Elsevier

The Lancet

Volume 371, Issue 9617, 22–28 March 2008, Pages 1030-1043
The Lancet

Seminar
Acute lymphoblastic leukaemia

https://doi.org/10.1016/S0140-6736(08)60457-2Get rights and content

Summary

Acute lymphoblastic leukaemia, a malignant disorder of lymphoid progenitor cells, affects both children and adults, with peak prevalence between the ages of 2 and 5 years. Steady progress in development of effective treatments has led to a cure rate of more than 80% in children, creating opportunities for innovative approaches that would preserve past gains in leukaemia-free survival while reducing the toxic side-effects of current intensive regimens. Advances in our understanding of the pathobiology of acute lymphoblastic leukaemia, fuelled by emerging molecular technologies, suggest that drugs specifically targeting the genetic defects of leukaemic cells could revolutionise management of this disease. Meanwhile, studies are underway to ascertain the precise events that take place in the genesis of acute lymphoblastic leukaemia, to enhance the clinical application of known risk factors and antileukaemic agents, and to identify treatment regimens that might boost the generally low cure rates in adults and subgroups of children with high-risk 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

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.

References (171)

  • AA Ferrando et al.

    Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation

    Blood

    (2003)
  • T Okuda et al.

    AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis

    Cell

    (1996)
  • BJ Druker

    Imatinib as a paradigm of targeted therapies

    Adv Cancer Res

    (2004)
  • GT Wong et al.

    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

    (2004)
  • T Van Dyke et al.

    Cancer modeling in the modern era: progress and challenges

    Cell

    (2002)
  • J O'Neil et al.

    TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB

    Cancer Cell

    (2004)
  • JF Amatruda et al.

    Zebrafish as a cancer model system

    Cancer Cell

    (2002)
  • N Kawamata et al.

    Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray

    Blood

    (2008)
  • WJ Tissing et al.

    Genomewide identification of prednisolone-responsive gene in acute lymphoblastic leukemia cells

    Blood

    (2007)
  • S Kishi et al.

    Ancestry and pharmacogenetics of antileukemic drug toxicity

    Blood

    (2007)
  • JC Rocha et al.

    Pharmacogenetics of outcome in children with acute lymphoblastic leukemia

    Blood

    (2005)
  • MV Relling et al.

    Thiopurine methyltransferase in acute lymphoblastic leukemia

    Blood

    (2006)
  • MV Relling et al.

    High incidence of secondary brain tumours after radiotherapy and antimetabolites

    Lancet

    (1999)
  • JM Hilden et al.

    Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group

    Blood

    (2006)
  • R Pieters et al.

    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

    (2007)
  • RA Larson

    Management of acute lymphoblastic leukemia in older patients

    Semin Hematol

    (2006)
  • CH Pui et al.

    Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital

    Blood

    (2004)
  • N Hijiya et al.

    Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia

    Blood

    (2006)
  • JM Rowe et al.

    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

    (2005)
  • AV Moorman et al.

    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

    (2007)
  • JB Nachman et al.

    Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia

    Blood

    (2007)
  • KR Schultz et al.

    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

    (2007)
  • AV Moorman et al.

    Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21)

    Blood

    (2007)
  • M Mancini et al.

    A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol

    Blood

    (2005)
  • CH Pui et al.

    Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region

    Lancet

    (2002)
  • B Gleissner et al.

    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

    (2005)
  • S Breit et al.

    Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia

    Blood

    (2006)
  • G Zaza et al.

    Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment

    Blood

    (2005)
  • CH Pui et al.

    Treatment of acute lymphoblastic leukemia

    N Engl J Med

    (2006)
  • B Bürger et al.

    Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture

    J Clin Oncol

    (2003)
  • A Vitale et al.

    The changing scene of adult acute lymphoblastic leukemia

    Curr Opin Oncol

    (2006)
  • CH Pui et al.

    Acute lymphoblastic leukemia

    N Engl J Med

    (2004)
  • WE Evans et al.

    Moving towards individualized medicine with pharmacogenomics

    Nature

    (2004)
  • LL Hjalgrim et al.

    Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies

    Am J Epidemiol

    (2003)
  • A Ahlbom et al.

    A pooled analysis of magnetic fields and childhood leukaemia

    Br J Cancer

    (2000)
  • PA Buffler et al.

    Environmental and genetic risk factors for childhood leukemia: appraising the evidence

    Cancer Invest

    (2005)
  • L Kinlen

    Infections and immune factors in cancer: the role of epidemiology

    Oncogene

    (2004)
  • M Greaves

    Infection, immune responses and the aetiology of childhood leukaemia

    Nat Rev Cancer

    (2006)
  • AT Maia et al.

    Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins

    Leukemia

    (2003)
  • D Hong et al.

    Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia

    Science

    (2008)
  • Cited by (1220)

    View all citing articles on Scopus
    View full text