This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. Because treatment of children with acute lymphoblastic leukemia (ALL) entails many potential complications and requires intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), this treatment is best coordinated by pediatric oncologists and performed in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the specialists directing the patient's care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.
Dramatic improvements in survival have been achieved in children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For ALL, the 5-year survival rate has increased over the same time from 60% to 89% for children younger than 15 years and from 28% to 50% for adolescents aged 15 to 19 years.[1,3] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Incidence and Epidemiology
ALL is the most common cancer diagnosed in children and represents 23% of cancer diagnoses among children younger than 15 years. ALL occurs at an annual rate of approximately 30 to 40 cases per million people in the United States.[4,5] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[5,6] Over the past 25 years, there has been a gradual increase in the incidence of ALL.
A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>80 cases per million per year), with rates decreasing to 20 cases per million for ages 8 to 10 years. The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is nearly tenfold greater than that for adolescents aged 16 to 21 years.
The incidence of ALL appears to be highest in Hispanic children (43 cases per million).[4,5] The incidence is substantially higher in white children than in black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in white children compared with black children.[4,5]
Childhood ALL originates in the T- and B-lymphocytes in the bone marrow (see Figure 1).
Figure 1. Blood cell development. Different blood and immune cell lineages, including T- and B-lymphocytes, differentiate from a common blood stem cell.
Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:
Most patients with acute leukemia present with an M3 marrow.
Risk Factors for Developing ALL
Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[13,14] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[13,14]
Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL. While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year), ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[16,17]
Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and hyperdiploidy) and unfavorable (t(9;22) or t(4;11) and hypodiploidy) cytogenetic findings and a lower incidence of T-cell phenotype.[15,16,17,18] Approximately 50% of children with Down syndrome and ALL have a recurring interstitial deletion of the pseudoautosomal region of chromosomes X and Y that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. The resulting P2RY8-CRLF2 fusion gene is observed at a much lower frequency (<10%) in children with B-precursor ALL who do not have Down syndrome.[19,20]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[21,22,23] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have the pseudoautosomal region deletion and express the P2RY8-CRLF2 fusion gene. Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL.
Inherited genetic polymorphisms
Genome-wide association studies show that some germline (inherited) genetic polymorphisms are associated with the development of childhood ALL. For example, the risk alleles of ARID5B are strongly associated with the development of hyperdiploid B-precursor ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[26,27]
Some cases of ALL have a prenatal origin. Evidence in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[28,29] Similarly, in ALL characterized by specific chromosomal abnormalities, data exist to support that patients had blood cells carrying the abnormalities at the time of birth with additional cooperative genetic changes acquired postnatally.[28,29,30]
In one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the TEL-AML1 translocation, far exceeding the number of cases of TEL-AML ALL in children. Other reports confirm  or do not confirm  this finding; nonetheless, this may support the hypothesis that additional genetic changes are needed for the development of this type of ALL. Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.
Overall Outcome for ALL
Among children with ALL, more than 95% attain remission, and approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.[35,36,37,38,39,40]
Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients/families.
Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Introduction to Risk-based Treatment
Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2,3]
Certain ALL study groups, such as the Children's Oncology Group (COG), use a more or less intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. Factors used by the COG to determine the intensity of induction include immunophenotype and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification stratifies risk according to age and white blood cell (WBC) count:
All study groups modify the intensity of postinduction therapy based on a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics.
Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which are described below. The factors described are grouped into the following three categories:
As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables.[5,6] Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.
A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic (risk) groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)
(Refer to the Prognostic Factors in Recurrent Childhood ALL section of this summary for information about important prognostic factors at relapse.)
Prognostic Factors Affecting Risk-based Treatment
Patient characteristics affecting prognosis
Patient characteristics affecting prognosis include the following:
Age at diagnosis
Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.
Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in the following groups: [8,9,10,11]
Approximately 80% of infants with ALL have an MLL gene rearrangement.[10,12,13] The rate of MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1 year the incidence of MLL translocations decreases but remains higher than that observed in older children.[10,14] Black infants with ALL are significantly less likely to have MLL translocations than white infants. Infants with leukemia and MLL translocations typically have very high WBC counts and an increased incidence of CNS involvement. Overall survival (OS) is poor, especially in infants younger than 6 months.[10,11]
Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[10,11,13,15] Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than infants with ALL characterized by MLL translocations.[10,11,13]
A gene expression profile analysis in infants with MLL-rearranged ALL revealed significant differences between patients younger than 90 days compared with older infants. Younger infants had highly unfavorable outcomes, suggesting distinctive biological and clinical behaviors for MLL-translocation ALL, compared with older infants.
Young children (aged 1 to <10 years) have a better disease-free survival (DFS) than older children, adolescents, and infants.[1,7,17] The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21), also known as the TEL-AML1 translocation).[7,18]
In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years. However, the outcome for older children, especially adolescents, has improved significantly over time.[19,20,21] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[22,23,24] (Refer to the Postinduction Treatment for Specifc ALL Subgroups section of this summary for more information about adolescents with ALL.)
WBC count at diagnosis
A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis, although the relationship between WBC count and prognosis is a continuous rather than a step function. Patients with B-precursor ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.
The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for B-precursor ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[6,25,26,27,28,29,30,31] One factor that might explain the lack of prognostic effect for WBC count at diagnosis may be the very poor outcome observed for T-cell ALL with the early T-cell precursor phenotype, as patients with this subtype appear to have lower WBC count at diagnosis (median <50,000/µL) than do other T-cell ALL patients.
CNS involvement at diagnosis
The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence or absence of blasts on cytospin as follows:
Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically) than patients who are classified as CNS1 or CNS2. The adverse prognostic significance associated with CNS2 status, if any, may be overcome by the application of more intensive intrathecal therapy, especially during the induction phase.[33,34]; [Level of evidence: 2A]
A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis appears to be associated with increased risk of CNS relapse and indicates an overall poorer outcome.[33,36] To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.
Testicular involvement at diagnosis
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most commonly in T-cell ALL.
In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[38,39] For example, the European Organization for Research and Treatment of Cancer (EORTC, [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.
The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation. The COG has also adopted this strategy for boys with testicular involvement that resolves completely by the end of induction therapy. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.
Down syndrome (trisomy 21)
Outcome in children with Down syndrome and ALL has generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome.[40,41,42,43]
The lower event-free survival (EFS) and OS of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the absence of favorable biological features.[40,41,42,43,44] Patients with Down syndrome and ALL have a significantly lower incidence of favorable cytogenetic abnormalities such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.
In a report from the COG, among B-precursor ALL patients who lacked MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome.
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[45,46,47] One reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.[45,46,47] However, in clinical trials with high 5-year EFS rates (>80%), outcomes for boys are closely approaching those of girls.[34,48]
Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[49,50] This difference may be therapy-dependent; a report from SJCRH found no difference in outcome by racial groups.
Asian children with ALL fare slightly better than white children. The reason for better outcomes in white and Asian children than in black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, blacks have a higher incidence of T-cell ALL and lower rates of favorable genetic subtypes of ALL. However, these differences do not completely explain the observed racial differences in outcome.
Leukemic cell characteristics affecting prognosis
Leukemic cell characteristics affecting prognosis include the following:
In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology. However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used.
Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., t(8;14)). Patients with this specific rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of B-cell ALL and Burkitt lymphoma.)
The World Health Organization (WHO) classifies ALL as either:
Either B or T lymphoblastic leukemia can co-express myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.
Prior to 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.
Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome.[10,54] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.
The major subtypes of precursor B-cell ALL are as follows:
Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.
Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with a t(4;11) translocation.
The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1) fusion (see below).[56,57]
Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.
Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and a translocation involving the C-MYC gene), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as mature B-cell leukemia. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with B-cell ALL and Burkitt lymphoma.)
T-cell ALL is defined by expression of the T cell-associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of clinical features, including the following:[17,25,48]
With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that of children with B-lineage ALL.[17,25,48]
There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL. The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.
Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[60,61]
Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) fusing to one of the T-cell receptor loci and resulting in aberrant expression of these transcription factors in leukemia cells.[60,62,63,64,65,66] These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR). High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL.[62,63,64,66] Overexpression of TLX3/HOX11L2 resulting from the t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be associated with increased risk of treatment failure, although not in all studies.
NOTCH1 gene mutations occur in approximately 50% of T-cell ALL cases, but their prognostic significance has not been established.[67,68,69,70,71,72]
A NUP214–ABL1 fusion has been noted in 4% to 6% of adults with T-cell ALL. The fusion is usually not detectable by standard cytogenetics. Tyrosine kinase inhibitors may have therapeutic benefit in this type of T-cell ALL.[73,74,75]
Early precursor T-cell ALL, a distinct subset of childhood T-cell ALL, was identified by gene expression profiling, flow cytometry, and single nucleotide polymorphism array analyses. This subset, identified in 13% of T-cell ALL cases, is characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and co-expression of stem cell or myeloid markers). Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases. Compared with other T-ALL cases, the early T-cell precursor group had significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells. A retrospective analysis suggested that this subset may have a poorer prognosis than other cases of T-cell ALL.
Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-cell ALL.[77,78] ABGD is characteristic of early thymic precursor cells, and many of the T-cell ALL patients with ABGD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.
Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL translocations and those with the ETV6-RUNX1 gene rearrangement.[79,80] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[79,80]
Leukemia of ambiguous lineage
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[81,82,83] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies. However, most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[84,85,86] In the WHO classification, the presence of myeloperoxidase is required to establish myeloid lineage. This is not the case for the EGIL classification.
Leukemias of mixed phenotype comprise the following two groups:
A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Others are associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).
Prognostically significant chromosomal abnormalities in childhood ALL include the following:
High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell ALL. Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low WBC count) and is itself an independent favorable prognostic factor.[89,90] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites, which may explain the favorable outcome commonly observed in these cases.
While the overall outcome of patients with high hyperdiploidy is considered to be favorable, the following factors have been shown to modify its prognostic significance:
Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group (CCG) analyses of NCI standard-risk ALL. POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.
Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t(9;22)) also had high hyperdiploidy, and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive (Ph+) high hyperdiploid patients.
Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy). These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.
Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy. Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[97,98,99] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[97,99]
A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome. Patients with fewer than 44 chromosomes have a worse outcome than patients with 44 or 45 chromosomes in their leukemic cells.
Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL. The t(12;21) occurs most commonly in children aged 2 to 9 years.[100,101] Hispanic children with ALL have a lower incidence of t(12;21) than white children.
Reports generally indicate favorable EFS and OS in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors: [103,104,105]
In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors. There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[103,106] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients. Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).
The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (see Figure 2).
This subtype of ALL is more common in older children with precursor B-cell ALL and high WBC count.
Historically, the Philadelphia chromosome t(9;22) was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic stem cell transplantation (SCT) in patients in first remission.[95,109,110,111] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL. A study by the COG, which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 3-year EFS rate of 80.5%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era. Longer follow-up is necessary to determine whether this treatment improves the cure rate or merely prolongs DFS.
Translocations involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases and are generally associated with an increased risk of treatment failure.[54,113,114,115] The t(4;11) translocation is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.
Patients with the t(4;11) translocation are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy. While both infants and adults with the t(4;11) translocation are at high risk of treatment failure, children with the t(4;11) translocation appear to have a better outcome than either infants or adults.[54,113] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.[54,113]
Of interest, the t(11;19) translocation occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL. Outcome for infants with the t(11;19) translocation is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation.
The t(1;19) translocation occurs in approximately 5% of childhood ALL cases and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1.[56,57] The t(1;19) translocation may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL immunophenotype (cytoplasmic Ig positive). Black children are more likely than white children to have pre-B ALL with the t(1;19).
The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy, but the adverse prognostic significance was largely negated by more aggressive multi-agent therapies. However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, the t(1;19) translocation was associated with a higher risk of CNS relapse.
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[127,128,129] For example, patients with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes, although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[131,132]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction minimal residual disease (MRD) and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols. Polymorphic variants involving the reduced folate carrier have been linked to methotrexate metabolism, toxicity, and outcome. While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; whether individualized dose modification based on these findings will improve outcome is unknown.
Response to initial treatment affecting prognosis
The rapidity with which leukemia cells are eliminated following onset of treatment and the level of residual disease at the end of induction are associated with long-term outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics, early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:
Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as PCR assays, which determine unique Ig/T-cell receptor gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[104,137,138,139] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities. Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.[104,136,137,138,141] End-induction MRD is used by almost all groups as a factor determining the intensity of postinduction treatment, with patients found to have higher levels allocated to more intensive therapies. MRD levels at earlier (e.g., day 8 and day 15 of induction) and later time points (e.g., week 12 of therapy) also predict outcome.[104,136,138,140,141,142,143,144,145]
MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS of 97% ± 1%) for patients with B-precursor phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).
There are fewer studies documenting the prognostic significance of MRD in T-cell ALL. In the AIEOP-BFM ALL 2000 trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-cell ALL. Patients with detectable MRD at end-induction who had negative MRD by day 78 did just as well as patients who achieved MRD-negativity at the earlier end-induction time point. Thus, unlike in B-cell precursor ALL, end-induction MRD levels were irrelevant in those patients whose MRD was negative at day 78. A high MRD level at day 78 was associated with a significantly higher risk of relapse.
There are few studies of MRD in the CSF. In one study, MRD was documented in about one-half of children at diagnosis. In this study, CSF MRD was not found to be prognostic when intensive chemotherapy was given.
Although MRD is the most important prognostic factor in determining outcome, there are no data to conclusively show that modifying therapy based on MRD determination significantly improves outcome in newly diagnosed ALL.
Day 7 and day 14 bone marrow responses
Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days following initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.
Peripheral blood response to steroid prophase
Patients with a reduction in peripheral blast count to less than 1,000/µL after a 7-day induction prophase with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response). Poor prednisone response is observed in fewer than 10% of patients.[17,148] Treatment stratification for protocols of the Berlin-Frankfurt-Münster (BFM) clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately prior to the initiation of multiagent remission induction).
Patients with no circulating blasts on day 7 have a better outcome than those patients whose circulating blast level is between 1 and 999/µL.[149,150]
Peripheral blood response to multiagent induction therapy
Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation. Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.
The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts at the end of the induction phase is observed in up to 5% of children with ALL. Patients at highest risk of induction failure have one or more of the following features:[153,154]
In a large retrospective study, the OS of patients with induction failure was only 32%. However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with B-precursor ALL between the ages of 1 and 5 years without adverse cytogenetics (MLL translocation or BCR-ABL). This group had a 10-year survival exceeding 50%, and SCT in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to 18 years, or who had the Philadelphia chromosome or MLL rearrangement. B-cell ALL patients younger than 6 years and T-cell ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic SCT after achieving complete remission than those who received further treatment with chemotherapy alone.
Prognostic (Risk) Groups
Children's Cancer Group (CCG)/Pediatric Oncology Group (POG) risk groups
Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk based on the NCI consensus age and WBC criteria, regardless of phenotype. The standard-risk category included patients aged 1 to younger than 10 years who had a WBC count at diagnosis less than 50,000/µL. The remaining patients were classified as high risk. Final treatment assignment for CCG protocols was based on early response to therapy with slow early responders being treated as high-risk patients.
Former POG studies defined the low-risk group based on the NCI consensus age and WBC criteria and required the absence of adverse translocations, absence of CNS disease and testicular disease, and the presence of either the ETV6-RUNX1 translocation or trisomy of chromosomes 4 and 10. The high-risk group required the absence of favorable translocations and the presence of CNS or testicular involvement, or the presence of MLL gene rearrangement, or unfavorable age and WBC count. The standard-risk category included patients not meeting the criteria for inclusion in any of the other risk group categories. In POG studies, patients with T-cell ALL were treated on different protocols than patients with precursor B-cell ALL. The very high-risk category for CCG and POG was defined by one of the following factors taking precedence over all other considerations: presence of the t(9;22), M3 marrow on day 29 or M2 or M3 marrow on day 43, or hypodiploidy (DNA index <0.95).
Children's Oncology Group (COG) risk groups
In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) based on a subset of prognostic factors, including the following:
EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/μL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 70%.[3,34,148,155,156] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage and MRD levels at the end of induction), considered in conjunction with presenting age, WBC count, and immunophenotype, can identify patient groups with expected EFS rates ranging from less than 40% to more than 95%.[3,104]
Subgroups of patients who have a poor prognosis with current risk-adapted, multiagent chemotherapy regimens may require different therapeutic approaches. For example, infants with ALL are at much higher risk for treatment failure than older children.[10,157] Infants with ALL are generally treated on separate protocols using more intensified regimens, although the likelihood of long-term EFS appears to be no better than 50% for infants with MLL translocations even with a more intensive therapeutic approach.[9,10,11,157] (Refer to the Infants with ALL section of this summary for information about infants with ALL.)
The following subgroups of patients are sometimes considered candidates for allogeneic SCT in first complete remission (CR1): [9,158,159,160]
However, because of small numbers, possible patient selection bias, and center preference, studies to definitively show whether transplantation in CR1 is superior to intensive chemotherapy for these very high-risk patients have not been feasible. The use of allogeneic SCT in CR1 for patients with Ph+ ALL is less clear in the era of tyrosine kinase inhibitors.
Berlin-Frankfurt-Münster (BFM) risk groups
Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two time points, end induction (week 5) and end consolidation (week 12).
The BFM risk groups include the following:
Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.
Prognostic (risk) groups under clinical evaluation
COG AALL08B1(Classification of Newly Diagnosed ALL): COG protocol AALL08B1 stratifies four risk groups for patients with B-precursor ALL (low risk, average risk, high risk, and very-high risk) based on the following criteria:
Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way.
For patients with B-precursor ALL:
The four risk groups for B-precursor ALL are defined in Table 1.
DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase vs. Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): On the current clinical trial conducted by the Dana-Farber Cancer Institute ALL Consortium, patients with B-precursor ALL are initially classified as either standard risk or high risk based on age, presenting leukocyte count, and the presence or absence of CNS disease (CNS3). At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined via PCR assay. Patients with high MRD (≥0.001) are classified as very-high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.001) continue to receive treatment based on their initial risk group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<44 chromosomes) are classified as very-high risk, regardless of MRD status or phenotype. Ph+ patients are removed from study midinduction and are eligible to enroll on the COG protocol for patients with Ph+ ALL.
SJCRH: Risk classification is based mainly on MRD level (assessed by flow cytometry) after 6 weeks of remission induction therapy as follows: low risk (<0.01%), standard risk (0.01% – <1%), and high risk (≥1%). Patients with early T-cell precursor ALL are also considered to be high risk.
Children with acute lymphoblastic leukemia (ALL) should be cared for at a center with specialized expertise in pediatric cancer. Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, patients must be closely monitored at diagnosis and during treatment.
Adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications.[2,3]
Nationwide clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the therapeutic innovations that produced increased survival rates in children with ALL have been established through nationwide clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. Treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment.
Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with modest therapy and to be spared more intensive and toxic treatment, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. (Refer to the Risk-based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.)
Phases of Therapy
Treatment for children with ALL is typically divided as follows:
Central nervous system (CNS)
Successful treatment of children with ALL requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes), as well as the prevention or treatment of extramedullary disease, particularly in the CNS. Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid specimen with ≥5 WBC/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. (Refer to the CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for more information.)
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[4,5] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation. The Children's Oncology Group has also adopted this strategy for boys with testicular involvement that resolves completely during induction chemotherapy.
Standard Treatment Options for Newly Diagnosed ALL
Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include the following:
Remission induction therapy
Induction chemotherapy consists of the following drugs, with or without an anthracycline:
The Children's Oncology Group (COG) protocols do not administer anthracycline during induction to patients with National Cancer Institute standard-risk precursor B-cell ALL. This three-drug induction regimen results in a complete remission rate of greater than 95% for standard-risk patients.
Patients treated by other study groups receive a four-drug induction regimen regardless of presenting features:
The most common four-drug induction regimen is vincristine, corticosteroid (either dexamethasone or prednisone), L-asparaginase, and either doxorubicin or daunorubicin. Some studies have suggested that this more intensive induction regimen may result in improved event-free survival (EFS) in patients presenting with high-risk features.[5,6] The COG reserves the use of a four-drug induction for patients with high-risk B-precursor ALL and T-cell ALL.
For patients who are at standard risk or low risk of treatment failure, four-drug or more induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[5,7,8]
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy.
The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio is 1:5 to 1:7 have shown a better result for dexamethasone, while studies using a 1:10 ratio have shown similar outcomes.
While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may be more toxic, especially in the context of more intensive induction regimens and in adolescents.
Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens.[15,16] The increased risk of infection with dexamethasone during the induction phase has not been noted with three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase). Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone  and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.
Several forms of L-asparaginase are available in the United States for use in the treatment of children with ALL including the following:
PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients.
PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion following a single injection.
A single intramuscular (IM) dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).
Studies have shown that a single dose of PEG-L-asparaginase given either IM or intravenously (IV) as part of multiagent induction results in serum enzyme activity (>100 IU/mL) in nearly all patients for at least 2 to 3 weeks.[20,21,22]
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase.
Pharmacokinetics and toxicity profiles are similar for IV and IM PEG-L-asparaginase administration. The toxicity of PEG-L-asparaginase seems to be similar to that observed with native E. coli asparaginase. It is safe to give IV PEG-L-asparaginase in pediatric patients.[21,22]
The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days). If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose to achieve adequate asparagine depletion.
Evidence (Erwinia L-asparaginase):
Response to remission induction chemotherapy
More than 95% of children with newly diagnosed ALL will achieve a complete remission (CR) within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[25,27,28]; [Level of evidence: 3iA] Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic stem cell transplant (SCT) once CR is achieved.[30,31,32] In a large retrospective series, the 10-year overall survival for patients with persistent leuekmia was 32%. A trend for superior outcome with allogeneic SCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and B-precursor patients younger than 6 years. B-precursor ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) had a relatively favorable prognosis, without any advantage in outcome with the utilization of SCT compared with chemotherapy alone.
For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, particularly the following:
Refer to the Effect of response to initial treatment on prognosis section of this summary for more information.
(Refer to the CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about central nervous system therapy to prevent CNS relapse in children with newly diagnosed ALL.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Standard Postinduction Treatment Options for Childhood ALL
Standard treatment options for consolidation/intensification therapy include the following:
Standard treatment options for maintenance therapy include the following:
Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols (Children's Oncology Group [COG], St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during maintenance, while others (Berlin-Frankfurt-Münster [BFM]) do not. (Refer to the CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about central nervous system therapy to prevent CNS relapse in children with ALL who are receiving postinduction therapy.
Once remission has been achieved, systemic treatment in conjunction with CNS sanctuary therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification following achievement of remission and before beginning maintenance therapy. Intensification may involve use of the following:
In children with standard-risk ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[10,11,12] For example, regimens utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase) have been used with good results for children with standard-risk ALL.[2,3,11] Similarly favorable results for standard-risk patients have been achieved with regimens utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without any postinduction exposure to alkylating agents or anthracyclines.[7,13]
Evidence (intensification for standard-risk ALL):
In high-risk patients, a number of different approaches have been used with comparable efficacy.[7,19]; [Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short- and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.
Evidence (intensification for high-risk ALL):
Very high-risk ALL
Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:[17,26]
Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase, often including agents not typically used in frontline ALL regimens for standard- and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide. However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,27]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic stem cell transplantation (SCT) in first remission, [27,28,29] although it is not clear whether outcomes are better with transplantation.
Evidence (allogeneic SCT in first remission):
Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally administer oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.
Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[32,33] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[32,33] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than do patients who are homozygous for the normal allele.
Evidence (maintenance therapy):
Other approaches to maintenance therapy include the following:
Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains controversial.
Evidence (vincristine/corticosteroid pulses):
When steroid pulses are used during the maintenance phase, dexamethasone is preferred over prednisone for younger patients. [14,48]
Evidence (dexamethasone vs. prednisone):
The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.[25,50]
Duration of maintenance therapy
Maintenance chemotherapy generally continues until 2 to 3 years of continuous complete remission. On some studies, boys are treated longer than girls; on others, there is no difference in the duration of treatment based on gender.[7,17] It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.
Treatment options under clinical evaluation
Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk for treatment failure. The Risk-based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.
Ongoing clinical trials include the following:
COG studies for B-precursor ALL
This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/WBC, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, and BCR-ABL).
All patients will receive a three-drug induction (dexamethasone, vincristine, and IV PEG-L-asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive either a regimen based on POG-9404, including six courses of intermediate-dose methotrexate (1 g/m2) but without any alkylating agents or anthracyclines, or a modified BFM backbone including two interim maintenance phases with IV methotrexate and one delayed intensification phase. The objective is not to prove superiority of either regimen, but rather to determine if excellent outcomes (at least 95% 5-year DFS) can be achieved.
All average-risk patients will receive a modified BFM-backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.
This protocol is open to patients aged 30 years or younger. Patients treated on this trial are classified as either high risk or very high risk. The presence of any of the following is sufficient to classify a patient as very high risk:
The high-risk group includes patients aged 10 to 12 years and/or those with WBC count greater than 50,000 who lack very high-risk features, and two groups of NCI standard-risk patients who otherwise lack very high-risk features: (1) those without favorable genetics (no ETV6-RUNX1 or double trisomies 4 and 10), and with day 8 peripheral blood MRD >1%; and (2) those with favorable cytogenetics and with high marrow MRD at day 29. Patients with BCR-ABL (Philadelphia chromosome–positive) are treated on a separate clinical trial.
Patients on this trial will receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV PEG-L-asparaginase) with intrathecal chemotherapy. Patients younger than 10 years receive dexamethasone during induction, and those aged 10 years and older receive prednisone. Postinduction therapy consists of a modified BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase. Very high-risk patients receive a second interim maintenance phase prior to beginning more standard maintenance. Only patients with CNS3 status at diagnosis receive cranial radiation. Those with M3 marrow at day 29 or low hypodiploidy are eligible for allogeneic SCT in first remission.
For high-risk patients, the study will compare, in a randomized fashion, triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS.
For very high-risk patients, the study will test, in a randomized fashion, whether intensified consolidation phases (including either cyclophosphamide/etoposide or clofarabine/cyclophosphamide/etoposide) improves 4-year DFS compared with the standard consolidation phase.
This protocol is also examining the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.