We searched Medline and PubMed with the keywords “acute lymphoblastic leukaemia”, “acute lymphocytic leukaemia”, and “acute lymphoid leukaemia” for articles published in English between Jan 1, 2007, and Nov 30, 2012. Additional information was obtained from abstracts presented to the American Society of Hematology and American Society of Clinical Oncology. We focused on publications from the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also
SeminarAcute lymphoblastic leukaemia
Introduction
An estimated 6000 new cases (male:female prevalence of roughly 1·3:1) of acute lymphoblastic leukaemia are diagnosed yearly in the USA.1 Patients are mainly children; roughly 60% of cases occur in people aged younger than 20 years.2, 3, 4, 5 Survival in childhood acute lymphoblastic leukaemia is approaching 90% (appendix),4, 6 but treatment in infants (ie, children younger than 12 months) and adults needs improvement.5, 7 We review advances in the epidemiology, pathobiology, and clinical management of acute lymphoblastic leukaemia.
Section snippets
Epidemiology
Acute lymphoblastic leukaemia, like cancer in general, probably arises from interactions between exogenous or endogenous exposures, genetic (inherited) susceptibility, and chance (figure 1). These factors account for the roughly 1 in 2000 risk of the disease in childhood (0–15 years). The challenge is to identify the relevant exposures and inherited genetic variants and decipher how and when these factors contribute to the multistep natural history of acute lymphoblastic leukaemia from
Contributing exposures
Exposures and their roles remain contentious. More than 20 candidate exposures that contribute to childhood disease have been identified through epidemiological and case-control studies,10 but very few of these findings are based on reproducible data or are biologically plausible. Some of these candidate exposures are of public concern, especially ionising and non-ionising (eg, electromagnetic field) radiation. Ionising radiation is an established causal exposure for childhood acute
Inherited susceptibility
Very little evidence shows inherited predisposition via highly penetrant mutations in children or adults.28 The high concordance in identical twin children has a non-genetic explanation (blood cell chimaerism).9 Infants born with constitutive trisomy 21 or Down's syndrome are, however, at substantially increased risk of acute lymphoblastic leukaemia (roughly 40 fold at age 0–4 years) and acute myeloid leukaemia.29 The seeming absence of familial clustering of acute lymphoblastic leukaemia or
Genetic basis
High-resolution profiling of genetic alterations has transformed understanding of the genetic basis of acute lymphoblastic leukaemia. That most childhood cases harbour gross chromosomal alterations has been known for several decades (figure 2).36 In B-cell disease, these alterations include high hyperdiploidy with non-random gain of at least five chromosomes (including X, 4, 6, 10, 14, 17, 18, and 21); hypodiploidy with fewer than 44 chromosomes; and recurring translocations including
Genome sequencing
Next-generation sequencing enables comprehensive identification of the genetic changes in leukaemia. Simultaneous sequencing of hundreds of thousands of nucleic acids (so-called massively parallel sequencing) might be used to identify sequence mutations and structural variants in the encoding portion of the genome (exome sequencing), the transcriptome (mRNA sequencing), or the entire genome. In 187 cases of high-risk B lymphoblastic leukaemia, 120 candidate genes and pathways targeted by DNA
Diagnosis
Morphological identification of lymphoblasts by microscopy and immunophenotypic assessment of lineage commitment and developmental stage by flow cytometry are essential for diagnosis.2 Chromosomal analysis still has an important role in the initial cytogenetic work-up. Reverse transcriptase PCR, fluorescence in-situ hybridisation or multiplex ligation-dependent probe amplification, and flow cytometry are used to identify leukaemia-specific translocations, submicroscopic chromosomal
Clinical and biological factors
Age (infant or ≥10 years old), presenting leucocyte count (≥50×109/L), race (Hispanic or black), male sex, and T-cell immunophenotype are adverse clinical prognostic factors in children, although their effect is diminished by contemporary risk-adapted treatment and improved supportive care.2, 3, 4, 5, 6 Infants with MLL rearrangements, especially those younger than 6 months old with more than 300×109 leucocytes per L at diagnosis, still have a dismal prognosis.7
Racial differences in prognosis
Treatment
Treatment typically spans 2–2·5 years, and comprises three phases: induction of remission, intensification (or consolidation), and continuation (or maintenance).2 Most of the drugs used were developed before 1970. However, their dosages and schedule in combination chemotherapy have been optimised on the basis of leukaemic-cell biological features, response to treatment (MRD), and pharmacodynamic and pharmacogenomic findings in patients, resulting in the high survival rate. CNS-directed
Remission-induction therapy
4–6 weeks of remission-induction therapy eradicates the initial leukaemic cell burden and restores normal haemopoiesis in 96–99% of children and 78–92% of adults with acute lymphoblastic leukaemia.2, 3, 4, 5 Chemotherapy generally includes a glucocorticoid (prednisone or dexamethasone), vincristine, and asparaginase, with or without anthracycline. This regimen seems sufficient for standard-risk disease when intensified postremission treatment is given. Patients at high or very high risk receive
Intensification (consolidation) therapy
Intensification (consolidation) therapy is given after remission-induction treatment, and eradicates residual leukaemic cells.2, 3 High-dose (ie, 1–8 g/m2) methotrexate with mercaptopurine is often given, as are frequent pulses of vincristine and glucocorticoids, uninterrupted asparaginase for 20–30 weeks, and reinduction therapy with drugs similar to those used during remission-induction therapy.
The accumulation of the active metabolites of methotrexate—methotrexate polyglutamates (MTXPG1–7
Continuation therapy
Continuation therapy typically lasts 2 years or longer and comprises mainly daily mercaptopurine and weekly methotrexate with or without pulses of vincristine and dexamethasone. Mercaptopurine and tioguanine are structural analogues of hypoxanthine and guanine, respectively, and inhibit de-novo purine synthesis. Although tioguanine forms the active-metabolite thioguanine nucleotides in fewer steps and is more cytotoxic in vitro to lymphoblasts than is mercaptopurine, randomised studies have not
Haemopoietic stem cell transplantation and cellular therapy
Allogeneic haemopoietic stem cell transplantation is an option for children with very-high-risk or persistent disease.125 Contemporary protocols with high-resolution HLA typing, case-based conditioning, and improved supportive care have reduced relapse-related mortality, regimen-related toxic effects, and infection.126, 127 Furthermore, leukaemia-free survival is not affected by the source of stem cells (matched related, matched unrelated, cord blood, or haploidentical donor).127, 128, 129
In
CNS-directed therapy
Control of CNS disease is a key component of treatment. Prophylactic cranial irradiation (12–18 Gy) is effective, but its use has been reduced or eliminated to prevent acute neurotoxic effects, neurocognitive deficits, endocrinopathies, secondary malignant disease, and excess late mortality.135 In the St Jude Total XV and Dutch Childhood Oncology Group acute lymphoblastic leukaemia-9 protocols,6, 136 cranial irradiation is replaced by triple intrathecal chemotherapy with methotrexate,
Remaining questions and future directions
Some subsets of acute lymphoblastic leukaemia still have an adverse prognosis. Further intensification of available regimens is unlikely to substantially improve survival but will increase short-term and long-term adverse effects. Reduction of treatment intensity should be sought in patients at low risk. Studies of chronic health complications in long-term adult survivors will help to refine treatments, reducing the toxic effects of treatment. Functional genomics and proteomics will improve
Search strategy and selection criteria
References (141)
- et al.
Acute lymphoblastic leukaemia
Lancet
(2008) - et al.
Treatment of childhood acute lymphoblastic leukemia
Semin Hematol
(2009) - 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
Lancet
(2007) - et al.
Leukemia in twins: lessons in natural history
Blood
(2003) Aetiology of acute leukaemia
Lancet
(1997)- et al.
Numbers and proportions of leukemias in young people and adults induced by radiation of natural origin
Leuk Res
(2011) Exposure to extremely low-frequency magnetic fields and the risk of childhood cancer: update of the epidemiological evidence
Progr Biophysics Mol Biol
(2011)Evidence for an infective cause of childhood leukaemia: comparison of a Scottish New Town with nuclear reprocessing sites in Britain
Lancet
(1988)- et al.
Immunisation and herd immunity
Lancet
(1990) - et al.
Risks of leukaemia and solid tumours in individuals with Down's syndrome
Lancet
(2000)