Treatment-related mortality was the main cause of failure in patients who received transplants.158 A large French multicenter trial (LALA 87) compared allogeneic SCT with chemotherapy or autologous SCT in rst CR.159 Of 257 randomized patients, 116 were allocated to receive allogeneic SCT and 114 were allocated to the control group (chemotherapy and autologous SCT). The 5-year survival rates were not signicantly different (48% and 35%, respectively; P 0.08). Among patients with high-risk ALL, the 5-year overall survival rate (44% vs. 20%, P 0.03) and the 5-year DFS rate (39% vs. 14%, P 0.01) were more favorable with allogeneic SCT. An update of the LALA 87 study presented the long-term comparative data of allogeneic SCT versus the control arm of these patients.160 Based on an intent-to-treat analysis, the overall survival rate was 46% with SCT versus 31% with chemotherapy (P 0.04). In the high-risk group, survival rates at 10 years were 44% with SCT and only 11% in the control arm (P 0.009). In the standard-risk group, the corresponding numbers were 49% and 39%, respectively (P 0.6). These results support the value of allogeneic SCT in rst CR in patients with high-risk ALL. In the international ALL trial (MRC UKALL XII/ Eastern Cooperative Oncology Group E2993), all pa-

1346

CANCER October 1, 2003 / Volume 98 / Number 7

tients received two phases of induction therapy and were assigned in CR to receive allogeneic SCT if they had a histocompatible donor.161 The remaining patients received either standard consolidation/maintenance therapy for another 2.5 years or autologous SCT. Early results have been presented for 170 patients receiving allogeneic SCT and 264 patients eligible for randomization. The reported data focus on Ph-negative patients and are based on an intent-totreat analysis from the time of their intended therapy. The 5-year event-free survival (EFS) rate was 54% in the allogeneic group and 34% in the randomized group (P 0.04). In the standard-risk group, the 5-year EFS rates were 66% with allogeneic SCT and 45% for the randomized group (P 0.06). The rates were 44% and 26%, respectively, for high-risk patients. Contrary to the ndings of other studies, these data suggested that allogeneic SCT was benecial in rst CR, regardless of the risk group.

the current approach of restricting allogeneic SCT to high-risk ALL patients in rst CR only.

Minimal Residual Disease (MRD)

MRD can be measured with ow cytometry and PCR techniques using either fusion transcripts resulting from chromosome abnormalities or patient-specic junctional regions of rearranged Ig and TCR genes.166 To determine residual disease at various time points during the rst 6 months after disease remission, Cave et al.167 used quantitative PCR for junctional sequences of TCR or Ig gene rearrangements in 246 children with ALL. There was a signicant correlation between detection of MRD and risk of early disease recurrence at each of the time points studied, particularly in patients with 102 residual blasts per 2 105 mononuclear bone marrow cells immediately after disease remission or with 103 at later time points. Less data are available on MRD in adult ALL and differences in pattern and dynamics of clearance of residual disease exist between adult and childhood ALL. Foroni et al.168 analyzed bone marrow samples from 33 adults and 21 children by PCR for IgH gene rearrangements at specic time points after diagnosis. Among patients who remained in CR, a decrease in MRD positivity occurred during the rst 12 months. The proportion of positive tests decreased more quickly in children than in adults, suggesting more rapid resolution of MRD, particularly in the rst 6 months of CR. Using quantitative PCR in 27 adults with ALL, Brisco et al.169 found a signicantly higher rate of disease recurrence (89%) if residual disease persisted above a level of 103 leukemic cells per bone marrow cell. However, even in patients with lower levels of residual disease, the risk of disease recurrence was still high (46%). In addition to reservations about the predictive threshold of residual disease, the optimal time point to measure residual disease is not clear. In a study of 85 adult patients with B-lineage ALL, residual disease was assessed by semiquantitative IgH gene analysis during 4 time points in the rst 24 months of treatment.170 MRD positivity was associated with increased disease recurrence rates at all times, but the association was most signicant 35 months after induction and beyond. The association between residual disease and DFS was independent of and greater than other standard predictors of outcome. Although data from analysis of MRD are increasingly applied in protocols and are integrated into clinical decision-making, important issues remain to be resolved by future studies. Even if early detection of residual disease by sensitive techniques predicts dis-

Autologous stem cell transplantation

In most studies, autologous SCT is inferior to allogeneic SCT.156 No advantage in DFS has been demonstrated with autologous SCT compared with chemotherapy alone.162,163 In the LALA 87 trial, the results were still not signicant, even when comparing highrisk and standard-risk patients.160 Investigators at The University of Texas M. D. Anderson Cancer Center (Houston, TX) found no signicant difference between the 3-year DFS and overall survival rates with autologous SCT in rst CR versus continued postremission chemotherapy (60% vs. 49% and 58% vs. 62%, respectively).164 Powles et al.165 combined conventional ALL therapy with autologous SCT. Seventy-seven patients in rst remission received autografts followed by posttransplantation maintenance chemotherapy with methotrexate, 6-mercaptopurine, vincristine, and prednisone. The cumulative incidence of disease recurrence at 10 years was 42%. The 10-year DFS and overall survival rates were 50% and 53%, respectively. The study performed by Powles et al. highlighted two important points: 1) patients who received at least two maintenance chemotherapy agents fared better than those who received one or none; and 2) there was no benet from autologous SCT in high-risk ALL. Whereas autologous SCT has not provided any benet compared with chemotherapy in rst CR, recent data on the role of allogeneic transplant for patients in rst CR are more intriguing. If the data from the international ALL trial are conrmed, then allogeneic SCT appears to be superior to chemotherapy even in standard-risk patients with ALL, challenging

Adult ALL/Faderl et al.

1347

ease recurrence, how can early detection of molecular disease recurrence guide therapy?, and does treatment of molecular disease recurrence improve survival? Finally, it may not be necessary to completely eliminate residual disease to achieve cure. Other homeostatic mechanisms may modulate growth of the leukemic clones that are currently not identiable with the assays applied to residual disease.166

identied in 35%, and 75% of these patients underwent SCT. Of 58 patients for whom an unrelated donor search was initiated, a donor was identied for 22 patients and 15 patients proceeded to an SCT from a matched unrelated donor.

PHILADELPHIA CHROMOSOMEPOSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA

Patients with Ph-positive ALL have long-term DFS rates of less than 10%.183 In a CALGB study, the CR rate in Ph-positive ALL was 79% and the 5-year continuous CR rate was 8% (vs. 38% with diploid ALL).184 Currently, SCT is recommended for all patients with Ph-positive ALL who achieve a CR. The international ALL trial group compared the outcome of 167 patients with Ph-positive ALL who received a matched related SCT (n 49), a matched unrelated donor transplant (n 23), autologous SCT (n 7), or continued chemotherapy (n 77).185 The treatment-related mortality rate was higher with SCT (37% for matched sibling transplants, 43% for matched unrelated donor transplants, 14% with autologous SCT, and 8% with chemotherapy). The 5-year risk of disease recurrence was lower with allogeneic SCT (29%) than with autologous SCT/chemotherapy (81%). The 5-year survival rates were 43% with allogeneic SCT and 19% with autologous SCT or chemotherapy. Imatinib mesylate (STI571, Gleevec; Novartis, East Hanover, NJ) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase.186 The M.D. Anderson Cancer Center studies combined imatinib with hyperCVAD for newly diagnosed patients with Ph-positive ALL.187 Eight induction/consolidation courses (hyperCVAD alternating with high-dose methotrexate and ara-C), during which imatinib is given for 14 days of each treament cycle, is followed by a 1-year maintenance with imatinib at a dose of 600 mg orally daily. Preliminary results showed that this combination is safe and that disease remission rates are high. The effect on long-term DFS remains unclear. In a study of 56 patients with recurrent and refractory Ph-positive ALL, imatinib 400 mg or 600 mg was given once daily.188 The CR rate was 29%. Responses were sustained for at least 4 weeks in only 6% of patients. The median time to progression and overall survival were 2.2 and 4.9 months, respectively. Limited experience exists with imatinib in Ph-positive ALL transplant failures.189 In a study of 20 consecutive Ph-positive patients with ALL who had disease recurrence after allogeneic SCT, imatinib induced a CR in 11 patients (55%).

SALVAGE THERAPY
The outcome of salvage therapy remains unsatisfactory. CR rates range from 10% to 50% and long-term DFS is poor. Salvage regimens are patterned according to promising leads from frontline therapy. Regimens are divided into combinations of vincristine, steroids, and anthracyclines, combinations of asparaginase and methotrexate, programs that integrate high-dose ara-C, and, nally, SCT.171 New agents are assessed continually and incorporated into salvage strategies.

Chemotherapy
The VAD regimen in 64 patients with recurrent or refractory ALL achieved a CR rate of 39%, with a median CR duration and survival of 7 and 6 months, respectively.128 The DFS rate at 2 years and the overall survival rate were 20% and 8%, respectively. Koller et al.172 compared hyper-CVAD with high-dose ara-C based treatments (mitoxantrone, high-dose ara-C, and granulocyte-macrophage colony-stimulating factor).172 The CR rates were similar with both regimens (44% and 38%), but survival was better with hyper-CVAD. L-asparaginase was administered in combination with methotrexate, anthracyclines, vinca alkaloids, and prednisone. Response rates ranged from 33% to 79% and the median DFS period ranged from 3 to 6 months.173175 Remission rates of 1770% have been reported with high-dose ara-C based regimens.176 178

Stem Cell Transplantation

Although SCT is superior to chemotherapy with longterm DFS rates of 20 40% in salvage therapy,179 only 30 40% of patients who achieved a second CR were eligible for SCT and fewer than one-half had enough time before disease recurrence to undergo SCT. Considering a DFS rate of about 25%, only a fraction of the total population at risk would benet from a transplant.180,181 In the absence of a matched related sibling donor, identifying an unrelated donor in a timely fashion can be difcult. Davies et al.182 studied the outcome of 115 consecutive patients with recurrent ALL over a 2-year period to determine the success rate of identifying a matched related or unrelated donor, as well as the feasibility of SCT.182 A matched related donor was

BURKITT ACUTE LYMPHOBLASTIC LEUKEMIA

Outcome with conventional ALL therapy for mature B-cell ALL was poor, with long-term DFS rates of less

1348

CANCER October 1, 2003 / Volume 98 / Number 7 TABLE 6 New Therapeutic Agents for Acute Lymphoblastic Leukemia
Agent type Agent Anti-CD20 (rituximab) Anti-CD19 ricin/genistein Anti-CD52 (alemtuzumab) Anti-CD33 Anti-CD7 ricin Imatinib mesylate Farnesyltransferase inhibitors (R115777, Sch66336) Nelarabine (compound 506U) Clofarabine BCX1777 Liposomal vincristine Pegylated asparaginase Liposomal ara-C (DepoCyt; Skye Pharma, London, United Kingdom)

TABLE 5 Outcome of Therapy for MatureB-Cell Acute Lymphoblastic Leukemia

Study Conventional (VAD) Kantarjian et al., 1990164 Short-time, dose-intensive Thomas et al., 1999151 Age 60 yrs Age 60 yrs Soussain et al., 1995194 Hoelzer et al., 2002199 Todeschini et al., 1997200 Fenaux et al., 1989201 n CR (%) % DFS (yrs)

Monoclonal antibody 86 26 14 12 65 89 21 18 4465 81 92 67 89 75 100 56 015 49 (3) 74 (3) 16 74 (3) 38 (4) 75a 57b

Tyrosine kinase inhibitor

Nucleoside analog Purine nucleoside phosphorylase inhibitor Other

CR: complete response; DFS: disease-free survival; VAD: vincristine, doxorubicin, and dexametnasone. a Event-free survival, with a median follow-up of 28 months. b Survival plateau at 7 months, with no late disease recurrences.

than 10%.37 Hyperfractionation of the alkylating agent cyclophosphamide, and use of different non crossresistant agents in tandem, formed the basis of many dose-intensive programs (Table 5).190 193 Complete disease remission was attained in 89 92% of patiemnts and 2-year DFS rates increased to 60 80%. Disease recurrence was rare after the rst year in remission. Intensive early prophylactic IT therapy (with or without cranial XRT), in addition to intensive systemic methotrexate and ara-C, signicantly reduced the rate of disease recurrence in the CNS. Hyper-CVAD, modeled after the total therapy B designed by Murphy et al. for childhood matureB-cell ALL,142 was given to 26 patients. The overall CR rate was 81%.102,194 The long-term DFS rate was 83% for patients younger than 60 years of age, but only 16% for patients 60 years of age or younger. The less favorable outcome in older patients was accounted for by both higher induction mortality and higher disease recurrence rates. Rituximab (anti-CD20 monoclonal antibody) is now incorporated into hyper-CVAD to further improve the prognosis of matureB-cell ALL. Cortes et al.195 studied hyper-CVAD for newly diagnosed patients with HIV-related matureB-cell ALL, adding highly active antiretroviral treatment (HAART). The CR rate in 13 patients was 92%, the median survival period was 12 months, and about 50% of the patients were alive more than 2 years after diagnosis. The outcome was better in the group receiving HAART early in the course of therapy (Cortes J. Personal communication). The role of autologous or allogeneic SCT in matureB-cell ALL is less clear. With short-term, doseintensive chemotherapy programs, most patients either achieve disease remission or experience rapidly

progressive disease not amenable to successful tumor reduction to allow consolidation with SCT.

CONCLUSIONS
Improvements in chemotherapy programs for adult ALL have achieved CR rates of about 90% and longterm DFS rates of 30 40%. Prognosis has improved remarkably in subsets of T-lineage ALL and mature B-cell ALL; about 50% of patients achieve disease remission. Conversely, patients with Ph-positive ALL and other high-risk cytogenetic abnormalities continue to do poorly. Improving the outcomes of these subsets of patients is a major future challenge. How can prognosis in these patients be improved? Better knowledge of the biologic subtleties of leukemic blasts and the pathophysiology of ALL will facilitate therapy-oriented discoveries (e.g., imatinib mesylate in Ph-positive ALL). The ultimate goal in ALL therapy will be to devise risk-group and disease-specic directed therapies. Many investigational approaches are promising (Table 6). Novel chemotherapy agents (e.g., compound 506U, liposomal vincristine, and clofarabine), use of monoclonal antibodies (e.g., rituximab in CD20-positive ALL, alemtuzumab, anti-CD19, and anti-CD22 monoclonal antibodies), reduced intensity SCT, or immunomodulatory strategies are being explored. Even though progress in adult ALL lags behind that achieved in childhood programs, the gap nally is starting to narrow.

REFERENCES
1. Greenlee RT, Hill-Harmon MB, Taylor M, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 2001;51:1536.

Adult ALL/Faderl et al.

2. Cortes J, Kantarjian HM. Acute lymphoblastic leukemia: a comprehensive review with emphasis on biology and therapy. Cancer. 1995;76:23932417. Ries LA, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda: National Cancer Institute, 1999. Groves FD, Linet MS, Devesa SS. Epidemiology of leukemia: overview of patterns of occurrence. In: Henderson ES, Lister TA, Greaves MF, editors. Leukemia, 6th edition. Philadelphia: W.B. Saunders, 1996:145159. Sandler DP. Epidemiology and etiology of leukemia. Curr Opin Oncol. 1990;2:39. Pombo de Oliveira MS, Awad el Seed FE, Foroni L, et al. Lymphoblastic leukaemia in Siamese twins: evidence for identity. Lancet. 1986;2:969 970. Schmitt TA, Degos L. [Familial leukemia]. Bull Cancer. 1978;65:83 88. Li FP. Epidemiology of cancer in childhood. In: Nathan DG, Oski FA, editors. Hematology of infancy and childhood, 4th edition. Philadelphia: W.B. Saunders, 1993:1102. Robison LL, Nesbit ME, Sather HN, et al. Down syndrome and acute leukemia in children: a 10 year retrospective survey from Childrens Cancer Study Group. J Pediatr. 1984; 105:235242. Fong C, Brodeur GM. Downs syndrome and leukemia: epidemiology, genetics, cytogenetics, and mechanisms of leukemogenesis. Cancer Genet Cytogenet. 1987;28:5576. Chessells JM, Harrison G, Richards SM, et al. Downs syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child. 2001;85: 321325. Taub JW. Relationship of chromosome 21 and acute leukemia in children with Down syndrome. J Pediatr Hematol Oncol. 2001;23:175178. Mertens AC, Wen W, Davies SM, et al. Congenital abnormalities in children with acute leukemia: a report from the Childrens Cancer Group. J Pediatr. 1998;133:617 623. Shaw MP, Eden OB, Grace E, Ellis PM. Acute lymphoblastic leukemia and Klinefelters syndrome. Pediatr Hematol Oncol. 1992;9:81 85. Janik-Moszant A, Bubala H, Stojewska M, Sonta-Jakimczyk D. [Acute lymphoblastic leukemia in children with Fanconi anemia]. Wiad Lek. 1998;51(Suppl 4):285288. Toledano SR, Lange BJ. Ataxia-telangiectasia and acute lymphoblastic leukemia. Cancer. 1980;45:16751678. Ichimura M, Ishimura T, Belsky JL. Incidence of leukemia in atomic bomb survivors belonging to a xed cohort in Hiroshima and Nagasaki, 1950-1971: radiation dose, years after exposure, age at exposure, and type of leukemia. J Radiat Res (Tokyo). 1978;19:262282. Mukhin VN. [Acute leukemia in adults: morbidity in Donetsk region of Ukraine before and after Chernobyls accident]. Ter Arkh. 2000;72:60 62. Brown WM, Doll R. Mortality form cancer and other causes after radiotherapy for ankylosing spondylitis. Br Med J. 1965;5474:13271332. Stewart A, Kneale GW. Radiation dose effects in relation to obstetric x-rays and childhood cancer. Lancet. 1970;1:1185 1188. Shore DL, Sandler DP, Davey FR, et al. Acute leukemia and residential proximity to potential sources of environmental pollutants. Arch Environ Health. 1993;48:414 420. 22.

1349

3.

23.

24. 25.

4.

5. 6.

26.

27.

7. 8.

28.

9.

29.

10.

30.

11.

31.

12.

32.

13.

33.

14.

34.

15.

35.

16. 17.

36.

37.

18.

38.

19.

39.

20.

40. 41.

21.

Lindquist R, Nilsson B, Eklund G, Gahrton G. Acute leukemia in professional drivers exposed to gasoline and diesel. Eur J Haematol. 1991;47:98 103. Brownson RC, Novotny TE, Perry MC. Cigarette smoking and adult leukemia: a meta-analysis. Arch Intern Med. 1993;153:469 475. Sandler DP. Recent studies in leukemia epidemiology. Curr Opin Oncol. 1995;7:1218. Wen W, Shu XO, Potter JD, et al. Parental medication use and risk of childhood acute lymphoblastic leukemia. Cancer. 2002;95:1786 1794. Bethwaite P, Cook A, Kennedy J, Pearce N. Acute leukemia in electrical workers: a New Zealand case-control study. Cancer Causes Control. 2001;12:683 689. Greaves MF, Alexander FE. An infectious etiology for common acute lymphoblastic leukemia in childhood? Leukemia. 1993;7:349 360. Lombardi L, Newcomb EW, Dalla-Favera R. Pathogenesis of Burkitts lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected B lymphoblasts. Cell. 1987;49:161170. Meltzer AA, Spitz MR, Johnson CC, Culbert SJ. Season-ofbirth and acute leukemia of infancy. Chronobiol Int. 1989; 6:285289. Timonen TT. A hypothesis concerning deciency of sunlight, cold temperature, and inuenza epidemics associated with the onset of acute lymphoblastic leukemia in northern Finland. Ann Hematol. 1999;78:408 414. Pedersen-Bjergaard J. Acute lymphoid leukemia with t(4; 11)(q21;q23) following chemotherapy with cytostatic agents targeting at DNA-topoisomerase II. Leuk Res. 1992; 16:733735. Frankel SR, Herzig GP, Bloomeld CD. Acute lymphoid leukemia in adults. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, editors. Clinical oncology, 1st edition. New York: Churchill Livingstone, 1995:19251958. Jaing TH, Hsueh C, Chiu CH, et al. Cutaneous lymphocytic vasculitis as the presenting feature of acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2002;24:555557. Mayo GL, Carter JE, McKinnon SJ. Bilateral optic disk edema and blindness as initial presentation of acute lymphocytic leukemia. Am J Ophthalmol. 2002;134:141142. Cortes J. Central nervous system involvement in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2001;15:145162. Ye CC, Echeverri C, Anderson JE, et al. T-cell blast crisis of chronic myelogenous leukemia manisfesting as a large mediastinal tumor. Hum Pathol. 2002;33:770 773. Attarbaschi A, Mann G, Dworzak M, et al. Mediastinal mass in childhood T-cell acute lymphoblastic leukemia: signicance and therapy response. Med Pediatr Oncol. 2002;39: 558 565. Gill PS, Meyer PR, Pavlova Z, et al. B cell acute lymphoblastic leukemia in adults. Clinical, morphological, and immunologic ndings. J Clin Oncol. 1986;4:737743. Fenaux P, Bourhuis JH, Ribrag V. Burkitts acute lymphocytic leukemia (L3 ALL) in adults. Hematol Oncol Clin North Am. 2001;15:3750. Wegelius R. Preleukemic states in children. Scand J Haematol. 1986;45:133139. Kiraly JF, Brooks JS. Bone marrow necrosis. Am J Med. 1976;60:361368.

1350
42.

CANCER October 1, 2003 / Volume 98 / Number 7

Shibata K, Watanabe M, Yamaguchi M. Two cases of acute lymphocytic leukemia associated with bone marrow necrosis: a brief review of the literature. Eur J Haematol. 1994; 52:115116. Paydas S, Ergin M, Baslamisli F, et al. Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am J Hematol. 2002;70:300 305. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classication of acute leukemia. French-American-British Cooperative Group. Br J Haematol. 1976;33:451 458. Bennett JM, Catovsky D, Daniel MT, et al. The morphologic classication of acute lymphoblastic leukemia: concordance among observers and clinical correlations. Br J Haematol. 1981;47:553561. Davey FR, Castella A, Lauenstein K, et al. Prognostic signicance of the revised French-American-British classication for acute lymphoblastic leukemia. Clin Lab Haematol. 1983;5:343351. Ferrari S, Mariano MT, Tagliaco E, et al. Myeloperoxidase gene expression in blast cells with a lymphoid phenotype in cases of acute lymphoblastic leukemia. Blood. 1988;72: 873 876. Serrano J, Roman J, Sanchez J, et al. Myeloperoxidase gene expression in acute lymphoblastic leukemia. Br J Haematol. 1997;97:841 843. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classication of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee MeetingAirlie House, Virginia, November 1997. J Clin Oncol. 1999;17:38353849. Rothe G, Schmitz G. Consensus protocol for the ow cytometric immunophenotyping of hematopoietic malignancies. Working Group on Flow Cytometry and Image Analysis. Leukemia. 1996;14:877 895. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classication of acute leukemias. Leukemia. 1995;9:17831786. Ludwig WD, Raghavachar A, Thiel E. Immunophenotypic classication of acute lymphoblastic leukaemia. Baillieres Clin Haematol. 1994;7:235262. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998;339:605 615. Vogler LB, Crist WM, Bockman DE, et al. Pre-B-leukemia: a new phenotype of childhood lymphoblastic leukemia. N Engl J Med. 1978;298:872 878. 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. 1990;76:117122. Crist W, Pullen J, Boyett J, et al. Acute lymphoid leukemia in adolescents: clinical and biological features predict a poor prognosisa Pediatric Oncology Group study. J Clin Oncol. 1988;6:34 43. Vasef MA, Brynes RK, Murata-Collins JL, et al. Surface immunoglobulin light chain-positive acute lymphoblastic leukemia of FAB L1 or L2 type: a report of 6 cases in adults. Am J Clin Pathol. 1998;110:143149. Lai JL, Fenaux P, Zandecki M, et al. Cytogenetic studies in 30 patients with Burkitts lymphoma or L3 acute lymphoblastic leukemia with special reference to additional chromosome abnormalities. Ann Genet. 1989;32:26 32. Pui CH, Behm FG, Crist WM. Clinical and biological relevance of immunologic marker studies in childhood acute lymphoblastic leukemia. Blood. 1993;82:343362. 60. Lai R, Hirsch-Ginsberg CF, Bueso-Ramos C. Pathologic diagnosis of acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2000;14:1209 1235. Thalhammer-Scherrer R, Mitterbauer G, Simonitsch I, et al. The immunophenotype or 325 adult acute leukemias: relationship to morphologic and molecular classication and proposal for a minimal screening program highly predictive for lineage discrimination. Am J Clin Pathol. 2002;117: 380 389. Matutes E, Morilla R, Farahat N, et al. Denition of acute biphenotypic leukemia. Haematologica. 1997;82:64 66. Den Boer ML, Kapaun P, Pieters R, et al. Myeloid antigen co-expression in childhood acute lymphoblastic leukaemia: relationship with in vitro drug resistance. Br J Haematol. 1999;105:876 882. Bene MC, Bernier M, Casasnovas RO, et al. The reliability and specicity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. Blood. 1998;92: 596 599. EGIL (European Group for the Immunological Classication of Leukemias). The value of c-kit in the diagnosis of biphenotypic acute leukemia [abstract]. Leukemia. 1998; 12:2038a. Nakase K, Kenkichi K, Shiku H, et al. Myeloid antigen, CD13, CD14, and/or CD33 expression in adult acute lymphoblastic leukemia patients: diagnostic and prognostic implication. Am J Clin Pathol. 1996;105:761768. Guyotat D, Campos L, Shi ZH, et al. Myeloid surface antigen expression in adult acute lymphoblastic leukemia. Leukemia. 1990;4:664 666. Wells SJ, Bray RA, Stempora LI, et al. CD117/CD34 expression in leukemic blasts. Am J Clin Pathol. 1996;106:192 195. Khalidi HS, Chang KL, Medeiros LJ, et al. Acute lymphoblastic leukemia. Survey of immunophenotype, FrenchAmerican-British classication, frequency of myeloid antigen expression, and karyotype abnormalities in 210 pediatric and adult cases. Hematopathology. 1999;111:467 476. Pui CH, Rubnitz JE, Hancock ML, et al. Reappraisal of the clinical and biologic signicance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia. J Clin Oncol. 1998;16:3768 3773. Cascavilla N, Musto P, Melillo L, et al. Is the scoring system an effective clinico-biological tool in myeloid antigen positive adult acute lymphoblastic leukemia? Results of a longterm study. Hematol J. 2002;3:251258. Czuczman MS, Dodge RK, Stewart CC, et al. Value of immunophenotype in intensively treated adult acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8364. Blood. 1999;93:39313939. Putti MC, Rondelli R, Cocito MG, et al. Expression of myeloid markers lacks prognostic impact in children treated for acute lymphoblastic leukemia: Italian experience in AIEOP-ALL 88-91 studies. Blood. 1998;92:795 801. Uckun FM, Sather HN, Gaynon PS, et al. Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report form the Childrens Cancer Group. Blood. 1997;90:28 35. Preti HA, Huh YO, OBrien SM, et al. Myeloid markers in adult acute lymphoblastic leukemia. Correlations with patient and disease characteristics and with prognosis. Cancer. 1995;76:1564 1570.

61.

43.

44.

62. 63.

45.

46.

64.

47.

65.

48.

66.

49.

67.

50.

68.

51.

69.

52.

53. 54.

70.

71.

55.

72.

56.

73.

57.

74.

58.

75.

59.

Adult ALL/Faderl et al.

76. Faderl S, Kantarjian HM, Talpaz M, Estrov Z. Clinical signicance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood. 1998;91:3995 4019. Groupe Francais de Cytogenetique Hematologique. Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with the hematologic ndings and outcome. A collaborative study of the Groupe Francais de Cytogenetique Hematologique. Blood. 1996;87: 31353142. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164 172. Preti HA, OBrien S, Giralt S, et al. Philadephia chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med. 1994;97:60 65. Zhou M, Gu L, Yeager AM, et al. Incidence and clinical signicance of CDKN2/MTS1/P16ink4A and MTS2/ P15ink4B gene deletions in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1997;14:141150. Rubnitz JE, Behm FG, Pui CH, et al. Genetic studies of childhood acute lymphoblastic leukemia with emphasis on p16, MLL, and ETV6 gene abnormalities: results of St. Jude Total Therapy Study XII. Leukemia. 1997;11:1201 1206. Heerema NA, Sather HN, Sensel MG, et al. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Group. Blood. 1999;94:15371544. Secker-Walker LM, Prentice HG, Durrant J, et al. Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. Adult Leukaemia Working Party. Br J Haematol. 1997; 96:601 610. Faderl S, Kantarjian HM, Manshouri T, et al. The prognostic signicance of p16INK4a/p14ARF and p15INK4b deletions in adult acute lymphoblastic leukemia. Clin Cancer Res. 1999;5:18551861. Hoshino K, Asou N, Okubo T, et al. The absence of the p15INK4B gene alterations in adult patients with precursor B-cell acute lymphoblastic leukaemia is a favourable prognostic factor. Br J Haematol. 2002;117:531540. Secker-Walker LM. General report on the European Union Concerted Action Workshop on 11q23, London, UK, May 1997. Leukemia. 1998;12:776 778. Harrison CJ, Cuneo A, Clark R, et al. Ten novel 11q23 chromosomal partner sites. Leukemia. 1998;12:811 822. Heerema NA, Arthur DC, Sather H, et al. Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group. Blood. 1994;83:2274 2284. Carroll AJ, Crist WM, Parmley RT, et al. Pre-B cell leukemia associated with chromosome translocation 1;19. Blood. 1984;63:721724. Hunger SP. Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood. 1996;87:12111224. 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. 1990;76:117122. Aguiar RC, Sohal J, van Rhee F, et al. TEL-AML1 fusion in acute lymphoblastic leukaemia of adults. M.R.C. Adult Leukaemia Working Party. Br J Haematol. 1996;95:673 677. 93.

1351

77.

94.

95.

78. 79.

96.

80.

97. 98.

81.

99. 100.

82.

101.

83.

102.

103. 104.

84.

85.

105.

86.

106.

87. 88.

107.

108.

89.

109.

90.

91.

110.

92.

111.

Raynaud S, Mauvieux L, Cayuela JM, et al. TEL/AML1 fusion gene is a rare event in adult acute lymphoblastic leukemia. Leukemia. 1996;10:1529 1530. Romana SP, Mauchauffee M, Le Coniat M, et al. The t(12; 21) of acute lymphoblastic leukemia results in TEL-AML1 gene fusion. Blood. 1995;85:36623670. Harbott J, Viehmann S, Borkhardt A, et al. Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse. Blood. 1997; 90:4933 4937. Seeger K, Adams HP, Buchwald D, et al. TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Munster Study Group. Blood. 1998;91:1716 1722. Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994;372:143149. Yeoh EJ, Ross ME, Shurtleff SA, et al. Classication, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression proling. Cancer Cell. 2002;1:133143. Staudt LM. Its ALL in the diagnosis. Cancer Cell. 2002;1: 109 110. Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures dene novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1:75 87. Golub TR, Slonim DK, Tamayo P, et al. Molecular classication of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531537. Hoelzer D, Ludwig WD, Eckhard E, et al. Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood. 1996;87:495508. Laport GF, Larson RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol. 1997;24:70 82. Larson RA, Dodge RK, Burns CP, et al. A ve-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995;85:2025 2037. Hoelzer D. Which factors inuence the different outcome of therapy in adults and children with ALL? Bone Marrow Transplant. 1989;4 Suppl 1:98 100. Goekbuget N, Hoelzer D, Arnold R, et al. Subtypes and treatment outcome in adult acute lymphoblastic leukemia (ALL) 55 yrs [abstract]. Hematol J. 2001;1:694a. Faderl S, Albitar M. Insights into the biologic and molecular abnormalities in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2000;14:12671288. Hoelzer D, Thiel E, Lo fer H, et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood. 1994;71:123131. 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 Childrens Cancer Study Group. J Clin Oncol. 1989;7:18071815. Faderl S, Thall PF, Kantarjian HM, Estrov Z. Time to platelet recovery predicts outcome of patients with de novo acute lymphoblastic leukaemia who have achieved a complete remission. Br J Haematol. 2002;117:869 874. Hoelzer D, Arnold R, Freund M, et al. Characteristics, outcome and risk factors in adult T-lineage acute lymphoblastic leukemia (ALL) [abstract]. Blood. 1999;94:2926a.

1352

CANCER October 1, 2003 / Volume 98 / Number 7

dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer. 2000;88:1964 1969. Bostrom BC, Sensel MR, Sather HN, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Childrens Cancer Group. Blood. 2003;101:3809 3817. Linker CA, Levitt LJ, ODonnell M, et al. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991;78:2814 2822. Nagura E. Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 1994;33:359 365. Go kbuget N, Hoelzer D. Recent approaches in acute lymphoblastic leukemia in adults. Rev Clin Exp Hematol. 2002; 6:114 141. Weiss M, Maslak P, Feldman E, et al. Cytarabine with high dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia (ALL) without the use of vincristine or prednisone. J Clin Oncol. 1996;14:2480 2485. Ottman OG, Hoelzer D, Gracien E, et al. Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized Phase III trial. Blood. 1995;86:444 450. Scherrer R, Bettelheim P, Gaissler K, et al. High efciency of the German multicenter ALL (GMALL) protocol for treatment of adult acute lymphoblastic leukemia (ALL)a single institution study. Ann Hematol. 1994;69:181188. Larson RA, Dodge RK, Linker CA, et al. A randomized controlled trial of lgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood. 1998; 92:1556 1564. Goekbuget N, Arnold R, Buechner T, et al. Intensication of induction and consolidation improves only subgroups of adult ALL: analysis of 1200 patients in GMALL study 05/93 [abstract]. Blood. 2001;98:802a. Ribera JM, Ortega JJ, Oriol A, et al. Late intensication chemotherapy has not improved the results of intensive chemotherapy in adult acute lymphoblastic leukemia. Results of a prospective multicenter randomized trial (PETHEMA ALL-89). Haematologica. 1998;83:222230. 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. 1991;5:425 431. Cassileth PA, Andersen JW, Bennett JM, et al. Adult acute lymphocytic leukemia: the Eastern Cooperative Oncology Group experience. Leukemia. 1992;62:178 181. Childhood ALL Collaborative Group. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomized children. Lancet. 1996;347:17831788. Mandelli F, Annino L, Rotoli B. The GIMEMA ALL 0183 trial: analysis of 10-year follow-up. Br J Haematol. 1996;92: 665 672. Cortes J, OBrien SM, Pierce S, 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. Blood. 1995;86:20912097.

112. Ludwig WD, Rieder H, Bartram CR, et al. Immunophenotypic and genotypic features, clinical characteristics, and treatment outcome of adult pro-B acute lymphoblastic leukemia: results of German multicenter trials GMALL 03/87 and 04/89. Blood. 1998;92:1898 1909. 113. Annino L, Vegna ML, Camera A, et al. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002; 99:863 871. 114. Tafuri A. Multidrug resistance proteins MDR1/P-gp, MRP1, and LRP in adult ALL patients uniformly treated according to the GIMEMA 0496 protocol: poor prognostic impact of MDR1/P-gp [abstract]. Blood. 1999;94:1265a. 115. Go kbuget N, Hoelzer D, Arnold R, et al. Treatment of adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin North Am. 2000;14:13071325. 116. Durrant IJ, Richards SM, Prentice HG, et al. The Medical Research Council trials in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2000;14:13271352. 117. Larson RA. Recent clinical trials in acute lymphocytic leukemia by the Cancer and Leukemia Group B. Hematol Oncol Clin North Am. 2000;14:13671379. 118. Kantarjian HM, OBrien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18:547561. 119. Schaison G, Sommelet D, Bancillon A, et al. Treatment of acute lymphoblastic leukemia French protocol Fralle 8387. Leukemia. 1992;6 Suppl 2:148 152. 120. Hussein KK, Dahlberg S, Head D, et al. Treatment of acute lymphoblastic leukemia in adults with intensive induction, consolidation, and maintenance chemotherapy. Blood. 1989;73:57 63. 121. GIMEMA Cooperative Group. GIMEMA ALL 0183: a multicentric study on adult acute lymphoblastic leukaemia in Italy. Br J Haematol. 1989;71:377386. 122. Linker C, Damon L, Ries C, Navarro W. Intensied and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol. 2002;20:2464 2471. 123. Durrant IJ, Prentice HG, Richards SM. Intensication of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA. Br J Haematol. 1997;99:84 92. 124. Todeschini G, Tecchio C, Meneghini V, et al. Estimated 6-year event-free survival of 55% in 60 consecutive adult acute lymphoblatsic leukemia patients treated with an intensive Phase II protocol based on high induction dose of daunorubicin. Leukemia. 1998;12:144 149. 125. Stryckmans P, Debusscher L. Chemotherapy of adult acute lymphoblastic leukaemia. Baillieres Clin Haematol. 1991;4: 115130. 126. Kantarjian HM, OBrien S, Smith T, et al. Acute lymphocytic leukaemia in the elderly: characteristics and outcome with the vincristine-Adriamycin-dexamethasone (VAD) regimen. Br J Haematol. 1994;88:94 100. 127. Kantarjian HM, Walters RS, Keating MJ, et al. Experience with vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy in adults with refractory acute lymphocytic leukemia. Cancer. 1989;64:16 22. 128. Jones B, Freeman AI, Shuster JJ, et al. Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol. 1991;19:269 275. 129. Hurwitz CA, Silverman LB, Schorin MA, et al. Substituting

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

Adult ALL/Faderl et al.

145. Bleyer WA, Poplack DA. Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol. 1985;12:131148. 146. Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. Childrens Cancer Study Group A. Cancer. 1970;26:404 409. 147. Matrangelo R, Poplack D, Bleyer A, et al. Report and recommendation from the Rome workshop concerning poorprognosis acute lymphoblastic leukemia in children: biologic bases for staging, stratication, and treatment. Med Pediatr Oncol. 1986;14:191194. 148. Mahmoud DH Jr., Rivera GK, Hancock ML, et al. Low leukocyte counts with blast cells in cerebrospinal uid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med. 1993;329:314 319. 149. Omura GA, Moftt S, Vogler WR, et al. Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous system prophylaxis. Blood. 1980;55:199 204. 150. Pavlovsky S, Eppinger-Helft M, Sackmann MF. Factors that inuence the appearance of central nervous system leukemia. Blood. 1973;42:935938. 151. Thomas DA, Cortes J, OBrien S, et al. Hyper-CVAD program in Burkitts-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999;17:24612470. 152. Kantarjian HM, Walters RS, Smith TL, et al. Identication of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood. 1988;72:1784 1789. 153. Blume K, Forman S, Snyder D, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukemia during rst complete remission. Transplantation. 1987;43: 389 392. 154. Chao N, Formen S, Schmidt G, et al. Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during rst complete remission. Blood. 1991;78: 19231927. 155. DeWitte T, Awwad B, Boezeman J, et al. Role of allogeneic bone marrow transplantation in adolescent or adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma in rst remission. Bone Marrow Transplant. 1994;14:767774. 156. Martin TG, Gajewski JL. Allogeneic stem cell transplantation for acute lymphocytic leukemia in adults. Hematol Oncol Clin North Am. 2001;15:97120. 157. Horowitz M, Messere D, Hoelzer D, et al. Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in rst remission. Ann Intern Med. 1991;115:1318. 158. Zhang M, Hoelzer D, Horowitz M, et al. Long-term follow-up of adults with acute lymphoblastic leukemia in rst remission treated with chemotherapy or bone marrow transplantation. Ann Intern Med. 1995;123:428 431. 159. Sebban C, Lepage E, Vernant J, et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in rst complete remission: a comparative study. J Clin Oncol. 1994;12:2580 2587. 160. Thiebault A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000;14:13531366. 161. Rowe JM, Richards S, Burnett AK, et al. Favorable results of allogeneic bone marrow transplantation (BMT) for adults

1353

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

with Philadelphia (Ph)-chromosome-negative acute lymphoblastic leukemia (ALL) in rst complete remission (CR): results from the International ALL Trial (MRC UKALL XII/ ECOG E2993) [abstract]. Blood. 2001;98:481a. Attal M, Blaise D, Marit G, et al. Consolidative treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. Blood. 1995;86:1619 1628. Vey N, Blaise D, Stoppa A, et al. Bone marrow transplantation in 63 adult patients with acute lymphoblastic leukemia in rst complete remission. Bone Marrow Transplant. 1994;14:383388. 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. 1990;8:994 1004. Powles R, Sirohi B, Treleaven J, et al. The role of posttransplantation maintenance chemotherapy in improving the outcome of autotransplantation in adult acute lymphoblastic leukemia. Blood. 2002;100:16411647. Stock W, Estrov Z. Studies of minimal residual disease in acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2000;14:1289 1305. Cave H, van der Werff ten Bosch J, Suciu S, et al. Clinical signicance of minimal residual disease in childhood acute lymphoblastic leukemia. N Engl J Med. 1998;339: 591598. Foroni L, Coyle LA, Papaioannou M, et al. Molecular detection of minimal residual disease in adult and childhood acute lymphoblastic leukaemia reveals differences in treatment response. Leukemia. 1997;11:17321741. Brisco MJ, Hughes E, Neoh SH, et al. Relationship between minimal residual disease and outcome in adult acute lymphoblastic leukemia. Blood. 1996;87:52515256. Mortuza FY, Papaioannou M, Moreira IM, et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol. 2002;20:1094 1104. Garcia-Manero G, Thomas DA. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am. 2001;15:163205. Koller CA, Kantarjian HM, Thomas D, et al. The hyperCVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia. 1997;11:2039 2044. Sur P, Fernandes DJ, Kute TE, et al. L-asparaginase-induced modulation of methotrexate polyglutamylation in murine leukemia L5178Y. Cancer Res. 1987;47:13131318. Esterhay RJ Jr., Wiernik PH, Grove WR, et al. Moderate dose methotrexate, vincristine, asparaginase, and dexamethasone for treatment of adult acute lymphocytic leukemia. Blood. 1982;59:334 345. Aguayo A, Cortes J, Thomas D, et al. Combination therapy with methotrexate, vincristine, polyethylene-glycol conjugated-asparaginase, and prednisone in the treatment of patients with refractory or recurrent acute lymphoblastic leukemia. Cancer. 1999;86:12031209. Willemze R, Peters WG, Colly LP. Short-term intensive treatment (VAAP) of adult acute lymphoblastic leukemia and lymphoblastic lymphoma. Eur J Haematol. 1988;41: 489 495.

1354

CANCER October 1, 2003 / Volume 98 / Number 7

190. Patte C, Philip T, Rodary C, et al. Improved survival rate in children with Stage III and Stage IV B cell non-Hodgkins lymphoma and leukemia using multi-agent chemotherapy: results of a study of 114 children from the French Pediatric Oncology Society. J Clin Oncol. 1986;4:1219 1226. 191. Reiter A, Schrappe M, Ludwig WD, et al. Favourable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood. 1992;80:24712478. 192. Murphy SB, Bowman WP, Abromowitch M, et al. Results of treatment of advanced-stage Burkitts lymphoma and B cell (sIg) acute lymphoblastic leukemia with high-dose fractionated cyclosphosphamide and coordinated highdose methotrexate and cytarabine. J Clin Oncol. 1986;4: 17321739. 193. Bowman PW, Shuster JJ, Cook B, et al. Improved survival for children with B cell acute lymphoblastic leukemia and Stage IV small noncleaved cell lymphoma: a Pediatric Oncology Group study. J Clin Oncol. 1996;14:12521261. 194. Soussain C, Patte C, Ostronoff M, et al. Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood. 1995;85:664 674. 195. Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethusone and highly active antivetroviral therapy for patients with acquired immunodeciency syndrome-related Borkitt lymphoma/leukemia. Cancer. 2002;94:14921499. 196. Bassan R, Pogliani E, Casula P, et al. Risk-oriented postremission strategies in adult acute lymphoblastic leukemia: prospective conrmation of anthracycline activity in standard-risk class and role of hematopoietic stem cell transplants in high-risk groups. Hematol J. 2001;2:117126. 197. Dekker AW, vant Veer MB, van der Holt B, et al. Postremission treatment with autologous stem cell transplantation (Auto-SCT) or allogeneic stem cell transplantation (AlloSCT) in adults with acute lymphoblastic leukemia (ALL). A Phase II clinical trial (HOVON 18 ALL) [abstract]. Blood. 2001;98:859a. 198. Hallbook H, Simonsson B, Bjorkholm M, et al. High dose ara-C as upfront therapy for adult patients with acute lymphoblastic leukemia (ALL). Blood. 1999;94:297a. 199. Hoelzer D, Arnold R, Diedrich H, et al. Successful treatment of Burkitts NHL and other high-grade NHL according to a protocol for mature B-ALL [abstract]. Blood. 2002; 100:159a. 200. Todeschini G, Tecchio C, Degani D, et al. Eighty-one percent event-free survival in advanced Burkitts lymphoma/ leukemia: no differences in outcome between pediatric and adult patients treated with the same intensive pediatric protocol. Ann Oncol. 1997;8 Suppl 1:77 81. 201. Fenaux P, Lai JL, Miaux O, et al. Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases. Br J Haematol. 1989;71:371376.

177. Suki S, Kantarjian H, Gandhi V, et al. Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia. Cancer. 1993;72:2155 2160. 178. Deane M, Koh M, Foroni L, et al. FLAG-idarubicin and allogeneic stem cell transplantation for Ph-positive ALL beyond frist remission. Bone Marrow Transplant. 1998;22: 11371143. 179. Advisory Committee of the International Bone Marrow Transplant Registry. Report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant. 1989;4:221228. 180. Fleming DR, Henslee-Downey PJ, Romond EH, et al. Allogeneic bone marrow transplantation with T cell-depleted partially matched related donors for advanced acute lymphoblastic leukemia in children and adults: a comparative matched cohort study. Bone Marrow Transplant. 1996;17: 917922. 181. Herzig RH, Bortin MM, Barrett AJ, et al. Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in rst and second remission. Lancet. 1987;1:786 789. 182. Davies SM, Ramsay NK, Weisdorf DJ. Feasibility and timing of unrelated donor identication for patients with ALL. Bone Marrow Transplant. 1996;17:737740. 183. Faderl S, Garcia-Manero G, Thomas DA, Kantarjian HM. Philadelphia chromosome-positive acute lymphoblastic leukemia current concepts and future perspectives. Rev Clin Exp Hematol. 2002;6:142160. 184. Wetzler M, Dodge RK, Mrozek K, et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia: the Cancer and Leukemia Group B experience. Blood. 1999;93: 39833993. 185. Goldstone AH, Prentice HG, Durant J, et al. Allogeneic transplant (related or unrelated donor) is the preferred treatment for adult Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL). Results from the International ALL Trial (MRC UKALLXII/ECOG E2993) [abstract]. Blood. 2001;98:856a. 186. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med. 1996;2:561566. 187. Thomas DA, Cortes J, Giles FJ, et al. Combination of hyperCVAD with imatinib mesylate (STI571) for Philadelphia (Ph)-positive adult acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia in lymphoid blast phase (CML-LBP) [abstract]. Blood. 2001;98:803a. 188. Ottmann OG, Druker BJ, Sawyers CL, et al. A Phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002;100:19651971. 189. Ottmann OG, Wassmann B, Pfeifer H, et al. Activity of the ABL-tyrosine kinase inhibitor Glivec (STI571) in Philadelphia chromosome positive acute lymphoblastic leukemia (PH ALL) relapsing after allogeneic stem cell transplantation (allo-SCT) [abstract]. Blood. 2001;98:589a.