We searched Medline and PubMed for articles published in English dating from 2002, with the keywords “acute lymphoblastic leukemia”, “acute lymphocytic leukemia”, and “acute lymphoid leukemia”. In some instances, review articles were selected over original articles because of space constraints.
SeminarAcute lymphoblastic leukaemia
Introduction
Addition of acute lymphoblastic leukaemia to the growing list of cancers that have succumbed to effective treatment is tempting. The decision would be easy to justify in view of data showing cure rates higher than 80% for children treated in modern centres, most of whom will lead healthy productive lives as long-term cancer survivors.1, 2, 3 Thus, the future management of acute lymphoblastic leukaemia might be viewed as simply tweaking existing protocols and devising alternative regimens for the fifth of patients who respond poorly to available agents. This scenario, however attractive, must be rejected on several grounds. It does not accommodate the poor prognosis for adults with acute lymphoblastic leukaemia or the complexity, expense, and toxic effects of contemporary multiagent treatments.1, 4 Most importantly, it overlooks our rapidly increasing ability to analyse the genetic and epigenetic abnormalities of leukaemic cells and to translate them into enhanced diagnostic methods and molecularly targeted therapy.5, 6 Although the molecular medicine approach is still in its investigative stage, with many new obstacles to overcome, it holds enormous promise. Put simply, we are about to enter an era in which leukaemia patients will probably receive individualised treatment based on the genetic features of their malignant cells and their own unique genetic make-up (so-called pharmacogenomics).7 Our intent in this Seminar is to review advances in both the fundamental understanding and clinical management of acute lymphoblastic leukaemia in children and adults.
Section snippets
Epidemiology and cause
The precise pathogenetic events leading to development of acute lymphoblastic leukaemia are unknown. Only a few cases (<5%) are associated with inherited, predisposing genetic syndromes, such as Down's syndrome, Bloom's syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome, or with ionising radiation or exposure to specific chemotherapeutic drugs. Although accumulating published work on high birthweight as a risk factor for childhood acute lymphoblastic leukaemia is becoming
Pathobiology
Acute lymphoblastic leukaemia is thought to originate from various important genetic lesions in blood-progenitor cells that are committed to differentiate in the T-cell or B-cell pathway, including mutations that impart the capacity for unlimited self-renewal and those that lead to precise stage-specific developmental arrest.6, 28 In some cases, the first mutation along the multistep pathway to overt acute lymphoblastic leukaemia might arise in a haemopoietic stem cell possessing multilineage
Phenotype
Immunophenotyping of leukaemic lymphoblasts by flow cytometry is essential to establish the correct diagnosis and define cell lineage. Although acute lymphoblastic leukaemia can be readily subclassified according to the many steps of normal B-cell and T-cell differentiation, the only findings with therapeutic importance are T-cell, mature B-cell, and B-cell precursor phenotypes.26, 58 Myeloid-associated antigen expression can be detected in as many as half the cases of acute lymphoblastic
Risk assessment
Careful assessment of the risk of relapse in individual patients ensures that very intensive treatment is given only to high-risk cases, thus sparing people at lower risk from undue toxic effects. Although enhanced treatment has abolished the prognostic strength of many clinical and biological risk factors identified in the past, we would stress that even so-called low-risk patients need a certain degree of treatment intensification to avoid unacceptable rates of relapse. Findings have shown
Treatment
With the exception of patients with mature B-cell acute lymphoblastic leukaemia, who are treated with short-term intensive chemotherapy (including high-dose methotrexate, cytarabine, and cyclophosphamide),109, 110, 111 treatment for acute lymphoblastic leukaemia typically consists of a remission-induction phase, an intensification (or consolidation) phase, and continuation therapy to eliminate residual disease. Treatment is also directed to the CNS early in the clinical course to prevent
Allogeneic haemopoietic stem-cell transplantation
Allogeneic haemopoietic stem-cell transplantation is the most intensive form of treatment for acute lymphoblastic leukaemia. Comparisons between this modality and intensive chemotherapy have yielded inconsistent results owing to the few patients studied and differences in case-selection criteria.137, 138, 139, 140 Nonetheless, allogeneic transplantation clearly benefits several subgroups of patients with high-risk acute lymphoblastic leukaemia, such as individuals with Philadelphia
Continuation treatment
For reasons that (currently) remain elusive, patients with acute lymphoblastic leukaemia need continuation treatment to prevent or forestall relapse. Although about two-thirds of childhood cases can be treated successfully with only 12 months of therapy, they cannot be identified prospectively with any degree of certainty.148 Hence, all patients receive chemotherapy for 2·0–2·5 years. Daily mercaptopurine and methotrexate every week constitute the backbone of continuation regimens. Many
CNS-directed treatment
CNS relapse is a major obstacle to cure, accounting for 30–40% of initial relapses in some studies.117, 129, 155 Factors associated with an increased risk of CNS relapse include a T-cell immunophenotype, hyperleucocytosis, high-risk genetic abnormalities, and presence of leukaemic cells in cerebrospinal fluid (even from iatrogenic introduction due to a traumatic lumbar puncture).3, 77, 156, 157, 158 Polymorphisms in genes that code for proteins implicated in the pharmacodynamics of
Remaining questions and the future
What are the major causative factors in the development of acute lymphoblastic leukaemia? Apart from isolated cases that can be attributed to inherited genetic syndromes or exposures to known leukaemogenic agents, identification of causal factors with a predictable effect on substantial numbers of children or adults has not been possible, impeding efforts to develop effective preventive measures against acute lymphoblastic leukaemia. In view of the failure of large-scale epidemiological studies
Search strategy and selection criteria
References (171)
- et al.
Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01
Blood
(2001) - et al.
Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia
Blood
(2007) - et al.
Prenatal origin of acute lymphoblastic leukaemia in children
Lancet
(1999) - et al.
Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia
Blood
(2002) - et al.
Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia
Blood
(2007) - et al.
Childhood acute lymphoblastic leukaemia: current status and future perspectives
Lancet Oncol
(2001) - et al.
Biological and therapeutic aspects of infant leukemia
Blood
(2000) - et al.
Cancer stem cells: lessons from leukemia
Trends Cell Biol
(2005) - et al.
Gene expression define novel oncogenic pathways in T-cell acute lymphoblastic leukemia
Cancer Cell
(2002) - et al.
Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling
Cancer Cell
(2002)
Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation
Blood
AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis
Cell
Imatinib as a paradigm of targeted therapies
Adv Cancer Res
Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation
J Biol Chem
Cancer modeling in the modern era: progress and challenges
Cell
TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB
Cancer Cell
Zebrafish as a cancer model system
Cancer Cell
Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray
Blood
Genomewide identification of prednisolone-responsive gene in acute lymphoblastic leukemia cells
Blood
Ancestry and pharmacogenetics of antileukemic drug toxicity
Blood
Pharmacogenetics of outcome in children with acute lymphoblastic leukemia
Blood
Thiopurine methyltransferase in acute lymphoblastic leukemia
Blood
High incidence of secondary brain tumours after radiotherapy and antimetabolites
Lancet
Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group
Blood
A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.l
Lancet
Management of acute lymphoblastic leukemia in older patients
Semin Hematol
Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital
Blood
Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia
Blood
Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial—MRC UKALL XII/ECOG E2993
Blood
Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial
Blood
Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia
Blood
Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)
Blood
Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21)
Blood
A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol
Blood
Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region
Lancet
CD10− pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL)
Blood
Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia
Blood
Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment
Blood
Treatment of acute lymphoblastic leukemia
N Engl J Med
Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture
J Clin Oncol
The changing scene of adult acute lymphoblastic leukemia
Curr Opin Oncol
Acute lymphoblastic leukemia
N Engl J Med
Moving towards individualized medicine with pharmacogenomics
Nature
Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies
Am J Epidemiol
A pooled analysis of magnetic fields and childhood leukaemia
Br J Cancer
Environmental and genetic risk factors for childhood leukemia: appraising the evidence
Cancer Invest
Infections and immune factors in cancer: the role of epidemiology
Oncogene
Infection, immune responses and the aetiology of childhood leukaemia
Nat Rev Cancer
Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins
Leukemia
Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia
Science
Cited by (1220)
Rationale, current state and opportunities in combining biologic disease modifying anti-rheumatic drugs in rheumatoid and psoriatic arthritis
2023, Revue du Rhumatisme (Edition Francaise)