AcuteLymphoblasticLeukemia-FRenPro3732

7/28/2019 AcuteLymphoblasticLeukemia-FRenPro3732

1/13

Acute Lymphoblastic Leukemia

Authors: Doctors Conter V, Rizzari C, Sala A, Chiesa R, Citter io M and ProfessorBiondi A1

Creation date: December 2004

Scientific Editor: Professor Riccardo Riccardi

1Centro Ricerca M. Tettamanti, Clinica Pediatrica Universit di Milano Bicocca, Ospedale San Gerardo,

Via Donizetti, 106, 20052 Monza, Italy. mailto:[email protected]

AbstractKey-wordsDefinition/Diagnostic criteriaPathogenesisClinical PresentationDiagnostic methodsEpidemiologyTreatmentRelapse of acute lymphoblastic leukemiaReferencesAbstractAcute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid cells blocked at an early stageof differentiation and accounts for of all cases of childhood leukaemia. About 3,000 children in theUnited States

and 5,000 children in Europeare diagnosed with ALL each year. The peak incidence of ALL

occurs between age 2 and 5 years. ALL is a biologically heterogeneous disorder, so that morphologic,immunologic, cytogenetic, biochemical, and molecular genetic characterizations of leukaemialymphoblasts are needed to establish the diagnosis or to exclude other possible causes of bone marrowfailure and, finally, to classify ALL subtypes. ALL may be either asymptomatic or acute with life-threatening hemorrhage, infection, or episode of respiratory distress. Although ALL is a disease primarilyof the bone marrow and peripheral blood, any organ or tissue may be infiltrated by the abnormal cells.The most frequent signs are lymphadenopathies, hepatosplenomegaly, fever, signs of hemorrhage, andbone pain. Biological findings include hyperleukocytosis due to circulating lymphoblasts, anemia andthrombocytopenia. Diagnosis is established by bone marrow biopsy, which evidences the leukemic cellsinfiltration. Most of the cases of ALL show chromosomal and genetic abnormalities, which occurspontaneously in important regulatory genes in a lymphoid cell population. The most common ALLtranslocation, the t(12;21), appears to have good prognostic implications. Four main treatment elementscan be generally recognized in chemotherapy protocols adopted by international cooperative groups:induction with the aim of complete remission, CNS preventive therapy, consolidation/reinduction, andmaintenance therapy. The survival rate for children younger than 15 years of age reaches about 75%,but, despite the significant improvement of outcome during the last decades, still roughly 25% of patientssuffer from a relapse of the disease. Even if the management of relapse remains largely controversial, anincreasing use of high dose chemotherapy blocks and stem cell transplantation is adopted in most cases.With the need to stratify patients in risk groups and to provide risk-adapted therapy, treatment requireshigh levels of organization, expertise and knowledge.

Key-wordsAcute lymphoblastic leukemia (ALL), childhood leukaemia, t(12,21), Philadelphia chromosome

Conter V, Rizzari C, Sala A, Chiesa R, Citterio M and Biondi A. Acute Lymphoblastic Leukemia. Orphanet Encyclopedia.December 2004. http://www.orpha.net/data/patho/GB/uk-ALL.pdf 1
mailto:[email protected]:[email protected]


2/13

Definition/Diagnostic c riteriaAcute lymphoblastic leukemia (ALL) is amalignant proliferation of lymphoid cells blockedat an early stage of differentiation. ALL is abiologically heterogeneous disorder, so that

morphologic, immunologic, cytogenetic,biochemical, and molecular geneticcharacterizations of leukaemia lymphoblasts areneeded to establish the diagnosis or to excludeother possible causes of bone marrow failureand, finally, to classify ALL subtypes. Thisheterogeneity reflects the fact that leukaemiamay develop at any point during the multiplestages of normal lymphoid differentiation.

ALL Morphologic Classi fi cationThe French-American-British (FAB) CooperativeWorking Group, defines three categories of

lymphoblasts: L1 lymphoblasts are small cellscharacterized by a high nucleus-to-cytoplasmratio. The pale blue cytoplasm is scanty and islimited to a small portion of the perimeter of thecell. The cells have indistinct nucleoli andnuclear membranes that vary from round toclefted; L2 lymphoblasts are larger, often in amore heterogeneous population, with a lowernucleus-to-cytoplasm ratio, prominent nucleoli(often with perinuclear chromatin condensation)and nuclear membranes that may be reniform orirregular. They may be indistinguishable from theM1 variant of myeloid leukaemia, and the

differentiation must be made primarily bymyeloperoxidase (MPO) staining; the M0 variantof myeloid leukaemia, which is MPO negative,may be indistinguishable from ALL without theimmunophenotype. L3 lymphoblasts is aheterogeneous group of cells identical to Burkitt-like leukaemia and characterized by deeplybasophilic cytoplasm and prominentcytoplasmatic vacuolization. Approximately 85%of children with ALL have predominant L1morphology, 14% have L2, and 1% have L3,while the L2 subtype is more common in adults.While L3 lymphoblasts represent an

immunophenotypically distinct population of

mature B cells, there is no correlation betweenthe various stages of pre-B cell differentiation orimmunophenotype and L1 or L2 morphology.

ALL immunophenotyp ic classif icationImmunologic surface and cytoplasmic marker

studies are of great significance for classificationof acute leukemias. By using a selected panelsof monoclonal antibodies (mAb) (Table 1) andthe development of the multiparameterfluorescence-activated cell sorter (FACS)machine, it is possible to classify B and T-lineage ALL into discrete stages on the basis ofthe degree of differentiation or maturation of thenormal B clone hit by neoplastic transformation,as shown in Figure 1. Mature B-cell ALL is rareand accounts for only 1 to 2% of all cases. Thistype of ALL is defined by the presence of surfaceimmunoglobulin, most often IgM, which is

monoclonal for or light chains. T-cell ALL hasbeen subclassified into three stages ofdifferentiation: early (stage I), intermediate(stage II), and late (stage III;). Frequently T-cellleukaemia presents with the antigen pattern ofthe early thymocyte (stage I), on the contrary ofT-cell lymphoma, where usually malignant cellsdisplay an intermediate or a mature phenotype.Whether there is a correlation between sub-classification into stages of differentiation andclinical characteristics remains controversial, aswell as controversial is the prognosticsignificance of this sub-classification. The

development of immunophenotyping techniques,with regard primarily to the use of monoclonalantibodies, has allowed to confirm that in someinstances individual leukemic cellssimultaneously express both lymphoid andmyeloid surface antigens, showingcharacteristics of more than one hematopoieticlineage.

These leukaemia have been referred to

as biphenotipic, mixed-lineage, or hybridleukaemia, and, depending on the criteriaapplied, the incidence of this subgroup of ALLranges from 7% to 25%.

Table 1. Monoclonal antibodies commonly used toimmunophenotypeleukaemia

MPO FITC / cyCD79a PE / cCD3 PerCP

TdT FITC / cyIgM PE

Negative control

Basic panel

CD13 PE

SIg FITC / CD20 PE

CD34 PE

CD45 FITC / CD14 PE

CD65 FITC

CD15 FITC

CD33 PE

CD2 FITC

CD7 FITC

CD41 FITC

CD10 FITC

CD3 FITC / CD19 PE

HLA-DR FITC

CD5 PE

CD4 FITC / CD8 PE

CD1a FITC

FITC / CD19 PEk FITC / CD19 PE

ALL panel

B - Panel

T- panel

CD13 PE

CD56 PE

CD34 PE

CD45 FITC / CD14 PE

CD65 FITC

CD15 FITC

CD33 PE

CD2 FITC

CD7 FITC

CD41 FITC

CD10 FITC

CD3 FITC / CD19 PE

HLA-DR FITC

CD117 PE

Glycophorine FITC

AML panel

LEGENDA pan-leukocyte of immaturity B-lymphoid T-lymphoid myeloid megakaryocytes erythroid

Figure 1 Representation of stages of lymphoiddifferentiation and immunophenotyping in B and Tcell precursor ALL of childhood

http://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLTable1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLTable1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLTable1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLTable1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLTable1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLTable1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=519http://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdf


3/13

ALL1 lymphoblasts

ALL2 lymphoblasts

ALL3 lymphoblasts

Immunoglobulin and T-cell receptor generearrangementsSomatic rearrangement of Ig and T-cell receptor(TcR) gene loci occurs during earlydifferentiation of any B and T cell, by joining thegermline variable (V), diversity (D) and joining (J)gene segments. By this process, eachlymphocyte gets a specific combination of V-D-J

segments that codes for the variable domains ofIg or TcR molecules. The uniqueness of eachrearrangement further depends on randominsertion and deletion of nucleotides at thejunction sites of V, D, and J gene segments,making the junctional regions of Ig and TcR

genes as fingerprint-like sequences. Thiscombined sequence constitutes a specificsignature of each lymphocyte. Due to the clonalorigin of the neoplasm, each malignant lymphoiddisease will represent the expansion of a clonalpopulation with a specific Ig/TcR signature.Therefore, junctional regions can be used asleukemia-specific targets for PCR analysis ofMinimal Residual Disease.

Conventional cytogenetics and moleculargeneticsConventional cytogenetic analysis detects only

in mitotically active (metaphase) neoplastic cells.Nowadays, the recent development of molecularcytogenetic techniques, including newermethods of chromosomal banding and standardfluorescent in situ hybridization (FISH) with themolecular genetic techniques of spectralkaryotyping (SKY) and comparative genomichybridization (CGH), allows to recognizechromosomal abnormalities in the leukaemiacells of most of the cases of pediatric ALL. Thecytogenetic abnormalities reported in ALLinvolve both chromosomal number (ploidy) andstructural rearrangement.

ALL can be classified into 4 subtypes based onthe modal number of chromosomes: hyperdiploidwith more than 47 chromosome (35-45% ofcases, defined by a DI greater than 1.0),pseudodiploid (46 chromosome with structural ornumeric abnormalities: about 40% of cases; DIof 1.0), diploid (46 chromosome: 10-15% ofcases; DI of 1.0) and hypodiploid (fewer than 46chromosome: about 8% of cases; DI less than1.0). DI becomes a statistically significativeprognostic factor when 1.16, whichcorresponds to a modal number of 53chromosomes:

children with higher ploidy

(greater than 50 chromosomes) have the bestprognosis; on the contrary, those in thepseudodiploid category have a relatively poorprognosis. An exception to the general rule thathyperdiploid ALL cases have good prognoses isthe relatively rare group of hyperdiploid ALLcases with the near-tetraploid subtype (82 to 84chromosomes), which appears to have a poorerprognosis.Translocations are the most common structuralchromosomal changes in ALL (Figure 2),particularly frequent in the pseudodiploid andhypodiploid groups.

They are assumed to play a

fundamental role in the leukemogenic processand in most cases [i.e. translocations t(9;22),

http://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure1.pdf


4/13

t(4;11), and t(1;19)] are associated with elevaterisk of early treatment failure; the most commonALL translocation, the t(12;21), however appearsto have good prognostic implications.The first fusion gene described in ALL was BCR-ABL, created by the del(22) of the

t(9;22)(q34;q11), also referred to as thePhiladelphia (Ph) chromosome, and has beenidentified as the translocation with the worstprognosis in pediatric ALL. The Ph chromosomehas been demonstrated in about 95% of casesofchronic myelogenous leukaemia (CML), 25%of adult ALL cases, and 3% to 5% of paediatricALL cases. Clinically, patients with Ph-positiveblasts are older, have higher leukocyte counts,larger percentages of circulating blasts, a higherfrequency of FAB L2 morphology, a higherfrequency of CNS leukaemia and more prevalentpseudodiploid karyotypes than are found in Ph

negative cases. Most Ph+ blasts have a B-lineage immunophenotype, although isolatedcases with a T-cell or mixed phenotype havebeen reported. The consistent lack of success intreating this form of ALL has prompted mostinvestigators to consider BMT during firstremission as a therapeutic option. In addition, itwas recently noted that children with Ph+ALLand low initial blood cell counts may have adurable response to chemotherapy.One of the most exciting development in ALLwas the identification of TEL-AML1 as the mostcommon genetic alteration in this disease. The

TEL-AML1 fusion is created by the translocationt(12;21); modern molecular techniques havedemonstrated this translocation in approximatelyone-fourth of childhood ALL cases. TEL-AML1expression has been associated with anexcellent prognosis, with event free survival(EFS) approaching 90%.Two recent studies have demonstrated that theincidence of TEL-AML1 in relapsed Ph-negativeB-cell precursor ALL was about 20-25%, a resultsimilar to the reported incidence at diagnosis. Inaddition, these two reports highlighted that theperiod of remission was significantly longer in

children expressing TEL-AML1 and that themajority of relapses in this group appeared late(>2 years after diagnosis). This could mean thatTEL-AML1 positivity predicts a favourable short-term outcome, while long-term results are stillunknown. Interestingly the outcome of TEL-AML1 positive relapsed ALL patients issignificantly better than the outcome of negativepatients, but it remains to be verified whetherTEL-AML1 is an independent risk factor.With an overall incidence of 5% to 6,5%, thet(1;19)(q23;p13) is the most commontranslocation detected by conventional

cytogenetics in childhood ALL. This translocationis found in 15% to 25% of pre-B (cIg+)

immunophenotype cases and in 1% of early pre-B (cIg-) or T-cell immunophenotype. It wasreported that t(1;19) accounted for the majorityof treatment failures in pre-B ALL.The q23 region of chromosome 11 is a relativelyfrequent site of structural rearrangements in

children with ALL; these abnormalities (includingtranslocation, deletion and partial duplication)are detected in 4.5% to 5.7% of blasts cells, 80%of infant leukemia (i.e., ALL and AML in patientsyounger than 1 year), and 85% of secondaryleukemias in patients who have receivedepipodophyllotoxin therapy. The patients with11q23 abnormalities are usually young, lackhyperdiploidy, and have high leukocyte counts,organomegaly, central nervous system (CNS)involvement, an early pre-B cellimmunophenotype, myeloid-related antigenexpression, and a poor prognosis.

The majority of cases with translocationsinvolving the 11q23 region results fromexchanges with chromosome 4. Thet(4;11)(q21;q23) has been reported in up to 5%of pediatric ALL cases, is mostly observed inchildren younger than 1 year, commonlynewborns; the t(4,11) fusing MLL and AF-4accounts for about 70% of MLL translocations ininfant ALL.MLL rearrangements are associated with long-term EFS rates of less than 20% despitetreatment with aggressive multiagentchemotherapy.

Figure 2: Distribution of chromosomalabnormalities in pediatric ALL

E2A-PBX1t(1;19)(q23; p13)

Hox

6%

E2A-HLF

t(17;19)(q22;p13)bZIP

1%Hox 11 LYL1, TAL1,

TAL2, LM01, LM027q35, 11q11

Hox, bHLH, LIM

8%

Translocations not

identified25%

MYCt(8;14), t(2;8), t(8;22)

bHLH

2%

Random25%

TEL-AML1t(12;21)(p12;q22)

Runt, ETS

25%

MLL11q23

Trithorax

4%

BCR-ABLt(9;22)(q34;q11)

tyrosine kinase

4%

Distribution of chromosomal abnormalities

in pediatric ALL

PathogenesisIn most cases of ALL, as in other lymphoidmalignancies, a single damaged progenitor cell,capable of expansion by (theoretically) indefiniteself-renewal, gives rise to malignant, poorlydifferentiated precursors. It is not completelyclear where in the normal course ofdifferentiation the leukaemia "clonal event"

occurs. In pediatric ALL there is evidence thatthese events occur in committed lymphoidprecursors, whereas in acute myeloid leukaemia

http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=521http://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdfhttp://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=521http://www.orpha.net/data/patho/GB/uk-ALLFigure2.pdf


5/13

(AML) and Philadelphia chromosomepositiveALL, it appears that they may occur at an earlierstage of blood cell development because there isevidence of mutation in multiple cell lineages.Many of the described molecular mutations bearevidence of immunoglobulin joining region (VDJ)

and T-cell receptor (TcR) recombinase activity.Greaves hypothesized a model, analogous tothat proposed by Knudson, that one or, morelikely, two sequential mutations (one initiationaland the other promotional), occurringspontaneously in important regulatory genes in alymphoid cell population undergoing significantproliferative stress, could account for most ALLcases. It has been suggested that first hitoccurs in utero based on concordance studies oftwins with leukaemia. Although these studiesprovide evidence that the development ofleukaemia may begin in utero, the question of

whether these genetic changes are the"accelerating" events or merely incidentalgenetic changes in patients who later developedleukaemia remains unresolved.Several congenital disorders are associated withan increased risk of leukaemia. Children withtrisomy 21 (i.e., Down syndrome) are up to 15times more likely to develop leukaemia thannormal children. Other less common pre-existingchromosomal abnormalities have been linked toleukemia. Included among these are Klinefelter'ssyndrome, Bloom syndrome, and Fanconi'sanemia. Lymphoid malignancies, with a

predominance of T-ALL, have been reported inpatients with ataxia-telangiectasia (AT), anautosomal recessive disorder characterized byincreased chromosomal fragility.Most of the cases of ALL show chromosomaland genetic abnormalities (described inConventional cytogenetics and moleculargenetics). Many of these molecular changesoccur at the location of immunoglobulin, TCR,and transcription factor encoding genes. Inaddition to chromosomal translocations, there isa variety of genetic events that appear to beleukemogenic but are undetectable with classic

cytogenetic methods. Other gene expressionmodalities are beginning to be used tocharacterize leukaemia. These includecomplementary DNA (cDNA) micro-array, real-time and other modifications of reversetranscriptase-polymerase chain reaction (RT-PCR), which examine messenger RNAexpression levels, and new mass spectroscopytechniques for proteins (proteomics). These andother new techniques allow researchers toexamine large patterns of gene expression ateither the RNA or protein level. If specificpatterns can be correlated with clinical response,

these new characterization methods should

allow increased refinement of current prognosis(risk)-based stratification systems.

Predisposing Factors

Radiation exposure

Ionizing radiation can play a role in thedevelopment of acute leukaemia; in fact a highincidence of leukaemia was seen after theatomic bomb explosions in Hiroshima andNagasaki with ALL being more frequent inchildren and AML more common in adults.However the cases of leukaemia attributable toradiation are rather few. Controversy persistsabout the risks from exposure to ionizingradiation from routine emissions from nuclearpower plants or as a result of fallout fromatmospheric nuclear testing. More recently it hasalso been suggested that exposure to

electromagnetic fields (EMF) may be related tothe development of childhood ALL. Conflictingstudies exist in the literature, but the most recentdata have concluded that EMF exposure doesnot cause childhood ALL.

Chemical exposureThe role of toxic chemical exposure (e.g., tobenzene) in the development of childhood ALL isquestionable, although it has been shown thatNAD(P)H:quinone oxidoreductase 1, one of theenzymes responsible for benzene and otherquinone metabolism, has a mutation with

decreased enzymatic activity that has beenlinked to the development of both AML and ALLin adults. Other factors that could be involved inthe development of ALL include parentalcigarette smoking; paternal herbicide andpesticide exposure; maternal use of alcohol,contraceptives, and diethylstilbestrol; householdradon exposure; and chemical contamination ofground water.

Definitive causal relationships

between these factors and childhood ALL havenot been demonstrated.

Other possible predisposing factors

The role played by viral infection in thepathogenesis of human leukaemia has beeninvestigated intensively. This reflects the factthat the age distribution of ALL at diagnosiscorresponds with a time when the immunesystem is developing and is perhaps morevulnerable to the oncogenic effects of someviruses. Some authors have suggested anincreased risk of ALL in children born to mothersinfected recently with influenza, varicella, orother viruses, but no definitive link betweenprenatal viral exposure and leukaemia risk hasbeen confirmed. The only link found is the

association between the Epstein-Barr virus(EBV) and cases of endemic Burkitt's

http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=870http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=484http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=484http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=125http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=84http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=84http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=100http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=100http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=84http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=84http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=125http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=484http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=484http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=870


6/13

lymphoma-leukaemia, the L3 morphologicsubtype of ALL.The GSTs represent a set of xenobioticdetoxifying enzymes with a known series ofpolymorphic mutations that affect function. GSTdeficiency, rather than high GST activity, has

been associated with an increased risk ofcancer, although deficiency of GSTT1 andGSTM1 could enhance chemotherapeuticefficacy in some patients. Conflicting resultshave been reported on the association betweenGSTM1 and GSTT1 genotypes and outcome aswell as on the association between the risk ofrelapse in childhood ALL and GSTspolymorphisms.

Clinical PresentationALL may present insidiously or acutely, as anincidental finding on a routine blood count of an

asymptomatic child or as a life-threateninghemorrhage, infection, or episode of respiratorydistress. Although ALL is a disease primarily ofthe bone marrow and peripheral blood, anyorgan or tissue may be infiltrated by theabnormal cells. The duration of symptoms inchildren presenting with ALL may vary from daysto months. The first symptoms are usually non-specific and include anorexia, irritability andlethargy. Fever is the most common finding,occurring in approximately 60% of patients.Progressive bone marrow failure leads to pallor(anemia), bleeding (thrombocytopenia) and

susceptibility to infections (neutropenia). Overone third of patients may present with a limp,bone pain, arthralgia or refusal to walk due toleukaemia infiltration of the periosteum, bone orjoint, or to the expansion of the marrow cavity byleukaemia cells. Less common signs andsymptoms include headache, vomiting,respiratory distress, oliguria and anuria. At initialdiagnosis, 60 to 70% of children haveenlargement of the liver or spleen, usuallyasymptomatic, with organs palpable more than 2cm below the costal margin. Lymphadenopathy(usually painless, localized or generalized) due

to leukaemia infiltration is an equally frequentpresenting sign (see Table 2).

Laboratory findingsAnemia, abnormal leukocyte and differentialcounts, and thrombocytopenia are usuallypresent at diagnosis, reflecting the degree towhich bone marrow has been replaced withleukemic lymphoblasts. The presentingleukocyte counts range widely, from 0.1 to 1500x 10

9/L (median 15 x 10

9/L) and are increased (>

10x109/L) in slightly over one half of the patients

(Table 2). Hyperleukocytosis (> 100x109/L)

occurs in 10% to 15% of the patients. Thedegree of leukocyte count elevation at diagnosisis a very strong predictor of prognosis in ALL.

Neutropenia (less than 500 granulocytes permm

3) is a common phenomenon and is

associated with an increased risk of seriousinfection.

Hypereosinophilia, generally reactive,

may be present at diagnosis. Decreased plateletcounts (median, 50x10

9/L) are usually present at

diagnosis and can be readily distinguished fromimmune thrombocytopenia, as isolatedthrombocytopenia is rare in leukemia. Severehemorrage is uncommon, even when plateletcounts are as low as 20x10

9/L, provided that

infection and fever are absent. Coagulopathy,usually mild, can occur in T-cell ALL and is onlyrarely associated with severe bleeding. Morethan 75% of patients presents with anemia,which is usually normochromic and normocyticand associated with a normal to low reticulocytecount. Anemia or thrombocytopenia is often mild(or even absent) in patients with T-cell ALL.

Pancytopenia followed by a period ofspontaneous hematopoietic recovery mayprecede the diagnosis of ALL in rare cases

and

must be differentiated from aplastic anemia.

Table 2: Clinical and laboratory features atdiagnosis in children with ALL

Clinical and laboratory featuresPercentage ofpatients

Symptoms and physical findings

Fever 60

Hepatosplenomegaly 70

Paleness 55

Bleeding (e.g., petechiae or purpura) 50

Lymphadenopathy 50

Bone pain 25

Abdominal pain 20

Weight loss 15

Laboratory features

Leukocyte count (mm3)

50,000 17

Hemoglobin (g/dL)

< 7.0 43

7.0 - 11.0 45

> 11.0 12

Platelet count (mm3)

< 20.000 28

20.000 99.000 47

> 100.000 25



7/13

Diagnostic methodsTo definitively establish the diagnosis ofleukaemia, inspection of smears of bone marrowaspirates is essential. Whereas normal bonemarrow has fewer than 5% blasts, leukaemiamarrow generally is almost completely infiltrated

by leukaemia blasts. The marrow specimen isusually hypercellular and characterized by anhomogeneous population of cells. Leukaemiamust be suspected in patients whose marrowscontain greater than 5%, but the diagnosisshould not be made on the basis of a singlemarrow smear with fewer than 25% blasts. Abone marrow aspirate may be difficult to obtainat the time of diagnosis. This is usually due tothe density of blasts in the marrow, but it may becaused by bone infarction, fibrosis,

or necrosis.

The distinction between ALL with lymph-nodeinvolvement and non-Hodgkins lymphoma

(NHL) with bone marrow invasion (stage IV) isarbitrary. Commonly, the disease is classified as

ALL when there are 25% lymphoblasts in themarrow and as NHL Stage IV when there are 5and < 25 per cent lymphoblasts in the marrow. Insome situations (e.g., to differentiate an aplasticpresentation of ALL from aplastic anemia)multiple bone marrow aspirates and biopsyspecimens are necessary.

EpidemiologyChildhood cancer incidence is around 120-150/million/year in subjects 0-14 years old and

the number of new cases/year worldwide isapproximately 250,000. Leukaemia is the mostcommon malignancy in children andaccounts forone-third of all childhood cancers. Approximately3/4 of all cases of childhood leukaemia are ALL.About 3,000 children in the United States

and

5,000 children in Europeare diagnosed with ALLeach year. The peak incidence of ALL occursbetween age 2 and 5 years. The incidence ofALL is higher among boys than girls, and thisdifference is greatest among pubertal children.T-cell ALL represents approximately 10-15% ofALL cases in developed countries and compared

with B-cell precursor ALL, it is characterized bymale predominance, mediastinal mass(approximately one-half of patients), highermedian age, higher white blood cell counts (one-third to one-half have initial leukocytes countsgreater than 100,000 per mm

3) and normal

hemoglobin levels at the time of diagnosis. Ingeneral, T-ALL associates with higher riskfeatures and prednisone poor response in 30%versus 10% in B-cell precursor ALL In the UnitedStates, ALL is more common among whitechildren than black children, and this is relatedprobably to geographical variation in biology or

different environmental exposure.

TreatmentFour main treatment elements can be generallyrecognized in chemotherapy protocols adoptedby international cooperative groups: induction,CNS preventive therapy, consolidation/reinduction, and maintenance therapy. The

biological heterogeneity, which characterizeschildhood ALL has determined an increasingneed to stratify patients in risk groups and toprovide risk-adapted therapy. Treatment hasthus become increasingly complex and highlevels of organization, expertise and knowledgeare nowadays requested to achieve optimalresults. For these reasons children with ALLshould be treated in centres which can offerspecialized personnel and provide up-to-datediagnostic tools and treatment strategies.

Induction

The treatment planned in this phase is aimed ateradicating signs and symptoms of the diseaseand to re-establish a normal hematopoiesis. Thisgoal is generally indicated with the term ofcomplete remission (CR). Children in CR musthave no physical evidence of leukaemia, normalcomplete blood cell count and normallyregenerating bone marrow (with < 5% leukemicblasts). Information on CR status also includesthe absence of detectable CNS orextramedullary disease as evaluable withphysical examination and cerebrospinal fluid(CSF) findings. Induction treatment intensity has

increased over the years, consisting of acombination of two (vincristine + steroids), three(+ anthracycline) or four (+ asparaginase) drugs,which can induce a complete remission ratecomprised from 85% to approximately 95%.

CNS

preventive therapy is administered in this phaseand mainly consists of intrathecal methotrexate(see following section). Conventionally, thesystemic chemotherapy is given in 4-6 weeksand allows a complete remission rate 95%;some patients (


8/13

Cranial irradiation is generally no longer used forpatients with a good prognosis; intrathecalmethotrexate alone or triple intrathecalchemotherapy, given periodically throughoutmaintenance chemotherapy, provide adequateCNS preventive therapy for these patients.

Consolidation/ReinductionIt is well known that the achievement ofremission is not a sufficient goal to obtain thecure of ALL and that a significant amount ofadditional therapy is necessary before leukaemiais totally eradicated. Consolidation/Reinductiontherapy is defined as one/more periods ofintensified treatment administered afterremission induction and is considered a relevantcomponent of many chemotherapy protocols,particularly for higher-risk patients. Eachcooperative group has its own tradition in the

type of consolidation/reiduction to be delivered.Commonly, agents and schedules are designedto minimize the development of drug resistanceonset.

Maintainance therapy and duration oftreatmentDrugs particularly effective as induction agentsare not generally used for maintenance therapy.In particular the use of low dose methotrexateand 6-MP, administered continuously, is widelyaccepted and constitutes the principal element inmost maintenance therapy regimens. In general,

weekly methotrexate and daily 6-MP appears theoptimal schedule. The dosage of the drugs usedin this phase seems to have a key role indetermining its efficacy. Patients who receivemaintenance therapy on a continuous ratherthan an interrupted schedule have longerremission durations. Compliance problems alsomay diminish the efficacy of maintenancetherapy. The optimal length of maintenancechemotherapy has not yet been definitelyestablished. However most groups treat patientsfor a total of 2 years (thus including themaintainance phase).

Recent results of the most importantinternational cooperative groupsDuring the 80s and 90s results obtained bymost large cooperative or institutional pediatriconcology groups have become rather similar.Interestingly, improvement of outcome wasobtained with markedly different therapeuticstrategies, all of them having however acommon approach toward treatmentintensification. The Berlin-Frankfurt-Mnster(BFM) group has treated more than fourthousand children in four consecutive trials

between 1981 and 1995. The probability for EFSat 8 years improved from 65.8% in study ALL-

BFM 81 to 75.9% in study ALL-BFM 90. Theincidence of isolated CNS relapses was reducedfrom 5.3% in study ALL-BFM 81 to 1.1% in studyALL-BFM 90. These studies have shown thatreintensification is a crucial part of treatment,even in low risk patients, that presymptomatic

cranial radiotherapy can be safely reduced to 12Gy, or even be eliminated if it is replaced byearly intensive systemic and intrathecalmethotrexate applied and that inadequateresponse to an initial 7-day prednisone window(combined with one intrathecal injection ofmethotrexate on day 1) defines about 10% of thepatients with a high risk of relapse. The leadingcause of failure in childhood ALL is stillrecurrence of disease which is more frequentlyassociated to clinical (e.g. age, WBC), andbiological characteristics (such asimmunophenotype and cytogenetics) and to poor

early in vivo treatment response. A veryimportant information has been obtained fromthe study 90 too, which showed, in the context ofan european intergroup study, that the responseevaluated with the detection of minimal residualdisease (MRD) at defined timepoints helps todefine the patient at high risk to relapse morespecifically. In study 95 treatment strategy wasfurther refined; in particular an increase oftreatment intensity was planned for HR patients(intensive use of polichemotherapy blocksfollowed by a protocol II). In this group ofpatients major benefits derived to PPR patients

(EFS 56+/- 4 in study 95 vs 34+/-3 in study 90).In the current study ALL 2000, MRD evaluationperformed with a semiquantitative method at 5and 12 weeks after treatment start allows theallocation of patients according to molecularresponse to treatment and is one of the mainstratification criteria.The Children's Cancer Group (CCG) hasreported marked improvements in trialsconducted during two successive series ofstudies (1983-1988 and 1989-1995). Overall, 10-year EFS was 62% +/- 10% for the 1983-1988series and 72% +/- 1% for the 1988-1995 series

(P< 0.0001). Five-year cumulative rates ofisolated CNS relapses were 5.9% and 4.4%.Therapy based on the BFM 76/79 studyimproved outcomes for intermediate and higherrisk patients in the first series. For intermediaterisk patients, delayed intensification (DI) wasmost crucial to improve outcome and cranialirradiation was safely replaced with maintenanceintrathecal methotrexate, providing patientsintensified systemic therapy. In the secondseries, randomized trials showed better outcomewith one vs no DI phase for lower risk patients,with two vs one DI phase for intermediate risk

patients, and with the CCG 'augmented regimen'for higher risk patients defined by a slow day 7



9/13

marrow response. Cranial irradiation was safelyreplaced with additional intrathecal methotrexatefor higher risk patients with a rapid day 7 marrowresponse. In a subsequent study, substitution ofdexamethasone in place of prednisone ininduction and maintenance improved outcome

for standard risk patients. All patients receiveddexamethasone in DI. These successfultreatment strategies form the basis for ourcurrent ALL trial.The St. Jude Childrens Research Hospital(SJCRH) has reported long-term results of themost recent trials (Total Therapy studies 11, 12and 13A). In particular the recent Total 13A wasstarted to patients recruitment in1991 and closedin 1994. Early intensive intrathecal therapy inthis study has yielded a very low 5-year isolatedCNS relapse rate of 1.2 +/- 0.9%, with a 5-yearevent-free survival rate of 76.9 +/- 3.3%. Factors

consistently associated with an adverseprognosis included male sex, infant oradolescent age group, leukocyte count >100 x10(9)/l, nonhyperdiploidy karyotype and poorearly response to treatment. Risk classificationbased on age and leukocyte count hadprognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions ormodifications for patients with specific geneticabnormalities or persistent minimal residualleukemia may further improve long-term results.

Relapse of acute lymphoblastic leukemia

Although the treatment of childhood ALL hasbeen gradually intensified during the last 30-40years, leading to a significant improvement ofthe outcome, still roughly 25% of patients sufferfrom a relapse of the disease. This percentageof children on its own represents the fourth mostcommon malignancy in children.The management of relapse remainscontroversial but increasingly involves the use ofhigh-dose chemo/radiotherapy and stem cellinfusion and despite recent improvements, theoverall results remain unsatisfactory andrelapsed ALL continues to make a major

contribution to the morbidity and mortality ofchildhood cancer.

DiagnosisALL can recur in the bone marrow (isolated bonemarrow relapse), in an extra-medullary site likethe central nervous system (CNS), testis orovary (isolated extra-medullary relapse) or in twoor more locations (combined relapse). Diagnosisis made by the morphological demonstration oflymphoblasts on smears obtained from the siteof relapse. Medullary ALL relapse is defined asthe presence of 25% lymphoblasts in a bone

marrow aspirate following the first completeremission (CR).

CNS relapse is defined as the presence ofmorphologically identified lymphoblasts onsmears of CSF cytocentrifugated preparationswith a CSF mononuclear cell count > 5 permicroliter, or as the evidence of tumor infiltrationin the CNS following the first CR. Testicular

relapse is defined as the histological evidence oflymphoblastic infiltration in one or both testes;relapses occurring in different organs than CNSor testis must be necessarely addressed afterbioptic examination. Combined ALL relapse isdefined as the presence of extramedullarylymphoblastic infiltration and 5% blasts in abone marrow aspirate following the first CR.

Prognostic factorsDuring the last 20 years the major internationalstudy groups have analysed the clinical andbiological features of patients with relapsed ALL,

in order to determine which have the strongestimpact on EFS. The identification of featuresable to predict the response to second-linetherapy may help to assign patients to treatmentprotocols with either reduced toxicity or a moreaggressive approach (e.g. stem celltransplantation).

Duration of firs t remissionDuration of first remission is the strongestpredictor for the achievement of second CR andsurvival; several reports confirm that laterelapses, occurring at least 30 months after

initial diagnosis are associated with a betterEFS, while early ( 18 months from diagnosisbut < 6 months from the end of front-linetherapy) or very early (< 18 months from initialdiagnosis) relapses have poor outcome. A studyon 600 children with ALL relapse treated withchemotherapy documented prolonged secondremissions in fewer than 5% of children whorelapsed within 18 months after achieving firstremission; in contrast, sustained secondremissions were observed in approximately 25%of children whose relapses occurred 18 monthsafter primary diagnosis.

Site of relapseDifferent sites of relapse are characterized bydifferent outcome: bone marrow (BM) relapse isthe main cause of treatment failure in childrenwith ALL and generally implies a poor prognosisfor most patients. The results of a number ofstudies suggest that prolonged secondremissions (greater than 2 years) can beobtained with aggressive chemotherapy inapproximately 10% of patients who relapse inthe BM on therapy and in up to 40-50% of

patients who relapse after cessation of therapy.Many studies suggest that combined (medullaryand extra medullary) relapses have a better



10/13

outcome compared to isolated BM relapses;combined relapses in fact tend to be later and todisplay better response to chemotherapy. Datapublished by the BFM study group evidenced anEFS at 7 years of 42% versus 15% for combinedBM and extramedullary relapses versus isolated

marrow relapses.Despite the success of front line CNS preventivetherapy in reducing the incidence of CNSrecurrence, CNS relapse remains a relevantcause of treatment failure in ALL; CNSrecurrence is in fact observed in about 10% ofpatients. In the past, the outcome for thesepatients was generally poor, with most patientssuffering of a subsequent CNS relapse orrecurrence at other sites, such as BM and testis.Intensive treatment plans have recently led theresults for patients with an isolated CNS relapseto an EFS of about 70%.

The outcome for patients with an isolated overttesticular recurrence appears to vary with thetime of presentation; an isolated testicularrelapse occurring in a patient on treatment isassociated with the worst prognosis;nevertheless a CCG study suggests that withlocal irradiation and intensive systemicretreatment, prolonged EFS can be obtained innearly one-half of such patients. In contrast, alate, isolated overt testicular relapse that occursoff therapy has a better prognosis, with aprolonged DFS obtained in more than two-thirdsof patients.

Immunophenotype

T-cell immunophenotype represents anindependent negative prognostic factor; datafrom the BFM group demonstrate that T lineageALL children relapsing at any site and treatedwith a chemotherapy schedule obtain a 5 yearsEFS of 5-10%.

Peripheral blast countAccording to the POG or BFM group experiencethe number of peripheral blood blast cells (10.000 L) at the time of relapse is a biologicalpredictor of negative outcome.

Cytogenetic aberrationsThe translocation t(9;22)(q34;q11), occurring inabout 10% of B-cell precursor ALL first relapses,has been shown to be an indipendent risk factorassociated with an adverse prognosis. Incontrast, the prognostic value of TEL-AML1fusion resulting from the cryptic translocationt(12;21)(p13;q22) is still not entirely clear.General characteristics of TEL-AML1 positive

childhood ALL, both at diagnosis and at relapse,include confinement to B-cell lineage, goodresponse to combination chemotherapy, and a

low WBC count, as well as a favourable agedistribution. The majority of relapses (80%)occur off-therapy and achieve and mantain long-lasting 2

ndCR when treated with chemotherapy

only.

Minimal residual diseaseSeveral studies have demonstrated theprognostic value of MRD during the early phasesof front line treatment in ALL. In particular, astudy conducted within the I-BFM group on 240children affected by ALL has shown a significantcorrelation between different MRD levels anddifferent risk of relapse: analysis of MRD at twodifferent time points (end of induction treatmentand beginning of consolidation) has shown themost significant relevance in the identification ofpatients with different risk of relapse,independently from other biological and clinicalparameters since then utilized as stratificationcriteria.MRD analysis represents a predictive parametereven for patients presenting a recurrence of ALL.In particular, a retrospective study conducted on30 patients with relapsed ALL and stratified inthe BFM intermediate risk group has shown thatthe persistance of MRD during the early phasesof second line treatment was significantly relatedto the prognosis.Children presenting MRD levels below 10

-3after

36 days of Induction therapy had an EFS of86%, while patients with MRD level above 10

-3

presented a subsequent recurrence of thedisease.These results suggest that in children with ALLrelapse, the extent of early response can beused to predict long-term outcome. Patientswhose MRD rapidly decreases are likely to havea very good outcome even if treated withchemotherapy. Thus, transplant procedures thathave a high risk for morbidity and mortality mightnot be necessary in these children.Another aspect of potential clinical relevance inthe study of MRD is the evaluation of remissionin patients undergoing bone marrowtransplantation after ALL relapse. It has beenrecently demonstrated that the detection of MRDlevels just before the accomplishment of stemcell transplantation is linked to the probability ofrelapse after transplant procedure.However the benefits of a more intensivetreatment in patients showing a slow reduction inMRD remain unclear.

Treatment The optimal treatment for relapsed childhoodALL is still controversial since the overall results

remain unsatisfactory worldwide, especially in



11/13

early bone marrow relapses and in heavily pre-treated patients.Despite continuing uncertainty about the besttreatment approach there have been nosuccessful randomized trials comparingchemotherapy and BMT.

Whether a child with ALL relapse should receivea chemo/radiotherapy schedule or a stem celltransplant is thus in many instances still a matterof intensive debate and the choice is mainlyperformed on policies adopted in each singlecooperative group.

Chemotherapy and RadiotherapyThe chemotherapy approach to the relapsedpatient should include aggressive multidrugreinduction therapy followed by intensivesystemic consolidation and maintenancechemotherapy. The combination of vincristine,prednisone, and L-asparaginase producescomplete remissions in approximately 70% to75% of patients. The addition of an anthracyclinecan increase the remission rate to >80%, even inchildren who have been treated on modernintensive trials; however the use ofanthracyclines may be restricted by the risk ofcardiotoxicity, given that these drugs are oftenextensively used during first-line therapy.Following induction, most protocols includefurther consolidation and intensified continuingtherapy for a total of about two years.Further administration of intensive courses ofcytarabine and teniposide, or high-doseifosfamide with etoposide may induce acomplete remission in approximately one-third ofpatients not achieving complete responses withthe four-drug reinduction regimen.Further CNS-directed treatment is essential toavoid overt CNS relapse as a second event andradiation therapy is normally given to sites ofextramedullary relapse. In spite of the effortsperformed, the overall results of chemotherapytreatment of ALL relapse remain disappointing:large series of patients treated consistently withmodern intensified protocols have an overallEFS after BM relapse of 30% to 60%. Noregimen is clearly superior, and the resultsmainly reflect the selection of patients. In allstudies, the reported EFS after chemotherapy forearly relapses involving the bone marrow is only5-10%. Furthermore, despite encouragingresults after intensive chemotherapy for latermarrow relapse, there is evidence that the risk ofsecond relapse continues for many years.Management of the 5-10% of children whodevelop isolated CNS relapse remainscontroversial and most reports have very small

numbers of patients. Now that few childrenreceive cranial irradiation in first remission,intensified systemic and intrathecal

chemotherapy and cranial or craniospinalirradiation could provide an appropriate andeffective treatment.Intrathecal methotrexate alone induces CNSremissions in more than 90% of patients but,unless followed by maintenance intrathecal

therapy or craniospinal irradiation, a furtherrelapse occurs within 3 to 4 months. Therapy forCNS relapse must also contain intensivesystemic therapy to prevent further relapses ofall types. A common approach is to induce aCSF remission with intrathecal chemotherapyfirst and then to administer craniospinalirradiation at doses of 2,400 to 3,000 cGy to thecranial vault and 1,200 to 1,800 cGy to the spinalaxis. However, an early CNS relapse inconjunction with other adverse prognosticfactors, has a poor prognosis, with reported EFSin recent CCG and MRC studies < 25%. The

Pediatric Oncology Group (POG) has reportedthat in relatively large trials for isolated CNSrelapse and in one early study incorporatingsystemic intensification, triple intrathecal therapyand cranial irradiation, an overall EFS of 46% at4 years was achieved. More recently in a seriesof 83 children who received intensifiedchemotherapy and delayed craniospinalirradiation for CNS relapse, the 4-year EFS was46.2% for those with initial CR of less than 18months and 83.3% for those with longer firstremissions.With the increased intensity of many protocols,

the incidence of testicular relapse appears to bedecreasing from the 10-15% seen in the 1970sand 1980s to 2-5% of more recent trials. Optimaltherapy for testicular relapse includes theadministration of local radiotherapy and the useof systemic chemotherapy. Radiation doseappears to be a crucial factor in local diseasecontrol. Doses less than 1,200 cGy are generallysuboptimal; doses of 2,400 cGy to both testeshave been considered adequate. Reports oflocal recurrence in patients treated with 2,400cGy, however, suggest that higher doses may bebetter. Bilateral testicular radiotherapy is

indicated for all patients; unilateral treatmentmay be followed by relapse in the contralateraltestis. Radiation therapy adversely affectsnormal testicular function. Sterility is an expectedconsequence at the radiation doses used.Studies also indicate that testicular endocrinefunction may be impaired at doses of 2,400 cGy.Elevated follicle-stimulating hormone andluteinizing hormone levels, decreasedtestosterone levels, and delayed sexualmaturation have been observed after gonadalirradiation. For this reason, such patients mustbe carefully followed for signs of delayed sexual

maturation and may require androgenreplacement therapy.



12/13

The impact of a testicular relapse on prognosisdepends on whether it was overt (clinicallydetectable) or occult (detected on routinetesticular biopsy), whether the recurrence wasan isolated event or accompanied by asimultaneous hematologic relapse, and whether

the relapse occurred during or after initialtreatment. Because isolated testicular relapsefrequently heralds a systemic relapse, treatmentmust include intensification of systemic therapyin addition to bilateral testicular irradiation. Mostcenters systemically "reinduce" patients whosuffer an overt testicular relapse with intensivesystemic chemotherapy. This strategy hasdramatically improved the prognosis for patientswith testicular relapse. A better prognosis isassociated with a testicular relapse occurring asan isolated event and appears to vary with thetime of presentation. An isolated testicular

relapse occurring in a patient on treatment isassociated with the worst prognosis, although aCCG study suggests that with local irradiationand intensive systemic retreatment, prolongedEFS can be obtained in nearly one-half of suchpatients. In contrast, a late, isolated, overttesticular relapse that occurs off therapy has aneven better prognosis. Prolonged DFS can beobtained for more than two-thirds of suchpatients.

Stem Cell Transplantation

Although successful BMT in patients with end-stage leukaemia have been performed for 30years, there is still no clear agreement about theindications for BMT in second remission.Furthermore, relapses rates after BMT remainhigh. As with chemotherapy, the chance of EFSafter BMT is influenced by length of first CR, siteof relapse and immunophenotype.The risks of allogeneic BMT and the paucity ofHLA-compatible siblings have lead to the use ofautologous BMT (ABMT) in second remission.Despite preliminary encouraging results,comparative studies from Germany and the UK

have shown that ABMT is not superior toconventional chemotherapy. It has beensuggested that ABMT may have a role inmanagement of patients with early CNS relapsewho lack an histocompatible sibling donor.Now that alternative donors are increasinglyavailable BMT could theoretically becomepossible for any child with relapsed ALL. A largeEuropean survey including both adults andchildren with ALL compared the results of ABMTand transplants from unrelated donors.Leukemia-free survival was similar in the twogroups, but transplant related mortality (TRM)

was higher in the BMT group (42% vs 17%)while relapse was lower (32% vs 61%).

However, TRM from selected single centers isalready similar in sibling and unrelated donortransplants and further general improvements intransplant related mortality (TRM) can beexpected. Use of partially mismatched relateddonors further extends the potential access to

allogeneic transplants.There are many difficulties in comparing theoutcome of BMT and chemotherapy for relapsedALL, including the lack of randomized trials,selection biases and duration of time totransplant.The largest study involved a comparison of datafrom the IBMTR and a cohort of patients treatedwith chemotherapy by the POG. A carefulattempt was made to match chemotherapy andBMT patients: irrespective of the duration of firstremission, BMT resulted in superior leukaemia-free survival when compared to chemotherapy.

Comparative data from Germany and Italy showsimilar results with a statistically significantbenefit for BMT over chemotherapy in earlymarrow relapses. Review of the outcome for allunselected children relapsing after MRC UKALLX in the UK demonstrated that BMT reduced therisk of a second relapse with an absoluteincrease in 5-year EFS of 14%. However, whenthe outcome of BMT was compared withstandardized intensive chemotherapy in UKALLR1, the overall EFS rates for chemotherapy,sibling donor BMT and unrelated donor BMTwere similar.

A reasonable conclusion is that BMT isassociated with a modest increase in leukaemia-free survival and that this may be most evident inchildren with a short early remission. Thebenefits may be reduced, or in some studies fullycounter-balanced by the TRM- a factor assumingclear relevance with the increasing use ofunrelated donors.

ReferencesPathogenesis and biologyChing-Hon Pui, M.D., Mary V. Relling,Pharm.D., and James R. Downing, M.D.Acute

Lymphoblastic Leukemia. N Engl J Med2004;350:1535-48.Gilliland DG, Tallman MS. Focus on acuteleukemias. Cancer Cell 2002;1:417-420.Hanahan D, Weinberg RA. The hallmarks ofcancer. Cell 2000;100:57-70.Tartaglia M, Martinelli S, Cazzaniga G, et al.Genetic evidence for a lineage- anddifferentiation stage-related contribution ofsomatic PTPN11 mutations to leukemogenesisin childhood acute leukemia. Blood.2004;104:307-13.Loh ML, Rubnitz JE. TEL/AML1-positive

pediatric leukemia: prognostic significance andtherapeutic approaches. Curr Opin Hematol2002;9:345-52



13/13

Ernst P, Wang J, Korsmeyer SJ. The role ofMLL in hematopoiesis and leukemia. Curr OpinHematol 2002;9:282-287.Yeoh EJ, Ross ME, Shurtleff SA, et al.Classification, subtype discovery, and predictionof outcome in pediatric acute lymphoblastic

leukemia by gene expression profiling. CancerCell 2002;1:133-143.Biondi A, Cimino G, Pieters R, Pui CH.Biological and therapeutic aspects of infantleukemia. Blood 2000;96:24-33.Campana D. Determination of minimal residualdisease in leukaemia patients. Br J Haematol2003;121:823-838.Greaves MF, Maia AT, Wiemels JL, Ford AM.Leukemia in twins: lessons in natural history.Blood 2003;102:2321-2333.Greaves MF, Wiemels J. Origins ofchromosome translocations in childhood

leukaemia. Nat Rev Cancer 2003;3:639-649.Alexander FE, Patheal SL, Biondi A, et al.Transplacental chemical exposure and risk ofinfant leukemia with MLL gene fusion. CancerRes 2001;61:2542-2546.Evans WE, McLeod HL. Pharmacogenomics --drug disposition, drug targets, and side effects.N Engl J Med 2003;348:538-549.

Clinical features, treatment resultsSchrappe M, Reiter A, Ludwig WD, et al.Improved outcome in childhood acutelymphoblastic leukemia despite reduced use of

anthracyclines and cranial radiotherapy: resultsof trial ALL-BFM 90. Blood 2000;95:3310-3322.Gaynon PS, Trigg ME, Heerema NA, et al.Children's Cancer Group trials in childhoodacute lymphoblastic leukemia: 1983-1995.Leukemia 2000;14:2223-2233.Harms DO, Janka-Schaub GE. Co-operativestudy group for childhood acute lymphoblasticleukemia (COALL): long-term follow-up of trials82, 85, 89 and 92. Leukemia 2000;14:2234-2239.Silverman LB, Gelber RD, Dalton VK, et al.Improved outcome for children with acute

lymphoblastic leukemia: results of Dana-FarberConsortium Protocol 91-01. Blood2001;97:1211-1218.Pui CH, Sandlund JT, Pei D, et al. Results oftherapy for acute lymphoblastic leukemia inblack and white children. JAMA 2003;290:2001-2007.Pui C-H, Cheng C, Leung W, et al. Extendedfollow-up of long-term survivors of childhoodacute lymphoblastic leukemia. N Engl J Med2003;349:640-649. [Erratum, N Engl J Med2003;349:1299.]Ar ic M, Valsecchi MG, Camitta B, et al.

Outcome of treatment in children withPhiladelphia chromosome-positive acute

lymphoblastic leukemia. N Engl J Med2000;342:998-1006.Pui CH, Gaynon PS, Boyett JM, et al. Outcomeof treatment in childhood acute lymphoblasticleukaemia with rearrangements of the 11q23chromosomal region. Lancet 2002;359:1909-

1915.


AcuteLymphoblasticLeukemia-FRenPro3732

Documents

Transcript of AcuteLymphoblasticLeukemia-FRenPro3732