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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, 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 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 ALL entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by pediatric oncologists 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.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,3,4] For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to more than 75% for adolescents aged 15 to 19 years.[1,5] 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 approximately 25% of cancer diagnoses among children younger than 15 years.[3,4] ALL occurs at an annual rate of 35 to 40 cases per 1 million people in the United States.[3,4,6] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[6,7] Over the past 25 years, there has been a gradual increase in the incidence of ALL.[3,4,8]
A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[3,4] The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.[3,4]
The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[3,4,6] 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 than in black children.[3,4,6]
Childhood ALL originates in the T- and B-lymphoblasts in the bone marrow (refer to 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),[16,17] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[16,17]
Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome.[18,19,20] 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.[18,19]
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 near absence of T-cell phenotype.[18,19,20,21,22] Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of this gene.[23,24,25]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-precursor ALL who do not have Down syndrome.[25,26,27] It does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance. However, IKZF1 gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[23,24,28,29,30] 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 CRLF2 genomic alterations.[23,24,25] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[24,29] but more study is needed to address this issue and the prognostic significance of IKZF1 gene deletions.
Inherited genetic polymorphisms
Genome-wide association studies show that some germline (inherited) genetic polymorphisms are associated with the development of childhood ALL.[32,33] 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.[34,35] Also, germline ETV6 variations have been associated with predisposition to childhood ALL. Several studies, including a meta-analysis of 11 published papers, have indicated that a polymorphism of CEBPE, a transcription factor essential for neutrophil development, is also associated with an increased risk of developing ALL.
In another genome-wide association study in the adolescent and young adult population, unique GATA3 polymorphisms were identified that strongly influence the susceptibility to leukemia in this population.
Prenatal origin of childhood ALL
Development of ALL is in most cases a multi-step process, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. 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.[39,40] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients appear to have blood cells carrying at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[39,40,41] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[39,42]
There is also evidence that some children who never develop ALL are born with very rare blood cells carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1 translocation, far exceeding the number of cases of ETV6-RUNX1 ALL in children. Other reports confirm  or do not confirm [45,46] this finding, and methodological issues related to fluorescence in situ hybridization testing complicate interpretation of the initial 1% estimate. Nonetheless, if confirmed, it would support the hypothesis that additional postnatal genomic changes are needed for the development of this type of ALL and that in most cases in which a leukemia-associated alteration is present at birth, the additional leukemogenic genomic changes do not occur and no leukemia develops.
The typical and atypical symptoms and clinical findings of childhood ALL have been published.[48,49,50]
The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[48,49,50,51]
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.[52,53,54,55,56,57]
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, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Check the list of NCI-supported 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 website.
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 After First Relapse of 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]; [Level of evidence: 2A]
Approximately 80% of infants with ALL have an MLL gene rearrangement.[10,13,14] 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.[10,15] 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] A gene expression profile analysis in infants with MLL-rearranged ALL revealed significant differences between patients younger than 90 days and older infants, suggesting distinctive age-related biological behaviors for MLL-translocation ALL that may relate to the significantly poorer outcome for the youngest infants.
Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[10,11,14,17] 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 do infants with ALL characterized by MLL translocations.[10,11,14]
Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants.[1,7,18] 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).[7,19,20]
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.[21,22,23] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[24,25,26] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[27,28,29] (Refer to the Postinduction Treatment for Specific 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.[6,30,31,32,33,34,35,36,37] 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 are patients who are classified as CNS1 or CNS2. Some studies have reported increased risk of CNS relapse and/or inferior event-free survival (EFS) in CNS2 patients, compared with CNS1 patients,[40,41] while others have not.[39,42,43,44]
A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies,[39,43,45] but not others.[40,42] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and MLL gene rearrangements.[39,42,43]
Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[39,46]; [Level of evidence: 2A] Other groups have not altered therapy based on CNS2 status.[40,47]
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.[49,50] 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.[51,52,53,54,55]
The lower EFS and OS of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the lower frequency of favorable biological features such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.[51,52,53,54,56,57] 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 a large retrospective study of patients with Down syndrome and ALL (N = 653), age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6-RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS. Failure to achieve remission and treatment-related mortality are also higher in patients with Down syndrome. Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK mutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[58,59,60,61,62] In one study of Down syndrome children with ALL, the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK mutations) was associated with an inferior prognosis.
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[63,64,65] 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.[63,64,65] While some reports describe outcomes for boys as closely approaching those of girls,[46,66] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[24,25,67]
Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[68,69] 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, black children have a higher relative incidence of T-cell ALL and lower rates of favorable genetic subtypes of precursor B-cell ALL. Differences in outcome may also be related to treatment adherence, as illustrated by two studies of adherence to oral 6-mercaptopurine in maintenance therapy. In the first study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even when adjusting for other known variables. However, at adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse. Ancestry-related genomic variations may also contribute to racial/ethnic disparities in both the incidence and outcome of ALL. For example, the differential presence of specific host polymorphisms in different racial/ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard. In the second study, adherence rates were significantly lower in Asian American and African American patients than in non-Hispanic white patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.
Weight at diagnosis and during treatment
Studies of the impact of obesity on the outcome of ALL have had variable results. In most of these studies, obesity is defined as weight above the 95th percentile for age and height. Three studies have not demonstrated an independent effect of obesity on EFS.[Level of evidence: 2Dii]; [75,76][Level of evidence: 3iiDi] Two studies have shown obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[77,78][Level of evidence: 3iiDi] In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease (MRD) at the end of induction and an inferior EFS.[Level of evidence: 3iiDi]
The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial (CCG-1961 [NCT00002812]).[Level of evidence: 2Di] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS, 64% vs. 74%; P = .002.) However, obese patients at diagnosis, who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.
In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (8% of the population) had an almost twofold higher risk of relapse compared with nonunderweight patients (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with loss of body mass index during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.
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 coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.
Before 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.[10,84] 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 MLL gene rearrangements.
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).[86,87]
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:[18,31,66]
With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that of children with B-lineage ALL.[18,31,34,35,66]
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.[6,31,32,33,34,35,36,37] 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.[90,91]
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.[90,92,93,94,95,96] 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.[92,93,94,96] Overexpression of TLX3/HOX11L2 resulting from the cryptic 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.
Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL.NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-cell ALL cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases have Notch pathway activation by mutations in at least one of these genes. The prognostic significance of Notch pathway activation by NOTCH1 and FBXW7 mutations in pediatric T-cell ALL is not clear, as some studies have shown a favorable prognosis for mutated cases,[99,100,101,102] while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.[98,103,104,105]
A NUP214–ABL1 fusion has been noted in 4% to 6% of T-cell ALL cases and is observed in both adults and children with a male predominance.[106,107,108] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region. T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have therapeutic benefit in this T-cell ALL subtype,[106,107,109] although clinical experience with this strategy is very limited.[110,111,112]
Early T-cell precursor ALL
Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors. The subset of T-cell ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression 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 a lower rate of NOTCH1 mutations and 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. Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other cases of T-cell ALL.[38,114,115] However, another study indicated that the early T-cell precursor ALL subgroup had nonsignificantly inferior 5-year EFS compared with non–early T-cell precursor cases (76% vs. 84%). Further study in additional patient cohorts is needed to firmly establish the prognostic significance of early T-cell precursor 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.[117,118] 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.[119,120] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[119,120]
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.[121,122,123] 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.[124,125,126] 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 historically have been 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 B-precursor 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. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase FISH may detect hidden hyperdiploidy. 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.[20,129,130] Within the hyperdiploid range of 51 to 66 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study. 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, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[132,133]
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 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.[138,139,140] 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.[138,140]
The genomic landscape of hyperdiploid ALL is represented by mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of mutation profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL.
Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying based on modal chromosome number into the following four groups:
Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[137,142] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.
The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL. In near-haploid ALL, alterations targeting RTK signaling, Ras signaling, and IKZF3 are common. In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.
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.[145,146] Hispanic children with ALL have a lower incidence of t(12;21) than do 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: [148,149,150,151,152]
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. It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6-RUNX1 fusion.[152,153] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[148,154] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients, with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis. 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).[157,158]
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 (refer to 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 hematopoietic stem cell transplantation (HSCT) in patients in first remission.[136,159,160,161] 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 5-year EFS rate of 70% ± 12%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[162,163,164]
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.[84,165,166,167] 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.[84,165] Irrespective of the type of MLL gene rearrangement, infants with leukemia cells that have MLL gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have an MLL gene rearrangement.[84,165] Whole-genome sequencing has determined that cases of infant ALL with MLL gene rearrangements have few additional genomic alterations, none of which have clear clinical significance. Deletion of the MLL gene has not been associated with an adverse prognosis.
Of interest, the t(11;19) translocation involving MLL and MLLT1/ENL occurs in approximately 1% of ALL 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 TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1.[86,87] The t(1;19) translocation may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the 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 multiagent therapies.[87,174] However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, patients with the t(1;19) translocation had an overall outcome comparable to children lacking this translocation, with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[46,175]
The t(17;19) translocation resulting in the TCF3-HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3-HLF fusion is associated at diagnosis with disseminated intravascular coagulation and with hypercalcemia. Outcome is very poor for children with the t(17;19) translocation, with a literature review noting mortality for 20 of 21 cases reported. In addition to the TCF3-HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by mutations in RAS pathway genes (NRAS, KRAS, and PTPN11).
Numerous new genetic lesions have been discovered by various array comparative hybridization and next-generation sequencing methods. Appreciation of these submicroscopic genomic abnormalities and mutations is redefining the subclassification of ALL:[177,178,179,180,181,182,183]
Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome on multivariate analyses.[177,188,190,191,192,193,194,195,196]; [Level of evidence: 2Di]
The hallmark of this entity is activated kinase signaling, with 50% containing CRLF2 genomic alterations  and 25% containing concomitant JAK mutations. Additional information about Ph-like ALL cases with CRLF2 genomic alterations is provided below.
Many of the remaining cases of Ph-like ALL have been noted to have a series of translocations with a common theme of involvement of either ABL1, JAK2, PDGFRB, or EPOR. Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo, suggesting potential therapeutic strategies for these patients. Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph–like ALL cases.
Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance on univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[180,202,203,204,205] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR-ABL-like expression signatures were associated with unfavorable outcome. There is also controversy about whether the prognostic significance of CRLF2 abnormalities should be analyzed based on CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[180,205]
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[206,207,208] 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.[210,211]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction 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 and methotrexate metabolism have been linked to toxicity and outcome.[213,214] 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 after initiation 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 IgH/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.[149,217,218] 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.[149,216,217,218] 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 time points during induction (e.g., day 8 and day 15) and later time points (e.g., week 12 of therapy) also predict outcome.[149,216,220]; [Level of evidence: 2A]
MRD levels obtained 10 to 12 weeks after the start of treatment (end-consolidation) have also been shown to be prognostically important; patients with high levels of MRD at this time point have a significantly inferior event-free survival compared with other patients.[218,219]
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).
Modifying therapy based on MRD determination has been shown to improve outcome in B-cell ALL. The UKALL2003 (NCT00222612) study demonstrated that reduction of therapy (i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-high–risk patients with favorable end-induction MRD.[Level of evidence: 1iiDii] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if end-induction MRD was greater than 0.01% (5-year EFS, 89.6% for augmented therapy vs. 82.8% for standard therapy).
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 after the initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow. MRD assessments at the end of induction therapy have generally replaced day 7 and day 14 morphological assessments as response to therapy prognostic indicators because the latter lose their prognostic significance in multivariate analysis once MRD is included in the analyses.[149,226]
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.[18,227] 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 before the initiation of multiagent remission induction).
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.
Peripheral blood MRD before end of induction (day 8, day 15)
MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy has also been evaluated as an early response-to-therapy prognostic factor. In a COG study involving nearly 2,000 children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with adverse prognosis, with increasing MRD levels being associated with a progressively poorer outcome. In multivariate analysis, end of induction therapy MRD was the most powerful prognostic factor, but day 8 peripheral blood MRD maintained its prognostic significance, as did NCI risk group and the presence of favorable trisomies. A smaller study assessed the prognostic significance of peripheral blood MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy. This study also observed multivariate significance for peripheral blood MRD levels after 1 week of multiagent induction therapy. Both studies identified a group of patients who achieved low MRD levels after 1 week of multiagent induction therapy who had a low rate of subsequent treatment failure.
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:[231,232]
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 HSCT 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 HSCT after achieving complete remission than those who received further treatment with chemotherapy alone.
Prognostic (Risk) Groups
For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens based on their estimated risk of treatment failure. Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response (e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate molecular characteristics of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at end of induction (and in some cases at later time points). The risk classification systems of the COG and the BFM groups are briefly described below.
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 75%.[3,46,227,233,234] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage for patients with Down syndrome and MRD levels in peripheral blood on day 8 and in bone marrow samples at the end of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the presence of extramedullary disease, and steroid pretreatment can identify patient groups for postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.[3,149]
Patients who are at very high risk of treatment failure include the following: [9,235,236,237]
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.
NCI-2014-00712; AALL1231 (NCT02112916)(Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II-IV T-Cell Lymphoblastic Lymphoma): For patients with T-cell ALL, COG uses the following criteria to assign risk category:
Very high risk
SJCRH (Total XVI): Patients are classified into one of three categories (low, standard, or high risk) based on the presenting age, leukocyte count, presence or absence of CNS3 status or testicular leukemia, immunophenotype, cytogenetics and molecular genetics, DNA index, and early response to therapy. Hence, definitive risk assignment (for provisional low-risk or standard-risk cases based on presenting features) will be made after completion of remission induction therapy. The criteria and the estimated proportion of patients in each category (based on data from TOTXV study) are provided below.
Criteria for low-risk ALL (approximately 48% of patients)
Criteria for standard-risk ALL (approximately 44% of patients)
Criteria for high-risk ALL (approximately 8% of patients)
Children with acute lymphoblastic leukemia (ALL) should be cared for at a center with specialized expertise in pediatric cancer. 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.
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]
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 were established through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial.
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 less intensive therapy and to be spared more toxic treatments, while allowing children with a historically lower probability of long-term survival to receive stronger 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:
Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that are poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL). The two most important sanctuary sites in childhood ALL are the central nervous system (CNS) and the testes. Successful treatment of ALL requires therapy that effectively addresses clinical or subclinical involvement of leukemia in these extramedullary sanctuary sites.
Central nervous system (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. CNS-directed treatments include intrathecal chemotherapy, CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current regimens for ALL. (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 chemotherapy
The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-precursor ALL achieve CR by the end of this phase, with somewhat lower rates in patients with T-cell ALL or high presenting leukocyte counts.[1,2,3,4,5]
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.
Patients treated by the following study groups receive an induction regimen with four or more drugs 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. In a randomized trial of doxorubicin and daunorubicin during induction, there were no differences between these two agents in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction minimal residual disease (MRD) levels.[Level of evidence: 1iiDiv] 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, but it may not be necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[7,8] The COG reserves the use of a four-drug induction for patients with high-risk B-precursor ALL and T-cell ALL.
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 was 1:5 to 1:7 have shown a better result for dexamethasone, while studies that used 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.[16,17] 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 patients aged 10 years and older.
Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:
Only PEG-L-asparaginase and Erwinia L-asparaginase are available in the United States. Native E. coli L-asparaginase remains available in other countries.
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 may be given either intramuscularly (IM) or intravenously (IV). Pharmacokinetics and toxicity profiles are similar for IM and IV PEG-L-asparaginase administration. There is no evidence that IV administration of PEG-L-asparaginase is more toxic than IM administration.[19,20,21]
PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion after a single injection.
Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of PEG-L-asparaginase given either IM or IV as part of multiagent induction results in serum enzyme activity (>0.1 IU/mL) in nearly all patients for at least 2 to 3 weeks.[19,20,23]
Evidence (use of PEG-L-asparaginase instead of native E. coli L-asparaginase):
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase.
Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or PEG-L-asparaginase.
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 to achieve adequate asparagine depletion.
Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):
Response to remission induction chemotherapy
More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-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).[25,29,30]; [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 hematopoietic stem cell transplant (HSCT) once CR is achieved.[32,33,4] In a large retrospective series, the 10-year overall survival for patients with persistent leukemia was 32%. A trend for superior outcome with allogeneic HSCT 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 HSCT compared with chemotherapy alone.
For patients who achieve CR, measures of the rapidity of blast clearance and MRD determinations have important prognostic significance, particularly the following:
(Refer to the Response to initial treatment affecting 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 CNS therapy to prevent CNS relapse in children with newly diagnosed ALL.)
Check the list of NCI-supported 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 and 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 CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia [ALL] who are receiving postinduction therapy.)
Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.
The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:
This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:
Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases:
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.[5,6,7] For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) and vincristine, have been associated with favorable outcomes. Favorable outcomes for standard-risk patients have also been reported by the POG, utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase),[6,9,10] and by the DFCI ALL Consortium utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[11,12]
However, the effects of end-induction and/or consolidation minimal residual disease (MRD) on outcome has influenced the treatment of patients originally diagnosed as National Cancer Institute (NCI) standard risk. Multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis.[13,14,15,16,17] Augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction. Therefore, standard-risk patients with higher levels of end-induction MRD are not treated with the approaches described for standard-risk patients who have low end-induction MRD, but are usually treated with high-risk regimens.
Evidence (intensification for standard-risk ALL):
In high-risk patients, a number of different approaches have been used with comparable efficacy.[11,25]; [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-term 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:[23,35]
COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion is not utilized by other groups.
Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM-backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk 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.[23,36]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, [36,37,38] although it is not clear whether outcomes are better with transplantation.
Evidence (allogeneic HSCT in first remission for very high-risk patients):
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 call for the administration of 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. Studies conducted by the COG have demonstrated significant differences in compliance with 6-mercaptopurine (6-MP) amongst various racial and socioeconomic groups. Importantly, nonadherence to treatment with 6-MP in the maintenance phase was associated with a significant increase in the risk of relapse.[43,44]
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.[45,46] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[45,46] 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):
SJCRH has modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase; low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).
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):
For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents. Dexamethasone has not been associated with an increased frequency of these complications in younger patients.[19,61,62,63,64]
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.[27,63]
Duration of maintenance therapy
Maintenance chemotherapy generally continues until 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls; on others, there is no difference in the duration of treatment based on gender.[11,23] 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.
Adherence to oral medications during maintenance therapy
Nonadherence to treatment with 6-MP during maintenance therapy is associated with a significant risk of relapse.
Evidence (adherence to treatment):
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 of 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 one of the following:
The objective is not to prove superiority of either regimen, but rather, to determine whether 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 12 years or younger. Patients treated on this trial are classified as high risk 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 greater than 1%; and (2) those with favorable cytogenetics and 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.
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.
Patients with very high-risk features are currently not eligible for enrollment on COG-AALL1131. The presence of any of the following features classify a patient as very high risk.
Check the list of NCI-supported 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.
Approximately 3% of patients have detectable central nervous system (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 acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy together with some form of CNS prophylaxis.
Because the CNS is a sanctuary site (i.e., an anatomic space that is poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.
Standard treatment options for CNS-directed therapy include the following:
All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for selective situations.
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 and, in many 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-Directed 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-directed 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 of 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 who do receive 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.[11,12] A meta-analysis of randomized trials of CNS-directed therapy has confirmed that radiation therapy can be replaced by intrathecal chemotherapy in most patients with ALL. Additional systemic therapy may be required depending on the agents and intensity used.[Level of evidence: 1iDi]
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.[11,12,13,14,15,16]
The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[17,18]
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 has decreased over the last 2 decades.
Evidence (cranial radiation):
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).[16,18] Spinal radiation is no longer used.
Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Treatment options under clinical evaluation include the following:
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.[31,32,33,34] 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 have a higher risk of 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.[38,39,40,41,42] At doses of 18 Gy, it does not appear that irradiated patients have more severe neurocognitive impairments than ALL survivors who were treated without radiation. On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose. Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of late effects.
The following groups have been associated with neurocognitive and neuroendocrine sequelae after 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, although high-grade lesions may occur.[28,49,50] 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 after cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
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 10-year overall survival (OS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) DFCI-95001 (NCT00004034) trial was 90.1% compared with 88.7% for patients with B-cell disease. However, in a review of a large number of patients treated on Children's Oncology Group (COG) trials over a 15-year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis.
Treatment options under clinical evaluation for T-cell ALL
Treatment options under clinical evaluation for T-cell ALL include the following:
Check the list of NCI-supported 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 of 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.[13,14,15] Infants diagnosed within the first few months of life have a particularly poor outcome. In one study, patients diagnosed within 1 month of birth had a 2-year OS rate of 20%.[Level of evidence: 2A] In another study, the 5-year EFS for infants diagnosed at younger than 90 days was 16%.[Level of evidence: 2A]
For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[13,14,16,18,19][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include the following:[14,17]; [Level of evidence: 3iDii]
Infants have significantly higher relapse rates than older children with ALL and are at higher risk of developing treatment-related toxicity, especially infection. With current treatment approaches for this population, treatment-related mortality has been reported to occur in about 10% of infants, a rate that is much higher than the rate in older children with ALL.[14,17] On the COG AALL0631 (NCT00557193) trial, an intensified induction regimen resulted in an induction death rate of 15.4% (4 of 26 patients); the trial was subsequently amended to include a less-intensive induction and enhanced supportive care guidelines, resulting in a significantly lower induction death rate (1.6%; 2 of 123 patients) and significantly higher complete remission (CR) rate (94% vs. 68% with the previous, more intensified induction regimen).
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 hematopoietic stem cell transplant (HSCT) during first remission in infants with MLL gene translocations remains controversial.
Evidence (allogeneic HSCT 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
Adolescents and Young Adults With ALL
Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in almost all studies of treatment are inferior in this age group compared with children younger than 10 years.[26,27,28] The reasons for this difference include more frequent presentation of adverse prognostic factors at diagnosis, including the following:
In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of treatment-related mortality [27,28,29,30] and nonadherence to therapy.[29,31]
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.[32,33,34,35,36]; [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 high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.
Evidence (pediatric treatment regimen):
The MD Anderson Cancer Center reported the outcome of 85 patients (aged 12–40 years) treated with the pediatric augmented BFM regimen. Duration of complete remission at 3 years was 70%, and OS was 74%. The regimen was reasonably well tolerated, although there appeared to be a higher incidence of thrombotic complications and grade 3 or 4 hyperbilirubinemia than what is typically observed in younger patients.
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (refer to Table 3).[33,35]; [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.[34,44] Before the use of postinduction intensification for treatment of ALL, osteonecrosis was infrequent. The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.
The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative interventions are needed for management of symptoms and impaired mobility in more than 40% of cases. The majority of the cases are diagnosed within the first 2 years of therapy and often the symptoms are recognized during maintenance.
Treatment options under clinical evaluation for adolescent and young adult patients with ALL
Philadelphia Chromosome–positive ALL
Philadelphia chromosome–positive (Ph+) ALL is seen in about 3% of pediatric ALL cases, increases in adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as extremely difficult to treat with poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS of 25%, with an OS of 36%. In 2010, the same group reported a 7-year EFS of 31% and an overall survival of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors. Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow transplantation, and currently to combination therapy using chemotherapy plus tyrosine kinase inhibitor.
Pre-tyrosine kinase inhibitor era
Before the use of imatinib mesylate, HSCT from a matched sibling donor was the treatment of choice for patients with Ph+ ALL.[47,48,49] 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-tyrosine kinase inhibitor 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 era
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 (tyrosine kinase inhibitor):
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. The results of a phase I trial of dasatinib in pediatric patients indicated that once-daily dosing was associated with an acceptable toxicity profile, with few nonhematologic grade 3 or 4 adverse events.
Check the list of NCI-supported 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 After First Relapse of Childhood ALL
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on multiple factors.[1,2,3,4,5,6,7,8,9,10,11,12,13,14]; [Level of evidence: 3iiDi]
The two most important prognostic risk factors after first relapse of childhood ALL are the following:
Other prognostic factors include the following:
Site of relapse
Patients who have isolated extramedullary relapse fare better than those who have relapse involving the marrow. In some studies, patients with combined marrow/extramedullary relapse had a better prognosis than did those with a marrow relapse; however, other studies have not confirmed this finding.[5,13,16]
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 example, survival rates 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).[13,17] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.
Age 10 years and older at diagnosis has been reported as an independent predictor of poor outcome.[13,16] A Children's Oncology Group (COG) study further showed that although patients aged 10 to 15 years at initial diagnosis do worse than patients aged 1 to 9 years (35% vs. 48%, 3-year postrelapse survival), those older than age 15 years did much worse (3-year OS, 15%; P = .001).
The Berlin-Frankfurt-Münster (BFM) 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.
Children with Down syndrome with relapse of ALL had inferior outcomes as reported in a BFM report before 2000, primarily due to increased induction deaths and treatment-related mortality. However, since 2000, with improvements in supportive care, there have been no differences in outcome between patients with and without Down syndrome. An analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) on 27 Down syndrome patients with ALL who underwent hematopoietic stem cell transplantation (HSCT) between 2000 and 2009 indicated that hematopoietic recovery, graft-versus-host disease (GVHD), and transplant-related mortality were within the expected range for non–Down syndrome ALL patients. In that series, relapse rather than transplant toxicity was the primary cause of treatment failure.[Level of evidence: 3iiiA]
Risk group classification at initial diagnosis
The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.
Response to reinduction therapy
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] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[22,24,25,26]; [Level of evidence: 3iiiDi] High levels of MRD at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse.
Changes in mutation profiles from diagnosis to relapse have been identified by gene sequencing.[28,29] While oncogenic gene fusions (e.g., TCF3-PBX1, ETV6-RUNX1) are present at both diagnosis and relapse, single nucleotide variants and copy number variants may be present at diagnosis, but not at relapse, and vice versa. For example, while RAS family mutations are common at both diagnosis and relapse, the specific RAS family mutations may change from diagnosis to relapse as specific leukemic subclones rise and fall during the course of treatment. By contrast, relapse-specific mutations in NT5C2 (a gene involved in nucleotide metabolism) have been noted in as many as 45% of ALL cases with early relapse.[28,30,31]
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 an increased likelihood of persistent leukemia after initial reinduction (38.5% TP53 alteration vs. 12.5% TP53 wild-type) and poor event-free survival (EFS) (9% TP53 alteration vs. 49% TP53 wild-type). Approximately one-half of the TP53 alterations were present at initial diagnosis and half were newly observed at time of relapse. A second genomic alteration found to predict for poor prognosis in patients with B-precursor ALL in first bone marrow relapse is IKZF1 deletion. The frequency of IKZF1 deletion in B-precursor ALL patients at first relapse patients was 33% in patients in the Acute Lymphoblastic Leukemia Relapse (ALL-REZ) BFM 2002 (NCT00114348 ) study, which was approximately twice as high as the frequency described in children at initial diagnosis of ALL.
RAS pathway mutations (KRAS, NRAS, FLT3, and PTPN11) are common at relapse in B-precursor ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children.[28,34] As observed at diagnosis, the frequency of RAS pathway mutations at relapse differs by cytogenetic subtype (e.g., high frequency in hyperdiploid cases and low frequency in ETV6-RUNX1 cases). The presence of RAS pathway mutations at relapse was associated with early relapse. However, presence of RAS pathway mutations at relapse was not an independent predictor of outcome.
Patients with ETV6-RUNX1-positive ALL appear to have a relatively favorable prognosis at first relapse, consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.[33,35] In the ALL-REZ BFM 2002 (NCT00114348 ) study, an EFS of 84% (± 7%, SE) was observed for patients with ETV6-RUNX1 ALL with bone marrow relapse. In this study, 94% of patients with ETV6-RUNX1 had a duration of first remission that extended at least 6 months beyond completion of their primary treatment, and on multivariate analysis, time to relapse (and not the presence of ETV6-RUNX1) was an independent predictor of outcome. Similarly, the 5-year OS for ETV6-RUNX1 patients enrolled on the French Acute Lymphoblastic Leukaemia (FRALLE) 93 study who relapsed at any site more than 36 months after diagnosis was 81%, and the presence of ETV6-RUNX1 was associated with a favorable survival outcome compared with other late relapsing patients. However, the 3-year OS of ETV6-RUNX1 patients who experienced an early relapse (<36 months) was only 31%.
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 are less likely to achieve a second remission and long-term EFS than are patients with B-cell ALL.[5,22]
Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL
Standard treatment options for first bone marrow relapse include the following:
Initial treatment of relapse consists of reinduction 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%).[22,36]
Evidence (reinduction chemotherapy):
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
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 for patients achieving a second complete remission (CR2)
Early-relapsing B-precursor ALL
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 higher leukemia-free survival than a chemotherapy approach.[7,27,46,47,48,49,50,51,52,53,54] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%. (Refer to the Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse section of this summary for more information.)
Late-relapsing B-precursor ALL
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.[5,9,37,55,56,57]; [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 HSCT) in CR2. Results from one study suggest that patients with a late marrow relapse who have high end-reinduction MRD may have a better outcome if they receive an allogeneic HSCT in CR2.
Evidence (MRD-based risk stratification for late-relapse of B-precursor ALL):
For patients with T-cell ALL who achieved remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor, and these patients are usually treated with allogeneic HSCT in CR2, regardless of time to relapse.
Standard Treatment Options for Second and Subsequent Bone Marrow Relapse
Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant is generally considered a reasonable approach for those achieving remission. Long-term survival for all patients after a second relapse is particularly poor, in the range of less than 10% to 20%. One of the main reasons for this is failure to obtain a third remission. In spite of numerous attempts at novel combination approaches, only about 40% of children with second relapse are able to achieve remission. If these patients achieve CR, HSCT has been shown to cure 20% to 35%, with failures occurring due to high rates of relapse and transplant-related mortality.[61,62,63,64,65][Level of evidence: 3iiA]
Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
Components of the transplantation process
An updated expert panel review of indications for HSCT has been published. Components of the transplant process that have been shown to be important in improving or predicting outcome of HSCT for children with ALL include the following:
TBI-containing transplant preparative regimens
For patients proceeding to allogeneic HSCT, 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 do chemotherapy-only preparative regimens.[46,67,68] Fractionated TBI (total dose, 12–14 Gy) is often combined with cyclophosphamide, etoposide, thiotepa, or a combination of these agents. Study findings with these combinations have generally resulted in similar rates of survival,[69,70,71] although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary. Many standard regimens include cyclophosphamide with TBI dosing between 1.32 and 1.4 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 1.2 Gy resulted in worse survival due to excessive toxicity.
MRD detection just before transplant
Disease status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates. Several studies have also demonstrated that the level of MRD at the time of transplant is a key risk factor in children with ALL in CR undergoing allogeneic HSCT.[25,74,75,76,77,78,79,80][Level of evidence: 3iiA]; [Level of evidence: 3iiB] Survival rates of patients who are MRD-positive pretransplant have been reported between 20% and 47%, compared with 60% to 88% in patients who are MRD-negative.
When patients have received two to three cycles of chemotherapy in an attempt to achieve an MRD-negative remission, the benefit of further intensive therapy for achieving MRD negativity must be weighed against the potential for significant toxicity. In addition, there is not clear evidence showing that MRD positivity in a patient who has received multiple cycles of therapy is a biological disease marker for poor outcome that cannot be modified, or whether further intervention bringing such patients into an MRD negative remission will overcome this risk factor and improve survival. In one report, 13 patients with ALL and high MRD at the time of planned transplant received an additional cycle of chemotherapy in an attempt to lower MRD before proceeding to HSCT. Ten of the 13 patients (77%) remained in CR post-HSCT, with no relapses observed in the eight patients who achieved low MRD after the additional chemotherapy cycle. In comparison, only 6 of 21 high-MRD patients (29%) who proceeded directly to HSCT without receiving additional pre-HSCT chemotherapy remained in CR.
MRD detection posttransplant
The presence of detectable MRD post-HSCT has been associated with an increased risk of subsequent relapse.[80,82,83,84,85] The accuracy of MRD for predicting relapse increases as time from HSCT elapses and for patients who have higher levels of MRD. One study showed higher sensitivity for predicting relapse using next-generation sequencing assays than with flow cytometry, especially early after HSCT.
Donor type and HLA match
Survival rates after matched unrelated donor and umbilical cord blood transplantations have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.[50,86,87,88,89]; [90,91][Level of evidence: 2A]; [Level of evidence: 3iiiA]; [Level of evidence: 3iiiDii] Rates of clinically extensive GVHD and treatment-related mortality remain higher after unrelated donor transplantation compared with matched sibling donor transplants.[51,61,86] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and CIBMTR analyses have demonstrated that rates of GVHD, treatment-related mortality, and OS have improved over time.; [95,96][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]
Role of GVHD/GVL in ALL and immune modulation after transplant to prevent relapse
Most studies of pediatric and young adult patients that address this issue suggest an effect of both acute and chronic GVHD in decreasing relapse.[86,100,101,102] In a COG trial of transplantation for children with ALL, grades I to III acute GVHD were associated with lower relapse risk (hazard ratio [HR], 0.4; P = .04) and better EFS (multivariate analysis, HR, 0.5; P = .02). Any effect of grade IV acute GVHD in decreasing relapse risk was obscured by a marked increase in transplant-related mortality (HR, 6.4; P = .003), while grades I to III acute GVHD had no statistically detectable effect on transplant-related mortality (HR, 0.6; P = .42). On multivariate model, both pretransplant MRD and acute GVHD were independent predictors of relapse, with the lowest risk of relapse observed in patients with both low pretransplant MRD and grades I to III acute GVHD. For patients who did not develop acute GVHD by day 55 post-HSCT, nearly all relapses occurred between days 100 and 400 post-HSCT.
Harnessing this GVL effect, a number of approaches to prevent relapse after transplantation have been studied, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.[103,104] Trials in Europe and the United States have shown that patients defined as having a high risk of relapse based upon increasing recipient chimerism (i.e., increased percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression without excessive toxicity.[105,106] One study showed that in 46 patients with increasing recipient chimerism, the 31 patients who underwent immune suppression withdrawal, donor lymphocyte infusion, or both therapies had a 3-year EFS of 37% versus 0% in the nonintervention group (P < .001). Other studies have shown better-than-expected rates of survival of pre-HSCT, MRD-positive patients when tapering has occurred for MRD detected after HSCT.
Intrathecal medication after HSCT to prevent relapse
The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial.[109,110,111,112]
Relapse after allogeneic HSCT for relapsed ALL
For patients relapsing after an allogeneic HSCT for 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.[113,114,115]; [65,116][Level of evidence: 3iiA] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with CR at the time of the second HSCT.[114,115,117] In addition, one study showed an improvement in survival after second HSCT if acute GVHD occurred, especially if it had not occurred after the first transplant.
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 Isolated 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%.[123,124,125] As with bone marrow and mixed relapses, time from initial diagnosis to relapse is a key prognostic factor in isolated extramedullary relapses. In addition, age older than 6 years at diagnosis was noted to be an adverse prognostic factor for patients with an isolated extramedullary relapse in one study. Of note, 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 (5-year EFS, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS, 60%).
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.[17,126,129,130]
Evidence (chemotherapy and radiation therapy):
A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.[131,132] The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.
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 in North America 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 intensive chemotherapy that includes high-dose methotrexate. Patients who do not respond with a CR after induction also receive local 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. A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease. 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.
Evidence (treatment of testicular relapse [case reports]):
Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
Trials for ALL in first relapse
Treatment options under clinical evaluation for ALL in first relapse include the following:
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.
Chimeric Antigen Receptor (CAR) T-cell Therapy
CAR T-cell therapy is a new strategy under clinical investigation for the treatment of relapsed and refractory ALL in second or subsequent relapse. This strategy includes engineering T cells with a chimeric antigen receptor (CAR) that redirects T-cell specificity and function. One widely utilized target of CAR-modified T cells is the CD19 antigen expressed on almost all normal B cells and most B-cell malignancies. Several clinical trials of CAR T cells targeting CD19 in relapsed/refractory ALL are being conducted, with encouraging initial results:
Check the list of NCI-supported 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.
General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
Added text to state that germline ETV6 variations have been associated with predisposition to childhood ALL (cited Moriyama et al. as reference 36).
Risk-Based Treatment Assignment
The Weight at diagnosis and during treatment subsection was renamed from Obesity at diagnosis.
Added text to state that in a study of 762 pediatric patients with ALL, the Dutch Childhood Oncology Group found that those who were underweight at diagnosis had an almost twofold higher risk of relapse compared with non-underweight patients, although this did not result in a difference in event-free survival or overall survival (OS). Patients with loss of body mass index during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse (cited den Hoed et al. as reference 81).
Added text to state that whole-genome sequencing has determined that cases of infant ALL with MLL gene rearrangements have few additional genomic alterations, none of which have clear clinical significance (cited Andersson et al. as reference 168).
Revised text to state that the t(1;19) translocation may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B ALL immunophenotype (cited Fischer et al. as reference 171).
Added text about the TCF3-HLF gene fusion (cited Minson et al. as reference 176).
Revised text to state that genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-precursor ALL and they represent approximately 50% of cases of Philadelphia chromosome–like ALL .
Treatment for Newly Diagnosed Childhood ALL
Added Place et al. as reference 21.
Added text about the results of a randomized comparison of intravenous (IV) PEG-L-asparaginase versus intramuscular native E. coli asparaginase (added level of evidence 1iiC).
Added text to state that a trial of IV Erwinia L-asparaginase given on Monday-Wednesday-Friday schedule to patients with an allergy to PEG-L-asparaginase demonstrated therapeutic serum asparaginase enzyme activity in 83% of patients 48 hours after a dose but in only 43% of patients 72 hours after a dose. If IV Erwinia is given on a Monday-Wednesday-Friday schedule, the authors suggest that 72-hour nadir enzyme activity levels be monitored to ensure therapeutic levels (cited Vrooman et al. as reference 28).
Postinduction Treatment for Childhood ALL
Added text to state that the frequency of grade 3 and 4 toxicities that occurred during therapy on the POG-9404 trial was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms. Three years after initial diagnosis, left ventricular shortening fraction and left ventricular wall thickness were both significantly worse in patients who received doxorubicin alone than in patients who received dexrazoxane, indicating that dexrazoxane was cardioprotective (cited Asselin et al. as reference 33).
CNS-Directed Therapy for Childhood ALL
Added text about a meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups that showed that the use of cranial radiation therapy did not appear to impact 5-year overall survival or cumulative incidence of any event (cited Vora et al. as reference 25).
Treatment of Relapsed Childhood ALL
Revised text to state that in some studies, patients with combined marrow/extramedullary relapse had a better prognosis than did those with a marrow relapse; however, other studies have not confirmed this finding (cited Masurekar et al. as reference 16).
Added hematopoietic stem cell transplantation as a standard treatment option for childhood ALL that has recurred in the central nervous system.
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 NCI website's Email Us. 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.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389206]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2016-03-30
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