Acute Lymphoblastic Leukaemia Lancet 2008

7/27/2019 Acute Lymphoblastic Leukaemia Lancet 2008

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1030 www.thelancet.com Vol 371 March 22, 2008

Acute lymphoblastic leukaemia

Ching-Hon Pui, Leslie L Robison, A Thomas Look

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 hasled to a cure rate of more than 80% in children, creating opportunities for innovative approaches that would preservepast gains in leukaemia-free survival while reducing the toxic side-effects of current intensive regimens. Advances inour 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 thisdisease. Meanwhile, studies are underway to ascertain the precise events that take place in the genesis of acutelymphoblastic leukaemia, to enhance the clinical application of known risk factors and antileukaemic agents, and toidentify treatment regimens that might boost the generally low cure rates in adults and subgroups of children withhigh-risk leukaemia.

IntroductionAddition of acute lymphoblastic leukaemia to the growinglist of cancers that have succumbed to effective treatmentis tempting. The decision would be easy to justify in viewof data showing cure rates higher than 80% for childrentreated in modern centres, most of whom will leadhealthy productive lives as long-term cancer survivors.13Thus, the future management of acute lymphoblasticleukaemia might be viewed as simply tweaking existingprotocols and devising alternative regimens for the fifthof patients who respond poorly to available agents. Thisscenario, however attractive, must be rejected on severalgrounds. It does not accommodate the poor prognosis

for adults with acute lymphoblastic leukaemia or thecomplexity, expense, and toxic effects of contemporarymultiagent treatments.1,4Most importantly, it overlooksour rapidly increasing ability to analyse the genetic andepigenetic abnormalities of leukaemic cells and totranslate them into enhanced diagnostic methods andmolecularly targeted therapy.5,6 Although the molecularmedicine approach is still in its investigative stage, withmany new obstacles to overcome, it holds enormouspromise. Put simply, we are about to enter an era inwhich leukaemia patients will probably receiveindividualised treatment based on the genetic features oftheir malignant cells and their own unique geneticmake-up (so-called pharmacogenomics).7 Our intent in

this Seminar is to review advances in both thefundamental understanding and clinical management ofacute lymphoblastic leukaemia in children and adults.

Epidemiology and causeThe precise pathogenetic events leading to developmentof acute lymphoblastic leukaemia are unknown. Only afew cases (03 or 04 T) ofresidential, power-frequency magnetic fields.9,10

Observations of a peak age of development of childhoodacute lymphoblastic leukaemia of 25 years, an associationof industrialisation and modern or affl uent societies withincreased prevalence of the disease, and the occasionalclustering of childhood leukaemia cases (especially in newtowns) have fuelled two parallel infection-based hypotheses

by British investigators: Kinlens population-mixinghypothesis and Greaves delayed-infection hypothesis(figure 1).11,12 Kinlens hypothesis predicts that clusters ofchildhood cases of acute lymphoblastic leukaemia resultfrom exposure of susceptible (non-immune) individualsto common but fairly non-pathological infections afterpopulation-mixing with carriers. The delayed-infectionhypothesis of Greaves is based on a minimal two-hitsmodel and suggests that some susceptible individualswith a prenatally acquired preleukaemic clone had low orno exposure to common infections early in life becausethey lived in an affl uent hygienic environment. Suchinfectious insulation predisposes the immune system ofthese individuals to aberrant or pathological responses

after subsequent or delayed exposure to commoninfections at an age commensurate with increasedlymphoid-cell proliferation.

Retrospective identification of leukaemia-specificfusion genes, hyperdiploidy, or clonotypic rearrange-ments of immunoglobulin or T-cell-receptor loci in

Lancet2008; 371: 103043

Department of Oncology

(Prof C-H Pui MD)and

Department of Epidemiology

and Cancer Control

(Prof L L Robison PhD), St Jude

Childrens Research Hospital

and University of Tennessee

Health Science Center,

Memphis, TN, USA; and

Department of Pediatric

Oncology, Dana-Farber Cancer

Institute and Harvard Medical

School, Boston, MA, USA(Prof A T Look MD)

Correspondence to:

Prof Ching-Hon Pui, St Jude

Childrens Research Hospital,

332 N Lauderdale, Memphis,

TN 38105, USA

[email protected]

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.


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www.thelancet.com Vol 371 March 22, 2008 1031

archived neonatal blood spots (Guthrie cards) and

studies of leukaemia in monozygotic twins indicateclearly a prenatal origin for some childhoodleukaemias.1215Screening of neonatal cord-blood sampleshas revealed a putative leukaemic clone with theTEL-AML1fusion gene (also known as ETV6-RUNX1)in1% of newborn babies, a frequency 100 times higherthan the prevalence of acute lymphoblastic leukaemiadefined by this fusion gene later in childhood.16 Thevariable incubation period and clinical outcome of suchcases, and the 10% concordance rate of leukaemia inidentical twins with this genotype, support the notionthat additional postnatal events are needed for fullleukaemic transformation.17 A recent study furtherestablished the presence of a preleukaemic clone with

the TEL-AML1fusion.15Investigations have also focused on the genetic

variability in xenobiotic metabolism, DNA repairpathways, and cell-cycle checkpoint functions that mightinteract with environmental, dietary, maternal, and otherexternal factors to affect development of acutelymphoblastic leukaemia. Although the number ofinvestigations and sample sizes are limited, data exist tosupport a possible causal role for polymorphisms ingenes encoding cytochrome P450, NAD(P)H quinoneoxidoreductase, glutathione S-transferases, methyl-enetetahydrofolate reductase, thymidylate synthase,serine hyroxymethyltransferase, and cell-cycle inhi-bitors.1823To date, however, no direct gene-environmentinteractions have been established convincingly.

In view of the scarcity of causal insights from large-scaleepidemiological studies, some investigators have adopteda strategy that focuses on distinct subtypes of childhoodacute lymphoblastic leukaemia. An important example isthe study of infant acute lymphoblastic leukaemia withMLLrearrangement,24a genetic abnormality that has alsobeen associated with secondary leukaemia after exposureto a topoisomerase II inhibitor.25Thus, dietary, medical,and environmental exposures to substances that inhibittopoisomerases, and the reduced ability of fetuses ortheir mothers to detoxify such agents, could lead todevelopment of infant leukaemia.26,27

PathobiologyAcute lymphoblastic leukaemia is thought to originatefrom various important genetic lesions in blood-progenitorcells that are committed to differentiate in the T-cell orB-cell pathway, including mutations that impart thecapacity for unlimited self-renewal and those that lead toprecise stage-specific developmental arrest.6,28 In somecases, the first mutation along the multistep pathway toovert acute lymphoblastic leukaemia might arise in ahaemopoietic stem cell possessing multilineage develop-mental capacity.29 The cells implicated in acutelymphoblastic leukaemia have clonal rearrangements intheir immunoglobulin or T-cell receptor genes andexpress antigen-receptor molecules and other

differentiation-linked cell-surface glycoproteins thatlargely recapitulate those of immature lymphoidprogenitor cells within the early developmental stages ofnormal T and B lymphocytes.6,28,30The dominant themeof contemporary research in pathobiology of acutelymphoblastic leukaemia is to understand the outcomesof frequently arising genetic lesions, in terms of theireffects on cell proliferation, differentiation, and survival,and then to devise selectively targeted treatments againstthe altered gene products to which the leukaemic cloneshave become addicted.31

Chromosomal translocationsChromosomal translocations that activate specific genesare a defining characteristic of human leukaemias andof acute lymphoblastic leukaemia in particular.6,28Gene-expression patterns studied in large series of newlydiagnosed leukaemias have substantiated the idea thatspecific chromosomal translocations identify uniquesubtypes of the disease.3235Usually, translocations activatetranscription-factor genes, which in many cases cancontrol cell differentiation (rather than cell division per

se), are developmentally regulated, and frequently encodeproteins at the apex of important transcriptionalcascades.28These so-called master oncogenic transcriptionfactors, which can exert either positive or negative controlover downstream responder genes, are expressedaberrantly in leukaemic cells as one gene product or as aunique fusion protein combining elements from twodifferent transcription factors.6,28

About 25% of cases of B-cell precursor acutelymphoblastic leukaemia, the most frequent form ofacute leukaemia in children, harbour the TEL-AML1fusion genegenerated by the t(12;21)(p13;q22)chromosomal translocation.6 Although the molecularpathogenesis of TEL-AML1-positive leukaemia remainsunclear, findings in mice establish the Tel gene as an

Fetal development Birth Infancy early childhood

Low exposure

to pathogensresulting indecreased

proliferativestress

Rapid cellproliferation

Exposure topathogens duringperiod of

increased lymphoidproliferation

Exposure to the new pathogens as a result ofincreased population mixing

Delayed exposure to common pathogens

Low or no

exposure tonon-endemic

pathogens

Live in an environmentwith decreased

exposure to commonpathogens

Randommutations

Greaves

hypothesis

Kinlens

hypoth

esis

Figure :Infection-based models of leukaemia development


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important regulator of haemopoietic-cell development,

essential for definitive haemopoiesis.36 Similarly, Aml1gene is essential for definitive embryonic haemo-poiesis.37,38Thus, the presence of the TEL-AML1 fusionprotein in B-cell progenitors seems to lead to disorderedearly B-lineage lymphocyte development, a hallmark ofleukaemic lymphoblasts. Analysis of TEL-AML1-inducedcord blood cells suggests that the fusion gene serves as afirst-hit mutation by endowing the preleukemic cell withaltered self-renewal and survival properties.15

In adults, the most frequent chromosomal translocationis t(9;22), or the Philadelphia chromosome, which causesfusion of the BCR signalling protein to the ABLnon-receptor tyrosine kinase, resulting in constitutivetyrosine kinase activity and complex interactions of thisfusion protein with many other transforming elements,

such as the signalling pathway for RAS (GTP-binding

protein that activates target genes involved in celldifferentiation, proliferation, and survival).39 As anactivated kinase, BCR-ABL offers an attractive therapeutictarget, and imatinib mesilate, a small-molecule inhibitorof the ABL kinase, has proven effective against leukaemiasthat express BCR-ABL.40

More than 50% of cases of T-cell acute lymphoblasticleukaemia have activating mutations that involveNOTCH1,41a gene encoding a transmembrane receptorthat regulates normal T-cell development.42 NOTCHreceptors become activated when ligands of theDelta-Serrate-Lag2 family of proteins bind to theextracellular portion of the transmembrane molecule.This interaction initiates a cascade of proteolytic cleavages,terminating in -secretase generation of intracellular

pre-Notch

NotchICN

Heterodimerisation

Glycosylation

Fucosylation andendoplasmic reticulum exit

Ubiquitination and

proteosome degradation

-secretasecomplex

S3cleavage

S2cleavage

S1Cleavage

ICN

GSI ICN

ICN

ICN

ICN

MINTdnMAML NRARP

Notch

ADAMmetalloprotease

pre-Notch

OFUT 1

Fringe

Fringe

Numb

Furin

DLL

Jagged

SEL 10

CSL

CSL

CoA

MAML

n300

CoR

Deltex?

NEURL

MIB

HES 1PRE TDELTEX

NRARPCD25MYC

Receiving cell

Nucleus

Golgi

Endoplasmic

reticulum

Ligand

endocytosis

and

degradation

Sending cell

A

B

C

E

F

G

Figure :NOTCH signalling in normal thymocytes

The NOTCH signalling pathway is complex and involves the coordinated activities of many different molecules. Briefly, NOTCH is synthesised in the endoplasmic

reticulum (A) as one protein consisting of an extracellular domain (pre-Notch) and an intracellular domain (ICN), which are transported in tandem to the Golgi (B),

where several post-translational modifications take pl ace, including a proteolytic cleavage (S1) that separates the two domains from ea ch other. The resultant

heterodimer is then transported to the cell membrane, where NOTCH interacts with ligands (C) and is cleaved twice (D) by the ADAM protease (S2) and a -secretase

complex (S3), enabling the liberated ICN domain to translocate to the nucleus (E). Nuclear ICN forms a binding/activator complex with a group of cooperating

proteins (F), resulting in transcriptional activation of several functionally important genes, including MYC and pre-T. Hyperphosphorylation of ICN via interaction of

its PEST domain (polypeptide enriched in proline, glutamate, serine, and threonine) with CDK8, MAML, and p300 facilitates ubiquitylation (G) by SEL1 family

members, targeting ICN to the proteosome. ADAM=a disintegrin and metalloproteinase domain. DLL=Delta ligand . hes1=hairy/enhancer of split. GSI=-secretase

inhibition.MAML=mastermind-like proteins. MIB=mindbomb. NEURL=neuralised-like. Nrarp=gene encoding NOTCH-regulated ankyrin-repeat protein.

OFUT1=O-fucosyltransferase1. Pre-T=pre-TCR. Deltex=positive regulator of Notch signalling pathway. CS1=DNA binding component. CoA=co-activators.

CoR=co-repressors. Fringe=regulator of Notch ligand. SEL10=positive regulator of Notch. Numb=negative receptor of Notch.


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NOTCH1, which translocates to the nucleus and regulates

by transcription a diverse set of responder genes,including the MYC oncogene (figure 2).43,44 The precisemechanisms by which aberrant NOTCH signalling (dueto mutational activation) causes T-cell acute lymphoblasticleukaemia are still unclear but probably entail constitutiveexpression of oncogenic responder genes, such as MYC,and cooperation with other signalling pathways (pre-TCR[T-cell receptor for antigen] and RAS, for example).Interference with NOTCH signalling by small-moleculeinhibition of -secretase activity has the potential toinduce remission of T-cell acute lymphoblasticleukaemia.

Evidence suggests that the MYC oncoprotein is animportant downstream mediator of the pro-growth

effects of NOTCH1 signalling in developing thym-ocytes.28,45 However, results of retroviral insertionalmutagenesis in murine models of transgenic T-cell acutelymphoblastic leukaemia show that Notch1 mutations,with outcomes similar to those in primary human T-cellacute lymphoblastic leukaemias, can potentiate theeffects of pre-existing MYCoverexpression,42,46suggestingthat NOTCH1 must have important transformationaltargets other than MYC. Activating mutations inNOTCH1 suffi cient to produce constitutive NOTCH1signalling can induce T-cell acute lymphoblasticleukaemia in experimental models and could be theinstigating event in most human T-cell leukaemias.28,42-secretase, a multicomponent membrane-associatedenzyme, is needed for NOTCH1 signalling throughmutant NOTCH receptors in T-cell acute lymphoblasticleukaemia, providing an attractive target for therapeuticintervention with newly developed -secretaseinhibitors.28,47

Cooperating mutationsAlthough chromosomal abnormalities are a hallmark ofpathogenesis of acute lymphoblastic leukaemia, evidencesuggests that they must act in concert with several othergenetic lesions to induce overt leukaemia. A primeexample is the biallelic deletion or epigenetic silencing ofthe cyclin-dependent kinase inhibitor 2A gene (CDKN2A),

which encodes both the tumour suppressors p16 INK4Aandp14ARFand whose inactivation neutralises both the TP53and retinoblastoma pathways in most cases of T-cell andmany cases of B-cell precursor acute lymphoblasticleukaemia.6 In a genome-wide analysis of 242 cases ofpaediatric acute lymphoblastic leukaemia usinghigh-resolution single nucleotide polymorphism arrays,deletions, amplifications, point mutations, and otherstructural rearrangements were identified in genesencoding regulators of B-lymphocyte development in40% of cases of B-cell precursor acute lymphoblasticleukaemia.48The PAX5 gene was the most frequent targetof somatic mutation, being altered in almost a third ofcases. Deletions were also detected in other B-celldevelopmental genes, such as TCF3(E2A), EBF1(EBF),

LEF1, IKZF1 (Ikaros), and IKZF3 (Aiolos). Finally, in

T-cell acute lymphoblastic leukaemia, at least fivemultistep mutational pathways leading to frank leukaemiahave been identified, and in some cases these pathwaysentail five or more documented genetic lesions.28,30,42

Ongoing research to define the oncogenic contributionsof various classes of genetic lesions relies heavily onanimal models that accurately recapitulate the molecularpathogenesis of B-cell precursor or T-cell acutelymphoblastic leukaemia.49 Most studies undertaken todate have used genetically engineered mice to elucidatethe multistep transformation pathways leading to T-cellacute lymphoblastic leukaemia.50 Such models dependon breeding strategies to combine one or more geneticlesions and show synergy in transformation,51 whereas

some investigators have also capitalised on the use ofretroviral insertional mutagenesis screens to uncovercollaborating oncogenes.46,52New models of T-cell acutelymphoblastic leukaemia in the zebrafish offer a powerfulalternative vertebrate system for leukaemia research,whose unique advantages complement those of extantmurine models.53Currently available zebrafish models ofacute lymphoblastic leukaemia include a myctransgene-driven system, in which lymphoblastsfaithfully reproduce the multistep oncogenic pathwaynoted in up to 60% of human T-cell acute lymphoblasticleukaemias,54,55 and a transgenic zebrafish model, inwhich the TEL-AML1 oncoprotein induces B-cellprecursor leukaemia.56

The challenge now is to understand how thesecooperative genetic lesions and their affected pathwaysinteract to alter the proliferation, differentiation, andsurvival of lymphocyte progenitors leading to theirleukaemic conversion. This research will undoubtedlyprovide the molecular rationales needed to select newtherapeutic targets and to develop interfering smallmolecules or antibodies with high levels of antileukaemicspecificity and activity.57The table provides a partial list ofmolecularly targeted drugs now in clinical testing.

DiagnosisPhenotype

Immunophenotyping of leukaemic lymphoblasts by flowcytometry is essential to establish the correct diagnosisand define cell lineage. Although acute lymphoblasticleukaemia can be readily subclassified according to themany 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 inas many as half the cases of acute lymphoblasticleukaemia. However, with contemporary treatment, thisso-called aberrant antigen expression has no prognosticimplications but can be used to distinguish leukaemiccells from normal progenitor cells, thereby enablingdetection of minimal (ie, submicroscopic) residualleukaemia.6,26


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GenotypeAlthough chromosomal analysis is still an integralcomponent of initial work-up of acute lymphoblasticleukaemia, other highly specific and sensitivetechniquessuch as RT-PCR, fluorescence in-situhybridisation, and flow cytometryare increasingly

used to detect specific fusion transcripts, gain or loss ofcellular DNA content, or specific chromosomes withprognostic or therapeutic relevance.26,58 Although still aresearch technique, gene-expression profiling can notonly identify accurately the major subtypes of acutelymphoblastic leukaemia but also implicate single genesor signalling pathways as important determinants ofclinical outcome.3234,5961 Once this method has beenrefined and made cost effective, it will undoubtedlyreplace many current diagnostic techniques.

PharmacogeneticsGenetic polymorphisms of drug transporters, receptors,targets, and drug-metabolising enzymes can affect theeffectiveness and toxic effects of antineoplastic drugs.7,62

Traditionally, pharmacogenetic studies have focused on

single genes identified on the basis of their influenceon the pharmacokinetics and pharmacological effectsof anticancer drugs. Findings of global gene-expressionprofiling studies have identified a growing number ofgenomic determinants of treatment responses thatcould allow development of polygenic models foroptimisation of treatment for acute lymphoblasticleukaemia.6,7,63

Despite the promise of pharmacogenetic studies toenhance treatment outcome in acute lymphoblasticleukaemia, only polymorphisms and the activity ofthiopurine methyltransferasean enzyme that catalysesS-methylation (inactivation) of thiopurines such asmercaptopurine and thioguaninehave been useful in

clinical practice.7,64,65 About 10% of the total populationinherit one wild-type gene encoding thiopurinemethyltransferase and one non-functional variant allele,resulting in intermediate enzyme activity, whereas 1 in300 people inherit two non-functional variant alleles withno enzyme activity. When treated with conventionaldoses of thiopurines, up to half of patients with theheterozygous deficiency and all homozygous-deficientpatients develop haemopoietic toxic effects, which can befatal in the homozygous group.7The enzyme deficiencyalso confers a high risk of developing therapy-relatedacute myeloid leukemia7 and radiation-induced braintumours, in the context of intensive thiopurinetreatment.66 Conversely, patients with high levels ofenzyme activity might be at greater risk of relapse owingto decreased exposure of leukaemic cells to active drugmetabolites.65 In most centres, studies of thiopurinemethyltransferase activity are undertaken only in peoplewith poor tolerance to antimetabolite-based therapy, andthe result is used to guide reductions in drug dosage.67We use a fairly high dose of mercaptopurine and, thus,study this enzyme prospectively in all patients, loweringthe dose of mercaptopurine in individuals with enzymedeficiency.64

Risk assessmentCareful assessment of the risk of relapse in individual

patients ensures that very intensive treatment is givenonly to high-risk cases, thus sparing people at lower riskfrom undue toxic effects. Although enhanced treatmenthas abolished the prognostic strength of many clinicaland biological risk factors identified in the past, wewould stress that even so-called low-risk patients need acertain degree of treatment intensification to avoidunacceptable rates of relapse. Findings have shown thatadolescents and young adults who were treated on adultprotocols fared significantly worse than the sameage-groups treated on paediatric protocols.6870 Thesuperior outcome achieved with paediatric regimenshas been attributed to more effective treatment and tobetter adherence by patients, parents, and doctors.6872To understand the actual basis for this difference in

Mechanism of action Subtype of

leukaemia targeted

Clofarabine Inhibits DNA polymerase and ribonucleotide

reductase; disrupts mitochrondria

membrane

All

Nelarabine Inhibits ribonucleotide reductase and DNA

synthesis

T-cell

Forodesine Inhibits purine nucleoside phosphorylase T-cell

-sec retase inhibitors Inhibit -secretase , an enzyme req uired for

NOTCH1 signalling

T-cell

Rituximab Anti-CD20 chimeric murine-human

monoclonal antibody

CD20-positive

Epratuzumab Anti-CD22 humanised monoclonal antibody CD22-positive

Alemtuzumab Anti-CD52 humanised monoclonal antibody CD52-positive

Gemtu zu mab o zo gamicin Ant i- CD33 mo no clonal antibo dy co njugat ed

with calicheamicin

CD33-positive

Imatinib mesilate ABL kinase inhibition BCR-ABL-positive

Nilotinib ABL kinase inhibition BCR-ABL-positive

Dasatinib BCR-ABL kinase inhibition BCR-ABL-positive

MK-0457 Aurora kinase inhibition BCR-ABL-positive

Lestaurtinib; midostaurin; tandutinib;

sunitinib malate; IMC-EB10

FMS-l ike ty ro sine k inase 3 inhibition MLL-rearranged;

hyperdiploid

Tipifarnib; lonafarnib Farnesyltransferase inhibition All

Azacytidine; decitabine;

temozolomide

DNA methyltransferase inhibition All

Romidepsin; vorinostat; valproic acid;

MD-27-275; AN-9

Histone deacetylase inhibition All

Sirolimus; temsirolimus; everolimus;

AP-23573

Mammalian target-of-rapamycin inhibition All

Bortzezomib Inhibition of ubiquitin proteasome pathway All

Flavopiridol Serine-threonine cyclin-dependent kinase

inhibition

All

Oblimersen Downregulation of BCL2 All

17-AAG Heat shock protein-90 inhibitor BCR-ABL-positive;

ZAP-70-positive

Table:Selected antileukaemic drugs being tested in clinical trials


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outcome, several combined adult and paediatric

consortia are using common regimens to treat patientsaged 150 years.

Clinical factorsAge at diagnosis has a strong prognostic effect (figure 3).In work done at St Jude Childrens Research Hospital,847 children with acute lymphoblastic leukaemia wereenrolled in four consecutive treatment protocols from 1991to 2006. Children aged 19 years had a better outcome thaneither infants or adolescents.26,58 5-year event-free survivalestimates were 88% (SE 2) for children aged 19 years,73% (4) for adolescents aged 1015 years, 69% (7) for thoseolder than 15 years, and 44% (11) for babies younger than12 months. Babies younger than 6 months have an

especially poor outcome.73,74The outcome of treatment inadults worsens with increasing age. Indeed, in the past,patients older than 60 years were not even included inclinical trials owing to their many coexisting healthproblems, their heightened susceptibility totreatment-related toxic effects, and their high frequency ofPhiladelphia chromosome-positive acute lymphoblasticleukaemia.1,4,75 This practice has begun to change, partlybecause of enhanced supportive care now available forolder adults and development of specific tyrosine kinaseinhibitors for Philadelphia chromosome-positive acutelymphoblastic leukaemia (table).75,76

Leucocyte count is a continuous prognostic variable,with increasing counts conferring a poorer outcome,especially in patients with B-cell precursor disease.58,76In T-cell acute lymphoblastic leukaemia, a leucocytecount greater than 100x109/L is associated with anincreased risk of relapse in the CNS.77 Patients withextreme hyperleucocytosis (>400x109/L) are at high riskfor early complications such as CNS haemorrhage andpulmonary and neurological events due to leucostasis.78A uniform risk-classification system, based on both ageand leucocyte count, was devised to facilitatecomparisons of treatment results in childhood acutelymphoblastic leukaemia.26Two-thirds of patients aged19 years with a leucocyte count less than 50x109/L werejudged to have a standard (or low) risk of relapse,

whereas the remaining third were classified as highrisk. This system by itself has limited value because upto a third of the so-called standard-risk patients couldrelapse, and individuals at very high riskwho needallogeneic haemopoietic stem-cell transplantationcannot be distinguished reliably from high-risk cases.26Moreover, risk criteria apply only to B-cell precursoracute lymphoblastic leukaemia and have little prognosticvalue in T-cell disease.

In US cooperative group studies, black and Hispanicpatients fared worse than similarly treated whiteindividuals.79The poor prognosis for black people could berelated to their high frequency of T-cell acute lymphoblasticleukaemia and the t(1;19) chromosomal abnormality withE2A-PBX1 fusion.80However, in single-institution studies,

black children had the same high cure rates as did whitechildren when given equal access to effective treatment,80underscoring the over-riding prognostic importance oftreatment. The adverse prognosis previously ascribed tomale sex has also been abolished with enhanced treatmentregimens.2,81

Likewise, the effect of obesity on outcome of acutelymphoblastic leukaemia is also treatment dependent. Areport by the Childrens Oncology Group showed thatoverweight children with acute lymphoblastic leukaemia,aged 10 years or older, have a poor treatment outcome.82By contrast, we noted no association between thebody-mass index of patients with acute lymphoblasticleukaemia and clinical outcome, toxic effects, or thepharmacokinetics of several drugs tested.83

Biological factorsT-cell and mature B-cell immunophenotypes, once

associated with a poor outcome, have little prognosticimportance in childhood acute lymphoblastic leukaemiaand are actually favourable features in adult disease in thecontext of contemporary treatment.2,76,81,84Although geneticabnormalities do not account entirely for treatmentoutcome they still provide indispensable prognosticinformation (figure 4). 841 children with acutelymphoblastic leukaemia and successful cytogenetic andimmunophenotypic studies were enrolled in fourconsecutive treatment protocols at St Jude ChildrensResearch Hospital from 1991 to 2006. Patients withhyperdiploidy (>50 chromosomes), TEL-AML1fusion, andt(1;19)/E2A-PBX1fusion had the most favourable outcome,whereas those with the t(9;22)/BCR-ABLfusion or t(4;11)/MLL-AF4fusion had a dismal prognosis. 5-year event-free

0

0

01

02

03

04

05

06

07

08

09

1

2 4 6 8Years from diagnosis

10 12 14 16

1815 years

15 years (n=78)

11 8 8 6 1 1 0 0

598 528 378 295 213 149 85 31 4

153 130 100 77 50 26 11 6 1

78 60 40 29 20 7 1 0 0

Probability

Figure :Kaplan-Meier estimates of event-free survival according to age at diagnosis of acute

lymphoblastic leukaemia


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survival estimates were 91% (SE 3) for hyperdiploidy, 89%

(3) for TEL-AML1 fusion, 86% (7) for E2A-PBX1 fusion,82% (3) for other B-lineage disease, 73% (5) for T-cell acutelymphoblastic leukaemia, 37% (12) for BCR-ABL fusion,and 32% (12) for MLL-AF4fusion.

In general, the Philadelphia chromosome, t(4;11) withMLL-AF4 fusion, and hypodiploidy (50 chromosomes), TEL-AML1fusion, andtrisomy 4, 10, and 17 are associated with favourableprognosis.6,8587About 2% of childhood cases were noted tohave intrachromosomal amplification of chromosome 21,which is associated with a B-cell precursor imm-unophenotype, older age, low white-cell counts, and, moreimportantly, a threefold increase in risk of relapse.88The

high frequency of unfavourable genetic features and lowrate of favourable genetic abnormalities in adults withacute lymphoblastic leukaemia partly explain their inferioroutcome compared with childhood cases.76

Age affects the prognostic importance of geneticabnormalities for unknown reasons. In children withPhiladelphia chromosome-positive acute lymphoblasticleukaemia, those aged 19 years fared better than didadolescents,89 who in turn had a better prognosis thanadults.90,91 In patients with MLL-AF4 fusion, infants andadults have a worse prognosis than children.9193 Thet(1;19) with E2A-PBX1 fusion has no prognosticimplications in childhood acute lymphoblastic leukaemiabut is still associated with a poor prognosis in some adultcases.76 Findings are scarce to suggest that activatingmutations of the NOTCH1 gene are associated with a

favourable prognosis in childhood T-cell acute

lymphoblastic leukaemia

94

but an unfavourable outcomein adults.95

Data of microarray analyses of leukaemic cells identifiedgenes that affect the intracellular disposition ofantileukaemic drugs and have shown distinct sets ofgenes that are associated with resistance to differentclasses of antileukaemic agents.5961,9699 Aberrantexpression of some genes also seemed to haveprognostic relevance.59,60 It is also noteworthy thatnumerical chromosomal abnormalities, depending onwhether the affected chromosomes contain the wild-typeor variant allele of the genes, can greatly affect thepharmacogenomics of cancer treatment and, thus,clinical outcome.100

Response to treatmentResponse to treatment is determined by the entire con-stellation of leukaemic-cell biological features (intrinsicdrug sensitivity) in concert with the pharmacodynamicsand pharmacogenomics of the host, the regimensadministered, and treatment adherence. Not surprisingly,the degree of reduction of the leukaemic cell clone earlyduring remission induction therapy has independentprognostic importance1,26,101104even in low-risk cases definedby clinical and biological features.105 However,morphology-based methods traditionally used to assesstreatment response are neither precise enough norsensitive enough to measure this cytoreduction reliably.26,106Molecular and flow-cytometric methods, which are at least100-fold more sensitive than morphological determinations,now allow minimal residual leukaemia to be detected atvery low levels (


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Treatment

With the exception of patients with mature B-cell acutelymphoblastic leukaemia, who are treated with short-term intensive chemotherapy (including high-dosemethotrexate, cytarabine, and cyclophosphamide),109111treatment for acute lymphoblastic leukaemia typicallyconsists of a remission-induction phase, an intensification(or consolidation) phase, and continuation therapy toeliminate residual disease. Treatment is also directed tothe CNS early in the clinical course to prevent relapseattributable to leukaemic cells sequestered in this site.1The drugs currently in use for these phases weredeveloped and tested between the 1950s and 1970s, butefforts to identify new antileukaemic agents have begunto intensify (table).

Remission-induction phaseThe goal of remission-induction treatment is to eradicatemore than 99% of the initial leukaemic cell burden andto restore normal haemopoiesis and healthy performancestatus. This approach typically includes administration ofa glucocorticoid (prednisone or dexamethasone),vincristine, and at least a third drug (asparaginase,anthracycline, or both). A three-drug induction regimenseems suffi cient for most standard-risk cases providedthey receive intensified post-remission treatment.Children with high-risk or very high-risk acute lymph-oblastic leukaemia, and virtually all adult cases of thedisease, are treated with four or more drugs for remissioninduction.1 We measure levels of minimal residualleukaemia after 2 weeks of remission induction and weintensify treatment in patients with high amounts ofresidual blasts (>1%). Clinical remission can now beinduced in 9699% of children and 7893% of adults.1Although no induction regimen is clearly superior to anyothers, addition of cyclophosphamide and intensivetreatment with asparaginase are widely consideredbeneficial to patients with T-cell acute lymphoblasticleukaemia,2,76and imatinib mesilate has greatly enhancedthe remission-induction rate, duration of disease-freesurvival, and quality of life of patients with Philadelphiachromosome-positive acute lymphoblastic leukaemia.112114

Whether the cure rate of this subtype of leukaemia canbe raised with imatinib or the newly developed, morepotent, tyrosine kinase inhibitors nilotinib and dasatinibremains unknown.115,116

Presumably because of its longer half-life andincreased penetration into the CNS, dexamethasonehas been deemed more effective than either prednisoneor prednisolone for treatment of acute lymphoblasticleukaemia.117,118However, findings of a small randomisedstudy showed that an augmented dose of prednisoloneproduced results comparable with those achieved withdexamethasone in the context of other intensivetreatment.119 Similarly, the pharmacodynamics ofasparaginase differ by formulation,120 and in terms ofleukaemia control, the dose intensity and duration of

asparaginase treatment (ie, the amount of asparagine

depletion) are far more important than the type ofasparaginase used.1,2 Compared with Escherichia coliasparaginase, Erwiniaasparaginase was associated withinferior antileukaemic response but fewer toxiceffects,121,122a finding now attributed to use of inadequatedoses of the Erwiniadrug. In some current protocols,polyethylene glycol-conjugated asparaginasea long-acting and less allergenic formhas replaced the nativeproduct in initial treatment.123126 Many complicationsrecorded during remission induction are attributable tothe synergistic effects of corticosteroid and asparaginase.In the context of multiagent treatment, a fairly smallincrease in dose of dexamethasone or asparaginase canresult in excessive toxic effects and death, especially in

older children and adults.

Consolidation (intensification) treatmentWith the restoration of normal haemopoiesis and bodyfunction, intensification treatment is generally used toeradicate drug-resistant residual leukaemic cells, thusreducing the risk of relapse. For example, patients withTEL-AML1-positive disease have an especially goodoutcome in clinical trials of intensive post-remissiontherapy with corticosteroids, vincristine, and aspara-ginase.81,127 Although the importance of this treatmentphase is rarely disputed, consensus is scarce on the bestregimens and duration of treatment. Frequently usedstrategies include high-dose methotrexate plusmercaptopurine, reinduction treatment with the sameagent that was given initially, frequent pulses ofvincristine and corticosteroid plus high-dose asparaginasefor 2030 weeks, and an augmented regimen consistingof reinduction treatment and additional doses ofvincristine, asparaginase, and intravenous methotrexateduring periods of myelosuppression.13,128 For patientswith high-risk or very high-risk acute lymphoblasticleukaemia, incorporation of high-dose methotrexate plusmercaptopurine into a regimen based on intensiveasparaginase treatment could be desirable. Findings ofongoing studies will establish if these approaches inchildren are effective and tolerable in adults.

Reinduction treatment has become an integralcomponent of contemporary protocols. In one randomisedstudy of intermediate-risk acute lymphoblastic leukaemia,double reinduction further enhanced treatment outcome,whereas additional pulses of vincristine and prednisoneafter one reinduction course were not beneficial, suggestingthat the increased dose-intensity of other drugssuch asasparaginaseled to the noted improvement.129Althougha standard intensification regimen for adult acutelymphoblastic leukaemia is absent, post-remissiontreatment with cytarabine, cyclophosphamide, anthra-cyclines, and methotrexate has improved outcome in somenon-randomised studies.130132

The best dose of methotrexate depends on theleukaemic-cell genotype and phenotype and host pharma-


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cogenetic and pharmacokinetic variables. Methotrexate

at 12 g/m is adequate for most patients withstandard-risk acute lymphoblastic leukaemia, but ahigher dose (eg, 5 g/m) might benefit individuals withT-cell or high-risk B-cell precursor disease.133,134The fairlylow accumulation of methotrexate polyglutamates inblast cells with either TEL-AML1 or E2A-PBX1 fusionsuggests that patients with these genotypes could alsobenefit from an increased dose of methotrexate.98However, mega doses of methotrexate (eg, 336 g/m) donot seem necessary for patients with acute lymphoblasticleukaemia.135 Finally, leucovorin rescue, althoughnecessary after treatment with high-dose methotrexate,must not be given too early or at too high a dosagebecause it might counteract the antileukaemic effects of

methotrexate.134136

Allogeneic haemopoietic stem-celltransplantationAllogeneic haemopoietic stem-cell transplantation is themost intensive form of treatment for acute lymphoblasticleukaemia. Comparisons between this modality andintensive chemotherapy have yielded inconsistent resultsowing to the few patients studied and differences incase-selection criteria.137140Nonetheless, allogeneic trans-plantation clearly benefits several subgroups of patientswith high-risk acute lymphoblastic leukaemia, such asindividuals with Philadelphia chromosome-positivedisease (even when treated with a tyrosine kinaseinhibitor) and those with a poor initial response totreatment.89,113,137,140142 It also improves the outcome ofadults with the t(4;11) subtype of acute lymphoblasticleukaemia, but its benefits in infants with this genotypeare controversial.74,92,143,144Findings of studies suggest thatmatched unrelated-donor or cord-blood transplantationcould produce results comparable with those obtainedwith matched related-donor transplantation.145,146In viewof the substantial morbidity and mortality associatedwith this procedure and the growing prospects foreffective targeted therapy, the need for allogeneictransplantation should be reassessed continuously.Autologous transplantation, despite several practical

advantages, has failed to enhance outcome in either adultor paediatric acute lymphoblastic leukaemia.138,147

Continuation treatmentFor reasons that (currently) remain elusive, patients withacute lymphoblastic leukaemia need continuationtreatment to prevent or forestall relapse. Although abouttwo-thirds of childhood cases can be treated successfullywith only 12 months of therapy, they cannot be identifiedprospectively with any degree of certainty.148 Hence, allpatients receive chemotherapy for 2025 years. Dailymercaptopurine and methotrexate every week constitutethe backbone of continuation regimens. Many investigatorsadvocate that drug dosages be adjusted to maintainleucocyte counts below 310/L and neutrophil counts

between 05 and 1510/L to ensure adequate dose

intensity during the continuation phase.

1

Since thioguanine is more potent than mercaptopurinein model systems and leads to higher concentrations ofthioguanine nucleotides in cells and cytotoxic concentra-tions in cerebrospinal fluid,149 several randomised trialshave been done to compare the effectiveness of these twodrugs.150152Thioguanine, given at a daily dose of 40 mg/mor more, produced superior antileukaemic responses tomercaptopurine but was associated with profoundthrombocytopenia, an increased risk of death inremission, and an unacceptably high rate (1020%) ofhepatic veno-occlusive disease.150152 Although the loweractivity of thiopurine methyltransferase is associated withthioguanine-related liver damage, this measure cannot

identify reliably patients at risk.153 Mercaptopurine,therefore, remains the drug of choice for acute lymph-oblastic leukaemia, although thioguanine could still begiven in short-term courses during the intensificationphase of treatment.

In a multicentre randomised trial, addition of six pulsesof vincristine and dexamethasone during early continu-ation treatment failed to improve outcome of childrenwith intermediate-risk acute lymphoblastic leukaemia.154Whether more intensive pulse therapy would enhanceoutcome in the context of contemporary therapy remainsto be studied.

CNS-directed treatmentCNS relapse is a major obstacle to cure, accounting for3040% of initial relapses in some studies.117,129,155Factorsassociated with an increased risk of CNS relapse includea T-cell immunophenotype, hyperleucocytosis, high-riskgenetic abnormalities, and presence of leukaemic cells incerebrospinal fluid (even from iatrogenic introductiondue to a traumatic lumbar puncture).3,77,156158 Poly-morphisms in genes that code for proteins implicated inthe pharmacodynamics of antileukaemic drugs have alsobeen associated with risk of CNS relapse.63

Because of its many associated acute and latecomplications,159,160cranial irradiation is now administeredto only 520% of patients at high risk for CNS relapse. 77

With effective systemic treatment, the radiation dose canbe lowered to 12 Gy for most patients and to 18 Gy forthose with CNS leukaemia at diagnosis.133In fact, 18 Gyirradiation was shown to be effective even in patientswith late isolated CNS relapse, in the context of intensivesystemic chemotherapy.161 We are testing the feasibilityof omitting radiation for all patients with acutelymphoblastic leukaemia, reserving its use exclusivelyfor remission retrieval therapy. Whether or not cranialradiation is used, the best regimen of intrathecal therapyshould be administered.162 To avoid traumatic lumbarpuncture from the repeated procedure and potentialCNS seeding, we give intrathecal therapy with the veryfirst diagnostic lumbar puncture, after the diagnosis ofleukaemia has been established. Some investigators


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recommend an Ommaya reservoir for this treatment in

adults with acute lymphoblastic leukaemia.

76

In onerandomised trial, triple intrathecal therapy withmethotrexate, cytarabine, and hydrocortisone was moreeffective than intrathecal methotrexate in preventingCNS relapse, but it was associated with an increasedfrequency of bone marrow or testicular relapse.163 Oneexplanation for this seemingly paradoxical finding is thatan isolated CNS relapse is, in fact, an early manifestationof systemic relapse, and the better CNS control securedwith triple intrathecal therapy does not obviate overtleukaemic relapse in other sites. If so, more effectivesystemic chemotherapy is needed before the full benefitof triple intrathecal therapy can be realised. Indeed,systemic treatment has a substantial role in prevention

of CNS relapse.117,118,122,152

Remaining questions and the futureWhat are the major causative factors in the developmentof acute lymphoblastic leukaemia? Apart from isolatedcases that can be attributed to inherited genetic syn-dromes or exposures to known leukaemogenic agents,identification of causal factors with a predictable effecton substantial numbers of children or adults has notbeen possible, impeding efforts to develop effective prev-entive measures against acute lymphoblastic leukaemia.In view of the failure of large-scale epidemiologicalstudies to find such associations, future research in thisarea will probably restrict its focus to patients with acommon primary genetic lesion, such as those witheither BCR-ABL, MLL-AF4, or TEL-AML1 fusion, orhyperdiploidy.

Assuming that molecular therapeutics will eventuallyreplace standard combination chemotherapy andhaemopoietic stem-cell transplantation in the manage-ment of patients with acute lymphoblastic leukaemia,which molecules implicated in disease pathogenesis aremost likely to yield substantial clinical benefits?Experience to date shows that transient responses can beobtained by inhibition of certain key enzymes, such astyrosine kinases, DNA methyltransferase, histonedeacetylase, secretase, serine-threonine kinases, and

proteosomes (table).164 However, rapid development ofdrug resistance suggests that curative treatment willneed alternative strategies. For example, short-livedremissions induced in BCR-ABL-positive acute lymph-oblastic leukaemia by imatinib mesilate suggest a needto combine this drug with newly developed ABL-kinaseinhibitors, agents whose mechanism of action differsfrom that of imatinib, or with specific inhibitors ofpathways downstream of, or parallel, to the BCR-ABLpathway.39,115,116,165 A different situation arises whenNOTCH signalling is interrupted. That is, proliferativeintestinal crypt cells are destined to become post-mitoticgoblet cells in the absence of NOTCH signals,47,166raisingthe spectre of on-target toxic effects in human trials of-secretase inhibitors and other targeted therapeutics. In

the case of -secretase inhibitors, alleviation of adverse

effects on gastrointestinal stem cells seems to be possiblethrough an intermittent schedule that is still effectiveagainst leukaemic cells. This pitfall, and possibleavoidance strategies based on drug scheduling, will loomespecially large in leukaemia subtypes in which malignantcells have become addicted to signalling pathways thatare also essential for maintenance and renewal of healthytissues. As daunting as these challenges can seem, thepayoff in terms of understanding the pathobiology ofacute lymphoblastic leukaemia and devising noveleffective treatments with few or no toxic effects could beenormous, making it our charge to bring this promise tofruition.

Are cancer stem cells likely to affect development of

future targeted treatments for acute lymphoblasticleukaemia? Current evidence suggests that the stem-cellproperties of certain human cancers could cause aresurgence of tumour unless the malignant stem cells arespecifically targeted by treatment.167Findings show thattransformation of committed haemopoietic progenitorsby the MLL-AF9 oncoprotein can impart stem-cellproperties, especially a self-renewal-associated geneticprogramme.168 Whether important subpopulations ofleukaemic cells with stem-cell properties underlie somecases of relapsed acute lymphoblastic leukaemia remainsto be determined and, therefore, they must be consideredin the design of molecular therapeutics. Finally, increasingevidence suggests that the homing and engraftmentproperties of leukaemic stem cells differ from those ofnormal haemopoietic stem cells169,170and that bone-marrowmesenchymal cells can protect leukaemic cells from thecytotoxic effects of chemotherapy.171 Possibly, enhancedunderstanding of the molecular interactions betweenleukaemic cells and the bone-marrow microenvironmentwill lead to treatment strategies that enhance theantileukaemic effects of chemotherapy.

Conflict of interest statement

C-HP received honoraria from Enzon, Sanofi Aventis, and Mundipharmfor lectures. ATL received research support from Merck.

Acknowledgments

Supported in part by grants CA21765, CA51001, CA60419, CA36401,CA78224, GM61393, NR07610, CA90246, CA52259, CA68484, CA06516from the National Institutes of Health, and by the Amercian LebaneseSyrian Associated Charities. These sponsors had no role in writing of theSeminar.

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Acute Lymphoblastic Leukaemia Lancet 2008

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