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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.
Successful treatment of children with acute lymphoblastic leukemia (ALL) requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes), and the prevention or treatment of extramedullary disease, particularly in the central nervous system (CNS).
Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid [CSF] specimen with ≥5 white blood cell [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. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis.
Historically, survival rates for children with ALL did not improve until CNS-directed therapy was instituted. The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in all patients. Standard treatment options for CNS-directed therapy include the following:
The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. Data suggest that the following groups of patients are at increased risk of CNS relapse:
CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 2:
A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.
All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation (four to eight doses of intrathecal chemotherapy given every 2–3 weeks), and, in certain protocols, continued throughout the maintenance phase.
Intrathecal chemotherapy typically consists of one of the following:
Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.
CNS-Penetrant Systemic Chemotherapy
In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. The following systemically administered drugs provide some degree of CNS prophylaxis:
Evidence (CNS-penetrant systemic chemotherapy):
The proportion of patients receiving cranial radiation has decreased significantly over time. At present, most newly diagnosed children with ALL are treated without cranial radiation. Many groups administer cranial radiation only to those patients considered to be at highest risk for subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/μL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count. In patients still receiving cranial radiation, the dose has been significantly reduced.
Ongoing trials seek to determine whether radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[10,11]
CNS Therapy for Standard-Risk Patients
Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[10,11,12,13,14,15]
The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[16,17]
Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
CNS Therapy for High-Risk Patients
Controversy exists as to which high-risk patients should be treated with cranial radiation. Depending on the protocol, up to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis. Patients receiving cranial radiation on many treatment regimens include the following:
Both the proportion of patients receiving radiation and the dose of radiation administered have decreased over the last 2 decades.
Evidence (cranial radiation):
Toxicity of CNS-Directed Therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of intrathecal chemotherapy will have at least one seizure during therapy. Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to intrathecal chemotherapy.
Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome. Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.
In general, patients who receive intrathecal chemotherapy without cranial radiation appear to have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[27,28,29,30] This modest decline is primarily seen in young children and girls.
A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[Level of evidence: 3iiiC]
Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances. Long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[34,35,36,37,38]
The following groups have been associated with neurocognitive and neuroendocrine sequelae following cranial radiation:
Evidence (toxicity of cranial radiation):
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas.[24,45,46] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered. In general, systemic methotrexate doses greater than 1 g/m2 should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Treatment options under clinical evaluation include the following:
CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis
Therapy for ALL patients with clinically evident CNS disease (>5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation (usual dose is 18 Gy).[15,17] Spinal radiation is no longer used.
Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 5-year event-free survival (EFS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols was 75% compared with 84% for children with precursor B-cell ALL.
Treatment options under clinical evaluation for T-cell ALL
Treatment options under clinical evaluation for T-cell ALL include the following:
COG-AALL0434 is a phase III trial utilizing a modified augmented BFM regimen for patients aged 1 to 30 years with T-cell ALL. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial include the following:
Patients with T-cell ALL are eligible to enroll on a DFCI ALL Consortium protocol that is comparing the pharmacokinetics and toxicity of two forms of intravenous (IV) PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
This protocol is also testing whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase. All T-cell patients are treated on the high-risk arm of this trial, regardless of other presenting characteristics.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Infants With ALL
Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL. Because of their distinctive biological characteristics and their high risk for leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.[12,13,14] Despite intensification of therapy, long-term EFS rates remain below 50%. Infants with congenital leukemia (diagnosed within 1 month of birth) have a particularly poor outcome (17% overall survival [OS]).[Level of evidence: 2A].
For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[12,13,15,16,17][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include the following:; [Level of evidence: 3iDii]
Treatment options for infants withMLLtranslocations
Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients.
Evidence (intensified chemotherapy regimens for infants with MLL translocations):
The role of allogeneic stem cell transplant (SCT) during first remission in infants with MLL gene translocations remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective.[19,20,21]; [Level of evidence: 3iA]
Evidence (allogeneic SCT in first remission for infants with MLL translocations):
Treatment options for infants withoutMLLtranslocations
The optimal treatment for infants without MLL translocations also remains unclear.
Treatment options under clinical evaluation for infants with ALL
Adolescent and Young Adult Patients With ALL
Older children and adolescents (aged 10 years and older) with ALL more frequently present with adverse prognostic factors at diagnosis, including T-cell immunophenotype and Philadelphia chromosome–positivity (Ph+), and have a lower incidence of favorable cytogenetic abnormalities.[26,27] These patients have a less favorable outcome than children aged 1 to younger than 10 years at diagnosis, and more aggressive treatments are generally employed.
Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens. Other studies have confirmed that older adolescent and young adult patients fare better on pediatric rather than adult regimens.[27,29,30,31,32]; [Level of evidence: 2A] These study results are summarized in Table 3.
Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for pediatric ALL, there is no role for the routine use of allogeneic SCT in first remission for adolescents and young adults with ALL.
Evidence (pediatric treatment regimen):
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (see Table 3).[27,29,30,31]; [Level of evidence: 2A]
The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following: 
Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[27,37,38,39] High body mass index is also a risk factor for osteonecrosis  and may be associated with a higher relapse rate in older patients.
Treatment options under clinical evaluation for adolescent and young adult patients with ALL
Philadelphia Chromosome–Positive ALL
Prior to use of imatinib mesylate (see below), hematopoietic stem cell transplantation (HSCT) from a matched sibling donor was the treatment of choice for patients with Ph+ ALL.[45,46,47] Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome than standard (pre-imatinib mesylate) chemotherapy. In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib mesylate era), transplantation with matched-related or matched-unrelated donors were equivalent. DFS at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and OS was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.
Factors significantly associated with favorable prognosis in the pre-imatinib mesylate era included the following:
Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may also be useful to help predict outcome for Ph+ patients.[52,53,54]
Tyrosine kinase inhibitor therapy
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[55,56]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[57,58,59] Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[60,61,62,63]
Evidence (imatinib mesylate):
Dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial treatment of Ph+ ALL. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.
Treatment options under clinical evaluation for Philadelphia chromosome–positive ALL
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Prognostic Factors in Recurrent Childhood ALL
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the following factors: [1,2,3,4,5,6,7,8,9,10,11,12,13]; [Level of evidence: 3iiDi]
Age 10 years and older at diagnosis has been reported as an independent predictor of poor outcome.
The Berlin-Frankfurt-Münster group has also reported that high peripheral blast counts (>10,000/μL) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.
Time from diagnosis to relapse
For patients with relapsed B-precursor ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For instance, survival rates after marrow relapse range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to 40% to 50% for those whose relapses occur more than 36 months from diagnosis.[5,13]
For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early relapse (<18 months from diagnosis) are 40% to 50% and 75% to 80% for those with late relapses (>18 months from diagnosis).[13,15] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.
Site of relapse
Patients who have combined marrow/extramedullary relapses fare better than those who have isolated marrow relapses.[5,13]
Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second complete remission (CR2).[Level of evidence: 2Di]; [Level of evidence: 3iiiA]
TP53 alterations (mutations and/or copy number alterations) are observed in approximately 11% of patients with ALL at first relapse and have been associated with inferior reinduction failure rate (38.5% TP53 alteration vs. 12.5% TP53 wild-type) and event-free survival (EFS) (9% TP53 alteration vs. 49% TP53 wild-type), of which approximately one-half are newly observed at time of relapse.
Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any time during treatment or posttreatment have a very poor prognosis.
Other prognostic factors for recurrent ALL include the following:
Standard Treatment Options for Recurrent Childhood ALL
Treatment of bone marrow relapse
Standard treatment options for reinduction therapy when cancer has recurred in the bone marrow include the following:
Standard treatment options for postreinduction therapy when cancer has recurred in the bone marrow include the following:
Initial treatment of relapse consists of induction therapy to achieve a CR2. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a CR2 at the end of the first month of treatment.; [Level of evidence: 2A]; [Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) than do those with late marrow relapses (approximately 95%).[17,24]
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
Other combinations of agents have been reported to induce remissions in patients with multiple-relapsed or refractory ALL. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 44% to 56% of patients with refractory or relapsed disease.; [Level of evidence: 2A]
Patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens than do patients with B-precursor phenotype. Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%. The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.
Postreinduction therapy (second complete remission)
Post-CR2 therapy for patients who experience a bone marrow relapse (either isolated or combined) while on therapy or within 6 months of discontinuing therapy generally includes hematopoietic stem cell transplantation (HSCT).[30,31]
For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in longer leukemia-free survival than a chemotherapy approach.[7,23,32,33,34,35,36,37,38] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%.
For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[9,39,40,41]; [Level of evidence: 3iiA] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no SCT) in CR2.
Evidence (chemotherapy for B-precursor ALL):
For patients with either an early or late relapse who are treated with chemotherapy and have a second relapse, there is evidence that an unrelated SCT may result in long-term disease-free survival.[Level of evidence: 3iiA] Patients with long first and second remission have the lowest relapse risk, but there is a high rate of nonrelapse mortality.
For patients with T-cell ALL who have marrow relapses, outcomes with chemotherapy alone have generally been poor, and these patients are usually treated with allogeneic SCT in CR2, regardless of time to relapse.
Stem cell transplantation
For patients proceeding to allogeneic SCT, total-body irradiation (TBI) appears to be an important component of the conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant conditioning regimens that include TBI produce higher cure rates than chemotherapy-only preparative regimens.[32,44,45] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent, although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary. The potential neurotoxic effects of TBI should be considered, particularly for very young patients. The use of post-HSCT intrathecal chemotherapy chemoprophylaxis does not appear to offer benefit; however, this is controversial.[49,50,51]
In addition to the conditioning regimen, disease status at the time of transplantation also appears to be an important predictor of outcome. Several studies have demonstrated that the level of MRD at the time of transplant is an important predictor of survival in patients in CR2.[22,52,53,54]
There is no apparent difference in outcome between children and adolescents transplanted in second remission.[Level of evidence: 3iiA]
Outcomes following matched unrelated donor and umbilical cord blood transplants have improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants.[36,56,57,58,59]; [Level of evidence: 2A]; [Level of evidence: 3iiiA] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related mortality remain higher with unrelated than with matched sibling transplants.[37,56,62] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and Center for International Blood and Marrow Transplant Research (CIBMTR) analyses have demonstrated that rates of GVHD, treatment-related mortality, and OS have improved over time.; [64,65][Level of evidence: 3iiA]
Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor. In certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered. For T cell-depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells may have a better outcome than those who receive paternal stem cells.[Level of evidence: 3iiA]
There are a number of new options under study for preventing subsequent relapse after transplantation, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.
Relapse after allogeneic HSCT for relapsed ALL
For patients relapsing after an allogeneic HSCT for relapsed ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure because of failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy. Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term EFS.[70,71,72] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with complete remission at the time of the second HSCT.[71,72]
Reduced intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a CR confirmed by flow cytometry.[Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.; [Level of evidence: 3iiiA]
Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is unknown, and a small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[Level of evidence: 3iA]
Treatment of extramedullary relapse
With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5%, and testicular relapse is less than 1% to 2%.[77,78,79] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse. In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques, and successful treatment strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis than patients with either no MRD or MRD less than 0.01%.
Standard treatment options for childhood ALL that has recurred in the CNS include the following:
While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.[15,82,83,84]
Evidence (chemotherapy and radiation therapy):
A number of case series describing SCT in the treatment of isolated CNS relapse have been published.[85,86]
The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.
Standard treatment options for childhood ALL that has recurred in the testes include the following:
The standard approach for treating isolated testicular relapse in North America is to administer chemotherapy plus radiation therapy.
In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control (surgical removal or radiation) is to be performed. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes is being tested in clinical trials.
Treatment Options Under Clinical Evaluation for Recurrent Childhood ALL
Treatment options under clinical evaluation include the following:
COG trials for ALL in first relapse
The COG has divided patients with first relapse into three risk categories as outlined in Table 4. Clinical trials in some risk categories are available.
Other trials for ALL in first relapse
Trials for ALL in second or subsequent relapse
Multiple clinical trials investigating new agents and new combinations of agents are available for children with second or subsequent relapsed or refractory ALL and should be considered. These trials are testing targeted treatments specific for ALL, including monoclonal antibody–based therapies and drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Postinduction Treatment for Specific ALL Subgroups
Revised text to state that the pilot study showed a 5-year event-free survival rate of 73% for all patients receiving nelarabine and 69% for those patients with a slow early response (cited Dunsmore et al. as reference 10).
Added Ram et al. as reference 32.
Treatment of Recurrent Childhood ALL
Added Leung et al. as reference 54.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-01-23
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