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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.
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975. Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,2,3] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,2,3] 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. Childhood and adolescent cancer survivors require close monitoring 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.)
ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[2,3] In the United States, ALL occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years. There are approximately 3,100 children and adolescents younger than 20 years diagnosed with ALL each year in the United States. Since 1975, there has been a gradual increase in the incidence of ALL.[4,6]
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.[2,3] 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.[2,3]
The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[2,3,7,8] 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.[2,3,7]
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:
Almost all patients with ALL 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 and associated genes (when relevant) include the following:
Children with Down syndrome have an increased risk of developing both ALL and AML,[20,21] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[20,21]
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.[22,23,24] 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.[22,23]
Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21)(p13;q22)/ETV6-RUNX1 [TEL-AML1]) and hyperdiploidy [51-65 chromosomes]) and unfavorable (t(9;22)(q34;q11.2)) or t(4;11)(q21;q23) and hypodiploidy [<44 chromosomes]) cytogenetic findings and a near absence of T-cell phenotype.[22,23,24,25,26]
Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin.[27,28,29]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with precursor B-cell ALL who do not have Down syndrome.[29,30,31] Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[26,28] 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.[28,32]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[27,28,33,34,35] 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 precursor B-cell ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[27,28,29] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[28,34] but more study is needed to address this issue, as well as the prognostic significance of CRLF2 alterations and IKZF1 gene deletions in this patient population.
Low- and high-penetrance inherited genetic variants
Genetic predisposition to ALL can be divided into the following several broad categories:
Prenatal origin of childhood ALL
Development of ALL is in most cases a multistep 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 to support 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.[49,50] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[49,50,51] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[49,52]
Evidence also exists 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 [55,56] this finding, and methodological issues related to fluorescence in situ hybridization testing complicate interpretation of the initial 1% estimate.
The typical and atypical symptoms and clinical findings of childhood ALL have been published.[58,59,60]
The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[58,59,60,61]
The 2016 revision to the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:
Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/genomics alterations section of this summary.
Overall Outcome for ALL
Among children with ALL, approximately 98% attain remission, and approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years.[63,64,65,66]
Despite the treatment advances 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 and 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
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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]
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, the presence or absence of extramedullary disease, steroid pretreatment, the presence or absence of Down syndrome, and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification for B-cell ALL 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 and genomic alterations. Detection of the Philadelphia chromosome leads to immediate changes in induction therapy.
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. Factors affecting prognosis 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. 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 and clinical disease characteristics
Patient and clinical disease 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:
Up to 80% of infants with ALL have a translocation of 11q23 with numerous chromosome partners generating an MLL (KMT2A) gene rearrangement.[9,11,13,14] The most common rearrangement is MLL (KMT2A)-AFF1 (t(4;11)(q21;q23)), but MLL rearrangements with many other translocation partners are observed.
The rate of MLL (KMT2A) gene rearrangements is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL rearrangements decreases but remains higher than that observed in older children.[9,15] Black infants with ALL are significantly less likely to have MLL rearrangements than are white infants.
Infants with leukemia and MLL (KMT2A) rearrangements typically have very high WBC counts and an increased incidence of CNS involvement. Event-free survival (EFS) and overall survival (OS) are poor, with 5-year EFS and OS rates of only 35% to 40% for infants with MLL-rearranged ALL.[9,10,11] A comparison of the landscape of somatic mutations in infants and children with MLL-rearranged ALL revealed significant differences between the two groups, suggesting distinctive age-related biological behaviors for MLL-rearranged ALL that may relate to the significantly poorer outcome for infants.[16,17]
Blasts from infants with MLL (KMT2A) rearrangements are often CD10 negative and express high levels of FLT3.[9,10,14,18] 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 rearrangements.[9,10,14,19]
(Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)
Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants.[3,7,20,21,22] 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 to 65 chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21)(p13;q22), also known as the TEL-AML1 translocation).[7,23,24]
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.[25,26,27] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975-1984) to 72% (2003-2009).[28,29,30]
Multiple retrospective studies have established that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[31,32,33] (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 precursor B-cell 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 precursor B-cell ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[34,35,36,37,38,39,40,41]
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.[42,43] Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 patients,[44,45] while others have not.[42,46,47,48]
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,[42,47,49] but not others.[45,46,50] 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 (KMT2A) gene rearrangements.[42,46,47]
Most clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[42,51,52]; [Level of evidence: 2A]
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.[54,55] 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.[56,57,58,59,60] In some studies, the lower EFS and OS of children with Down syndrome appear to be related to increased frequency of treatment-related mortality, as well as higher rates of induction failure and relapse in Down syndrome patients.[56,57,58,59,61,62] The inferior anti-leukemic outcome may be due, in part, to favorable biological features such as ETV6-RUNX1 or hyperdiploidy (51-65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.[61,62]
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[69,70,71] 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.[69,70,71] While some reports describe outcomes for boys as closely approaching those of girls,[22,51,72] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[21,28,29,73]
Race and ethnicity
Over the last several decades in the United States, survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[74,75]
The following factors associated with race and ethnicity influence survival:
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.
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 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 MYC gene translocation identical to those seen in Burkitt lymphoma (i.e., t(8;14)(q24;q32), t(2;8)) that join MYC to one of the immunoglobulin genes. 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 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics.[89,90] (Refer to the Diagnosis section of this summary for more information.)
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 (KMT2A) rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[9,91] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.
The major immunophenotypic 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 (KMT2A) 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)(q21;p13) translocation with TCF3-PBX1 (previously known as E2A-PBX1) fusion (see below).[93,94]
Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, 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 an 8q24 translocation involving MYC), 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 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:[20,36,72]
With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that of children with B-lineage ALL.[20,36,39,40,72]
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.[35,36,37,38,39,40,41,96] 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, 51-65 chromosomes) are rare in T-cell ALL.[98,99]
Multiple chromosomal translocations have been identified in T-cell ALL, with structural chromosome rearrangements fusing many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) to one of the T-cell receptor loci and resulting in aberrant expression of these transcription factors in leukemia cells.[98,100,101,102,103,104] These translocations are often not apparent by examining a standard karyotype, but can be 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 t(10;14)(q24.3;q11.2) 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.[100,101,102,104] Overexpression of TLX3/HOX11L2 resulting from the cryptic t(5;14)(q35;q32) 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,[107,108,109,110] while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.[106,111,112,113]
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.[114,115,116] 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,[114,115,117] although clinical experience with this strategy is very limited.[118,119,120]
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-cell 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.[121,123,124] 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%). Similarly, the COG AALL0434 trial observed similar 5-year EFS rates for early T-cell precursor cases and non-early T-cell precursor cases, with both at approximately 87%. Further study in additional patient cohorts is needed to firmly establish the prognostic significance of early T-cell precursor ALL, but most ALL treatment groups do not change patient treatment based on early T-cell precursor status.
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.[127,128] 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 (KMT2A) rearrangements and those with the ETV6-RUNX1 gene rearrangement.[129,130] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[129,130]
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.[131,132,133] 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.[134,135,136] 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 precursor B-cell ALL. Some chromosomal alterations 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)(q34;q11.2)), rearrangements of the MLL (KMT2A) gene, hypodiploidy, and intrachromosomal amplification of the AML1 gene (iAMP21).
In recognition of the clinical significance of many of these genomic alterations, the 2016 revision of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for precursor B-cell ALL:
These and other chromosomal and genomic abnormalities for childhood ALL are described below.
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 fluorescence in situ hybridization (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 white blood cell [WBC] count) and is itself an independent favorable prognostic factor.[24,139,140] Within the hyperdiploid range of 51 to 65 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.[142,143]
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 National Cancer Institute (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)(q34;q11.2)) 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.[148,149,150] 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.[148,150]
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.[147,152] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells. One study of 20 patients with near-haploid or low-hypodiploid ALL indicated that MRD may have prognostic significance in the hypodiploid population.
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 is present in 20% to 25% of cases of precursor B-cell ALL but is rarely observed in T-cell ALL. The t(12;21)(p12;q22) produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[156,157] Hispanic children with ALL have a lower incidence of t(12;21)(p13;q22) than do white children.
Reports generally indicate favorable event-free survival (EFS) and overall survival (OS) in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[159,160,161,162,163]
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.[163,164] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other precursor B-cell ALL.[159,165] 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)(p13;q22) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[168,169]
The Philadelphia chromosome t(9;22)(q34;q11.2) 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). Figure 2. The Philadelphia chromosome is a translocation between the ABL-1 oncogene (on the long arm of chromosome 9) and the breakpoint cluster region (BCR) (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL1. BCR-ABL1 encodes an oncogenic protein with tyrosine kinase activity.
This subtype of ALL is more common in older children with precursor B-cell ALL and high WBC count, with the incidence of the t(9;22)(q34;q11.2) increasing to about 25% in young adults with ALL.
Historically, the Philadelphia chromosome t(9;22)(q34;q11.2) 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.[146,170,171,172] Inhibitors of the BCR-ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL. A study by the Children's Oncology Group (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.[174,175]
Rearrangements involving the MLL (KMT2A) gene occur in approximately 5% of childhood ALL cases overall, but in up to 80% of infants with ALL. These rearrangements are generally associated with an increased risk of treatment failure.[91,176,177,178] The t(4;11)(q21;q23) is the most common rearrangement involving the MLL gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[176,179]
Patients with the t(4;11)(q21;q23) are usually infants with high WBC counts; they are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy. While both infants and adults with the t(4;11)(q21;q23) are at high risk of treatment failure, children with the t(4;11)(q21;q23) appear to have a better outcome than either infants or adults.[91,176] Irrespective of the type of MLL (KMT2A) 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.[91,176] 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)(q23;p13.3) involving MLL (KMT2A) 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) is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19).
The t(1;19) 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.[93,94] The t(1;19) 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 relatively more likely than white children to have pre-B ALL with the t(1;19).
The t(1;19) 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.[94,185] However, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) on which all patients were treated without cranial radiation, patients with the t(1;19) 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.[51,186]
The t(17;19) 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), 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).
Approximately 5% of standard-risk and 10% of high-risk pediatric precursor B-cell ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[188,189] The frequency in older adolescents (aged >15 years) is approximately 10%. The most common rearrangement produces IGH-DUX4 fusions, with ERG-DUX4 fusions also observed. Approximately 50% of DUX4-rearranged cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes,[188,189] and DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with these focal deletions in ERG.[190,191,192]IKZF1 alterations are observed in 35% to 40% of DUX4-rearranged ALL.[188,189]ERG deletion connotes an excellent prognosis, with OS exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.[190,191,192] Patients with DUX4 rearrangements who lack ERG deletion also appear to have favorable prognosis.
Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 4% of childhood ALL cases.[193,194] Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[193,195] The interstitial deletion producing the MEF2D-BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D-CSFR1 that have a Philadelphia chromosome (Ph)-like gene expression profile.[193,196] The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[193,194] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS was 72% (standard error, ±10%), which was inferior to that for other patients.
ZNF384 is a transcription factor that is rearranged in approximately 4% to 5% of pediatric B-cell ALL cases.[193,197,198] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[193,197,198]ZNF384 rearrangement does not appear to confer independent prognostic significance.[193,197,198] The immunophenotype of B-cell ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[197,198] Cases of mixed phenotype B/myeloid acute leukemia that have ZNF384 gene fusions have been reported, but it is unclear whether the clinical behavior of these cases is the same as that of ZNF384-rearranged B-cell ALL.[199,200]
This entity is included in the 2016 revision of the WHO classification of tumors of the hematopoietic and lymphoid tissues. The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IL3-IGH fusion as the underlying genetic basis for the condition.[201,202] The joining of the IGH locus to the promoter region of the interleukin-3 gene (IL3) leads to dysregulation of IL3 expression. Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IL3-IGH fusion.
The number of cases of IL3-IGH ALL described in the published literature is too small to assess the prognostic significance of the IL3-IGH fusion.
iAMP21 with multiple extra copies of the RUNX1 (AML1) gene at 21q22 occurs in approximately 2% of precursor B-cell ALL cases and is associated with older age (median, approximately 10 years), presenting WBC of less than 50 × 109 /L, a slight female preponderance, and high end-induction minimal residual disease (MRD).[205,206,207]
The United Kingdom (UK)-ALL clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS, 29%). In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS, 78%). Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS, 73% vs. 80%). On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients. The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for SCT in first remission.
PAX5 amplification was identified in approximately 1% of B-cell ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations. Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5 amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%-61%), and the OS rate was 67% (95% CI, 54%-77%), suggesting a relatively poor prognosis for this B-cell ALL subtype.
BCR-ABL1-negative patients with a gene expression profile similar to BCR-ABL1-positive patients have been referred to as BCR-ABL1-like.[209,210,211] This occurs in 10% to 20% of pediatric ALL patients, increasing in frequency with age, and has been associated with a poor prognosis and with IKZF1 deletion or mutation.[209,210,212,213,214] The 5-year EFS rate of 90% observed in one study of 40 patients with BCR-ABL1-like ALL suggested that the adverse prognostic significance of this subtype may be abrogated when patients are treated with risk-directed therapy based on MRD levels. Six of these 40 patients were classified as high risk and all proceeded to allogeneic SCT.[Level of evidence: 2A]
The hallmark of BCR-ABL1-like ALL is activated kinase signaling, with 50% containing CRLF2 genomic alterations [211,216] and half of those cases containing concomitant JAK mutations. Additional information about BCR-ABL1-like ALL cases with CRLF2 genomic alterations is provided below.
Many of the remaining cases of BCR-ABL1-like ALL have been noted to have a series of translocations with a common theme of involvement of kinases, including ABL1, ABL2, CSF1R, JAK2, and PDGFRB.[212,217] 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.
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 precursor B-cell ALL; they represent approximately 50% of cases of BCR-ABL1-like ALL.[218,219,220] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IgH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8-CRLF2 fusion.[213,216,218,219]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[63,213,216,219,221] they are also more common in children with Down syndrome. Point mutations in tyrosine kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing 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.[216,218,219,222,223] 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-ABL1-like expression signatures were associated with unfavorable outcome. Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed based on CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[222,223]
Approximately 9% of BCR-ABL1-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR). The C-terminal region of the receptor that is lost is the region that is mutated in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development.
IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of precursor B-cell ALL cases. Less commonly, IKZF1 can be inactivated by deleterious point mutations. Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore, more common in NCI high-risk patients than in NCI standard-risk patients.[210,221,225,226] A high proportion of BCR-ABL1 cases have a deletion of IKZF1,[221,227] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in Ph-like (BCR-ABL1-like) ALL (see above).[190,209,221]
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.[190,209,210,214,221,228,229,230,231,232]; [Level of evidence: 2Di] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERG deletion.
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[234,235,236] For example, patients with mutant phenotypes of thiopurine methyltransferase (TPMT, a gene involved in the metabolism of thiopurines, such as mercaptopurine [6-MP]), 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.[238,239] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[240,241]
Germline variants in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[240,242] The variants are most common in East Asians and Hispanics, and they are rare in Europeans and Africans. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[240,243]
Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.
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.[246,247] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; it is unknown whether individualized dose modification based on these findings will improve outcome.
Response to initial treatment
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 Ig/T-cell receptor gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[160,250,251] 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.[160,249,250,251]
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.[160,249,253]; [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 EFS compared with other patients.[251,252]
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 precursor B-cell 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). The excellent outcomes in patients with low MRD at the end of induction is sustained for more than 10 years from diagnosis.
Modifying therapy based on MRD determination has been shown to improve outcome.
Compared with previous trials conducted by the same group, therapy was deintensified for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS (87%) and OS (92%) were superior to the previous Dutch studies.
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.[160,260]
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.[20,261] 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.
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.
Marrow morphology at the end of induction (induction 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 1% to 2% of children with ALL.[21,22,264,265]
Patients at highest risk of induction failure have one or more of the following features:[266,267]
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 precursor B-cell ALL between the ages of 1 and 5 years without adverse cytogenetics (MLL [KMT2A] rearrangement or BCR-ABL1). 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 CR than those who received further treatment with chemotherapy alone.
Some investigators have suggested that the definition of induction failure should be expanded to include end-of-induction MRD of more than 5%, regardless of morphologic findings. In the UKALL2003 (NCT00222612) study, 59 of 3,113 patients (1.9%) had morphologic induction failure; the 5-year EFS was 51%, and the OS was 58%. However, 2.3% of patients had a morphologic remission, with MRD of 5% or more measured by real-time quantitative IgH-T-cell receptor (TCR) PCR; this group had a 5-year EFS of 47%, similar to those with morphologic induction failure. The authors suggest that using both morphologic and MRD criteria to define induction failure more precisely identifies patients with poor outcomes.
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 cytogenetics and genomic lesions 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%.[4,51,261,269,270] 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%.[4,160]
Patients who are at very high risk of treatment failure include the following: [271,272,273,274]
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)(q34;q11.2) or the t(4;11)(q21;q23) 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 precursor B-cell 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 precursor B-cell ALL:
The four risk groups for precursor B-cell 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 the Total XV 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)
DFCI ALL 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL): Patients are assigned an initial risk group by day 10 of therapy on the basis of presenting features and leukemia biology:
Patients with BCR-ABL1 are removed from protocol therapy at day 15. The final risk group is based on the initial risk group and MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 of therapy (second time point):
Special Considerations for the Treatment of Children With Cancer
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 a multidisciplinary team in cancer centers or hospitals with all of the necessary pediatric supportive care facilities.  A 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:
Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy 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.[2,3,4,5] 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.
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 more intensive therapy that may increase their chance of cure. (Refer to the Risk-Based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.)
Phases of Therapy
Treatment for children with ALL is typically divided as follows:
Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that are poorly penetrated by many of the orally and intravenously 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)
At diagnosis, approximately 3% of patients have CNS3 disease (defined as cerebrospinal fluid specimen with ≥5 white blood cells/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. 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 ALL 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.[6,7] 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 precursor B-cell ALL achieve CR by the end of this phase, with somewhat lower rates in infants and in noninfant patients with T-cell ALL or high presenting leukocyte counts.[1,2,3,4,5]
Induction chemotherapy typically consists of the following drugs, with or without an anthracycline (either doxorubicin or daunorubicin):
The Children's Oncology Group (COG) protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to National Cancer Institute (NCI) standard-risk B-cell ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-cell ALL and all T-cell ALL patients. Other groups use a four-drug induction for all patients.[1,2,3]
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy, although controversy exists as to whether dexamethasone benefits all subsets of patients. Some trials also suggest that dexamethasone during induction may be associated with more toxicity than prednisone, including higher rates of infection, myopathy, and behavioral changes.[1,6,7,8] The COG reported that dexamethasone during induction was associated with a higher risk of osteonecrosis in older children (aged >10 years), although this finding has not been confirmed in other randomized studies.[1,7]
Evidence (dexamethasone vs. prednisone during induction):
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.
Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:
Only pegaspargase and Erwinia L-asparaginase are available in the United States. Native E. coli L-asparaginase remains available in other countries.
Pegaspargase, a form of L-asparaginase in which the E. 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 treated in the United States and Western Europe.
Pegaspargase may be given either intramuscularly (IM) or intravenously (IV). Pharmacokinetics and toxicity profiles are similar for IM and IV pegaspargase administration. There is no evidence that IV administration of pegaspargase is more toxic than IM administration.[11,12,13]
Pegaspargase 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 pegaspargase given either IM or IV as part of multiagent induction results in serum enzyme activity of more than 0.1 IU/mL in nearly all patients for at least 2 to 3 weeks.[11,12,15,16]
Evidence (use of pegaspargase instead of native E. coli L-asparaginase):
Patients with an allergic reaction to pegaspargase are typically switched to Erwinia L-asparaginase. Measurement of SAA levels after a mild or questionable reaction to pegaspargase may help to differentiate patients for whom the switch to Erwinia is indicated (because of inadequate SAA) versus those for whom a change in preparation may not be necessary.[17,18]
Several studies have identified a subset of patients who experience silent inactivation of asparaginase, defined as absence of therapeutic SAA levels without overt allergy.[19,20] In a trial conducted by the Dana-Farber Cancer Institute (DFCI) Consortium, 12% of patients treated initially with native E.coli L-asparaginase demonstrated silent inactivation; these patients had a superior EFS if their asparaginase preparation was changed. The frequency of silent inactivation in patients initially treated with pegaspargase appears to be low (<10%).[13,19] Determination of the optimal frequency of pharmacokinetic monitoring for pegaspargase-treated patients, and whether such screening impacts outcome, awaits further investigation.
Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or pegaspargase.
The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or pegaspargase (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):
Anthracycline during induction
The COG protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to NCI standard-risk B-cell ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-cell ALL and all T-cell ALL patients. Other groups use a four-drug induction for all patients.[1,2,3]
In induction regimens that include an anthracycline, either daunorubicin or doxorubicin are typically utilized. In a randomized trial comparing the two agents during induction, there were no differences 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]
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 caused by infection) and the other half will have resistant disease (persistent morphologic leukemia).[24,25,26]; [Level of evidence: 3iA]
Most 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.[28,29,4] In a large retrospective series, the 10-year OS 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 precursor B-cell patients younger than 6 years. Precursor B-cell ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL (KMT2A) rearrangement, BCR-ABL1) 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 section of this summary for more information.)
(Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with newly diagnosed ALL.)
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 ALL 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 B-cell 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.[6,7,8] 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 Pediatric Oncology Group (POG), utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase),[7,10,11] and by the DFCI ALL Consortium utilizing multiple doses of pegaspargase (20-30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[12,13]
However, the prognostic impact of end-induction and/or consolidation minimal residual disease (MRD) 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.[14,15,16,17,18] 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.[12,26]; [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):
Because treatment for high-risk ALL involves more intensive therapy, leading to a higher risk of acute and long-term toxicities, a number of clinical trials have tested interventions to prevent side effects without adversely impacting EFS. Interventions that have been investigated include the use of the cardioprotectant dexrazoxane (to prevent anthracycline-related cardiac toxic effects) and alternative scheduling of corticosteroids (to reduce the risk of osteonecrosis).
Evidence (cardioprotective effect of dexrazoxane):
Evidence (reducing risk of osteonecrosis):
(Refer to the Osteonecrosis section of this summary for more information.)
Very high-risk ALL
Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:[24,35]
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.[24,36]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.[36,37,38,39] However, there are limited data regarding the outcome of very high-risk patients treated with allogeneic HSCT in first CR. Controversy exists regarding which subpopulations could potentially benefit from HSCT.
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 practice generally calls for the administration of oral mercaptopurine in the evening, based on evidence from older studies 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 mercaptopurine (6-MP) amongst various racial and socioeconomic groups. Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase was associated with a significant increase in the risk of relapse.[43,44]
Some patients may develop severe hematologic 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 hematologic toxicity than do patients who are homozygous for the normal allele. Polymorphisms of the NUDT15 gene, observed most frequently in East Asian and Hispanic patients, have also been linked to extreme sensitivity to the myelosuppressive effects of mercaptopurine.[47,48]
Evidence (maintenance therapy):
Based on these findings, 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 contemporary multiagent chemotherapy 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.[20,64,65,66,67]
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.[27,66]
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 sex.[12,24] 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 mercaptopurine 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.
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
COG studies for precursor B-cell ALL
All patients will receive a three-drug induction (dexamethasone, vincristine, and IV pegaspargase) with intrathecal chemotherapy. Postinduction therapeutic questions have been answered for low-risk and average-risk patients, and trials have met accrual goals and are closed; protocol therapy ends after the first month of therapy for all patients, except for those with Down syndrome who have low bone marrow MRD on day 29. The study objective is to describe the outcome of standard-risk Down syndrome patients treated with a standardized treatment and enhanced supportive care. Non-Down syndrome patients on this study who are found to have high-risk features are eligible to enroll on COG-AALL1131 after induction.
High-risk and very high-risk ALL
This protocol is open to B-cell ALL patients aged 30 years or younger. Patients on this trial are classified as high risk if they are:
Patients are classified as very high risk if they meet any of the following criteria:
Patients on this trial receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV pegaspargase) with intrathecal chemotherapy. Patients younger than 10 years receive 2 weeks of dexamethasone during induction, and those aged 10 years and older receive 4 weeks of prednisone.
For high-risk patients, postinduction therapy consists of a modified augmented BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase. The study compares triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate in a randomized fashion to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS. Patients identified as having BCR-ABL1-like ALL and who have a gene fusion involving a kinase that is sensitive to dasatinib (e.g., ABL1, ABL2, CSF1F, and PDGFRB) are assigned to treatment with dasatinib added to standard chemotherapy. Dasatinib treatment is initiated after induction therapy is complete, and it continues through maintenance therapy.
For very high-risk patients, the study had evaluated whether intensification of the consolidation phase and second-half of delayed intensification phases improved DFS. However, that portion of the trial was closed when a futility boundary was crossed, indicating that the study would not be able to demonstrate the superiority of the experimental arm. Therefore, very high-risk patients are removed from protocol therapy at the end of induction.
Patients are assigned an initial risk group by day 10 of therapy. Patients are considered initial very high risk if any of the following are present: IKZF1 deletion, MLL gene rearrangement, or low hypodiploidy (<40 chromosomes). Patients are considered initial low risk if they meet all of the following criteria: B-cell ALL, aged 1 year to younger than 15 years, WBC count less than 50 × 109, CNS1 or CNS2, absence of iAMP21, and absence of very high-risk features. Initial high-risk patients include all other patients lacking very high-risk features, including all patients with T-cell ALL.
Intensity of induction depends on initial risk group. Initial low-risk patients receive a three-drug induction (no anthracycline). All other patients receive a four-drug induction (with anthracycline).
Final risk group, which determines the intensity of postinduction therapy, is assigned based on MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 (second time point).
Treatment for all risk groups includes 30 weeks of pegaspargase (15 doses given every 2 weeks) during postinduction therapy. All final low-risk/high-risk patients are eligible to participate in a randomized comparison of postinduction pegaspargase dosing: standard dose (2,500 IU/m2 /dose) or pharmacokinetic-adjusted reduced dose (starting dose: 2,000 IU/m2). In all patients, nadir serum asparaginase activity (NSAA) is checked before each pegaspargase dose; any patient found to have a nondetectable NSAA is switched to Erwinia asparaginase. On the pharmacokinetic-adjusted reduced-dose arm, the dose may be decreased further to 1,750 IU/m2 if NSAA is found to be extremely high (>1.0 IU/mL) after the fourth pegaspargase dose; the dose will be increased up to standard dose (2,500 IU/m2) if NSAA is low but detectable (<0.4 IU/mL) at any time point. The trial is also piloting a strategy to rechallenge patients with grade 2 hypersensitivity reactions to pegaspargase with pharmacokinetic-monitoring to determine whether such patients will switch to Erwinia or may continue to receive pegaspargase with premedication.
At diagnosis, approximately 3% of patients have central nervous system 3 (CNS3) disease (defined as cerebrospinal fluid [CSF] specimen with ≥5 white blood cells [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. 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 radiation, the cranial radiation dose has been significantly reduced and administration of spinal irradiation is not standard.
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.[11,12,14,15,16,17]
The use of cranial radiation is not a necessary component of CNS-directed therapy for these patients.[18,19] Some regimens use triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone), while others use intrathecal methotrexate alone throughout therapy.
Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
CNS Therapy for High-risk and Very High-risk Patients
Controversy exists as to whether high-risk and very 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).[17,19] Spinal radiation is no longer used.
Larger prospective studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Toxicity of CNS-Directed Therapy
Toxic effects of CNS-directed therapy for childhood ALL can be acute and subacute or late developing. (Refer to the Late Effects of the Central Nervous System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Acute and subacute toxicities
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. Intrathecal and high-dose intravenous methotrexate has also been associated with a stroke-like syndrome, which, in most cases, appears to be reversible.
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.
Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.
Subsequent neoplasms are observed primarily in survivors who received cranial radiation. Meningiomas are common and typically of low malignant potential, but high-grade lesions also occur. In a SJCRH retrospective study of more than 1,290 ALL patients who had never relapsed, the 30-year cumulative incidence of a subsequent neoplasm occurring in the CNS was 3%; excluding meningiomas, the 30-year cumulative incidence was 1.17%. Nearly all of these CNS subsequent neoplasms occurred in previously irradiated patients.
Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy. In general, patients treated without cranial radiation 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.[30,31,32,33] For patients who receive cranial radiation therapy, the frequency and severity of toxicities appear dose-related; patients treated with 18 Gy of cranial radiation therapy appear to be at lower risk for severe impairments compared with those treated with doses of 24 Gy or higher. Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.
Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments. 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. In a SJCRH study of nonirradiated long-term survivors, treatment with dexamethasone was associated with increased risk for impairments in attention and executive function. Conversely, 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.
Evidence (neurocognitive late effects of cranial radiation):
Evidence (neurocognitive late effects in nonirradiated patients):
Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. 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. However, 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. Another example is the COG trial for T-cell ALL (AALL0434 [NCT00408005]) that observed a 4-year disease-free survival (DFS) of 89.3%.
Treatment options for T-cell ALL
Treatment options under clinical evaluation for T-cell ALL
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
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.[18,19,20]
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 (KMT2A) gene rearrangement, the EFS rates continue to be in the 35% range.[18,19,20,22][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL rearrangements include the following:[19,20]; [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.[19,20] 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 withMLL(KMT2A) rearrangements
Infants with MLL (KMT2A) gene rearrangements 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 [KMT2A] rearrangements):
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with MLL (KMT2A) gene rearrangements remains controversial.
Evidence (allogeneic HSCT in first remission for infants with MLL [KMT2A] rearrangements):
Treatment options for infants withoutMLL(KMT2A) rearrangements
The optimal treatment for infants without MLL (KMT2A) rearrangements also remains unclear.
Treatment options under clinical evaluation for infants with ALL
The following is an example of national and/or institutional clinical trial that is currently being conducted:
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.[29,30,31] 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 [30,31,32,33] and nonadherence to therapy.[32,34]
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.[35,36,37,38,39,40,41,42]; [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 (use of a pediatric treatment regimen for adolescents and young adults with ALL):
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (refer to Table 3).[36,38,41,42]; [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.[37,49] 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
This protocol is open to patients aged 30 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-ABL1 (Ph+) are treated on a separate clinical trial.
Patients on this trial receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and intravenous pegaspargase) with intrathecal chemotherapy. Patients younger than 10 years receive 2 weeks of dexamethasone during induction, and those aged 10 years and older receive 4 weeks of prednisone. Postinduction therapy consists of a modified augmented BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase.
For high-risk patients, the study compares triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate in a randomized fashion to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS.
The presence of any of the following features classify a patient as very high risk on COG-AALL1131.
For very high-risk patients, the AALL1131 study initially evaluated whether intensification of the last 4 weeks of consolidation/intensification improved outcome. However, that portion of the trial was closed when a futility boundary was crossed, indicating that the study would not be able to demonstrate the superiority of the experimental arm. Therefore, very high-risk patients are removed from protocol therapy at the end of induction.
Philadelphia Chromosome-positive (BCR-ABL1-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 a 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. 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 (PCR) for the BCR-ABL1 fusion transcript may also be useful to help predict outcome for Ph+ patients.[55,56,57]
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.[58,59]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[60,61,62] Outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[63,64,65,66,67] Clinical trials have also demonstrated that many pediatric Ph+ ALL patients can be successfully treated without transplant using a combination of intensive chemotherapy and a tyrosine kinase inhibitor.[67,68]
Evidence (tyrosine kinase inhibitor):
Dasatinib, a second-generation inhibitor of tyrosine kinases, has also been 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.
Treatment options under clinical evaluation for Ph+ ALL
Standard-risk patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy (2 years of treatment). The objective of the standard-risk randomization is to determine whether the less-intensive chemotherapy backbone is associated with a similar DFS but lower rates of treatment-related toxicity compared with the standard therapy (EsPhALL chemotherapy backbone).
High-risk patients (approximately 15%-20% of patients) will proceed to HSCT after completion of three consolidation blocks of chemotherapy. Imatinib will be restarted after HSCT and administered from day +56 until day +365 to test the feasibility of post-HSCT administration of this agent and describe the outcome of patients treated in this manner.
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 precursor B-cell 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 and at relapse have been reported as independent predictors 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 have generally had inferior outcomes resulting from increased induction deaths, treatment-related mortality, and relapse.
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 (CR).[Level of evidence: 2Di]; [Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of second CR 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 almost always observed between the time of initial 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 precursor B-cell ALL in first bone marrow relapse is IKZF1 deletion. The frequency of IKZF1 deletion in precursor B-cell 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 precursor B-cell 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]
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 second CR. 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 second CR 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 second CR (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 second CR with standard reinduction regimens than do patients with precursor B-cell 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.
Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT. Approaches have traditionally included the use of drug combinations distinct from the first attempt at treatment; these regimens often contain newer agents under investigation in clinical trials. Although survival is progressively less likely after each attempt, two to four additional attempts are often pursued, with diminishing levels of success measured after each attempt.
Postreinduction therapy for patients achieving a second complete remission
Early-relapsing precursor B-cell ALL
For precursor B-cell 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.[7,27,48,49,50,51,52,53,54,55,56] 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 precursor B-cell ALL
For patients with a late marrow relapse of precursor B-cell ALL, a primary chemotherapy approach after achievement of second CR has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[5,9,37,57,58,59]; [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 second CR. 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 second CR.
Evidence (MRD-based risk stratification for late-relapse of precursor B-cell 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 second CR, regardless of time to relapse. At 3 years, OS after allogeneic transplant for T-cell ALL in second remission was reported to be 48% and DFS was 46%.[Level of evidence: 3iiiA]
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. Numerous attempts at novel combination approaches have resulted in only about 40% of children in second relapse achieving remission. However, two studies that added bortezomib to standard reinduction agents in multiply relapsed refractory patients have resulted in 70% to 80% complete remission rates.[Level of evidence: 3iiiA]; [Level of evidence: 3iiiDiv] 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.[64,65,66,67,68][Level of evidence: 3iiA]
Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
Components of the transplantation process
An expert panel review of indications for HSCT was published in 2012. 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.[48,70,71] 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,[72,73,74] 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 13.2 and 14 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 12 Gy resulted in worse survival resulting from excessive toxicity.
Although some studies of non-TBI approaches have shown reasonable outcomes [76,77] and have prompted a large BFM study comparing TBI versus non-TBI regimens, TBI for all but the youngest children (age <3 or <4 years) remains the most commonly used therapy in most centers in North America.[62,67]
MRD detection just before transplant
Remission 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.[25,79,80,81,82,83,84,85][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.
MRD detection posttransplant
The presence of detectable MRD post-HSCT has been associated with an increased risk of subsequent relapse.[85,87,88,89,90] The accuracy of MRD for predicting relapse increases as time from HSCT elapses and relapse risk is also higher for patients who have higher levels of MRD detected at any given time. 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 transplantation have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.[52,91,92,93,94]; [95,96][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.[53,64,91] 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.[99,100,101]; [102,103][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.
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.[91,106,107,108]
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.[109,110] 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.[111,112]
Intrathecal medication after HSCT to prevent relapse
The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial.[115,116,117,118]
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% will achieve long-term EFS.[119,120,121]; [68,122][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.[120,121,123] 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 after HSCT is unknown. A small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[Level of evidence: 3iA]
Immunotherapeutic Approaches for Refractory ALL
Immunotherapeutic approaches to the treatment of refractory ALL include monoclonal antibody therapy and chimeric antigen receptor (CAR) T-cell therapy.
Monoclonal antibody therapy
The following two immunotherapeutic agents have been studied for the treatment of refractory B-cell ALL:
CAR T-cell therapy
Chimeric antigen receptor (CAR) T-cell therapy is a therapeutic strategy for pediatric B-cell ALL patients with refractory disease or those in second or subsequent relapse. This treatment involves engineering T cells with a 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.
Treatment with CAR T cells has been associated with cytokine release syndrome, which can be life-threatening.[133,134] Severe cytokine release syndrome has been effectively treated with tocilizumab, an anti-interleukin 6 receptor antibody. Neurotoxicity, including aphasia, altered mental status, and seizures, has also been observed with CAR T-cell therapy and is typically reversible.[133,135] Long-term persistence of CAR T cells can lead to B-cell aplasia, necessitating immunoglobulin replacement.
Several clinical trials of CAR T cells targeting CD19 in relapsed/refractory ALL have been conducted, with encouraging initial results.
Evidence (CAR T cell therapy):
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%.[137,138,139] 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 relapse was noted in one study as an adverse prognostic factor for patients with an isolated extramedullary relapse, while a second study suggested age 10 years as a better cutoff.[16,141] 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%).
Isolated CNS relapse
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.[17,140,143,144]
Evidence (chemotherapy and radiation therapy):
A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.[145,146] Although some reports have suggested a possible role for HSCT for patients with isolated CNS disease with very early relapse and T-cell disease, there is less evidence for the need for HSCT in early relapse and no evidence in late relapse. The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.
Isolated testicular relapse
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
Trials for ALL in second or subsequent relapse or refractory ALL
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.
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.
Risk-Based Treatment Assignment
Added text about the characteristics of MEF2D-rearranged acute lymphoblastic leukemia (ALL) (cited Gu et al., Liu et al., Suzuki et al., and Lilljebjörn et al. as references 193, 194, 195, and 196, respectively).
Added text about the characteristics of ZNF384-rearranged ALL (cited Hirabayashi et al., Qian et al., Shago et al., and Yao et al. as references 197, 198, 199, and 200, respectively).
Added text about the PAX5 amplification in B-cell ALL cases (cited Schwab et al. as reference 208).
Treatment of Newly Diagnosed Childhood ALL
Added Tram Henriksen et al. as reference 16.
Postinduction Treatment for Specific ALL Subgroups
Added text about the AALL15P1 trial as a treatment option under clinical evaluation for infants with ALL.
Added text to state that for very high-risk patients, the AALL1131 study initially evaluated whether intensification of the last 4 weeks of consolidation/intensification improved outcome. However, that portion of the trial was closed when a futility boundary was crossed, indicating that the study would not be able to demonstrate the superiority of the experimental arm. Therefore, very high-risk patients are removed from protocol therapy at the end of induction.
Added Treatment options under clinical evaluation for Philadelphia chromosome-positive (Ph+) ALL as a new subsection.
Treatment of Relapsed Childhood ALL
Revised text to state that the combination of bortezomib plus vincristine, dexamethasone, pegaspargase, and doxorubicin has been reported to induce complete response in 70% to 80% of multiply relapsed patients with precursor B-cell ALL (cited Bertaina et al. as reference 42 and level of evidence 3iiiA).
Revised text to state that numerous attempts at novel combination approaches have resulted in only about 40% of children in second relapse achieving remission. However, two studies that added bortezomib to standard reinduction agents in multiply relapsed refractory patients have resulted in 70% to 80% complete remission rates (added level of evidence 3iiiDiv).
The CAR T-cell therapy subsection was extensively revised.
Added text about the TACL 2012-002 trial as a treatment option under clinical evaluation for relapsed childhood ALL.
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
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389206]
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Last Revised: 2017-12-01
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