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Home > Health Library > Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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.
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 Ig 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 mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia.) Rarely, blasts with L1/L2 (not L3) morphology will express surface Ig. These patients should be treated in the same way as are patients with B-ALL.
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,[22,23] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[22,23]
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 (noting a prevalence of Down syndrome during childhood of approximately 0.1%).[24,25,26,27] ALL in children with Down syndrome has an age distribution similar to that of ALL in children without Down syndrome, with a median age of 3 to 4 years.[24,25] In contrast, the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year).
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.[24,25,26,28,29]
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.[30,31,32]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-ALL who do not have Down syndrome.[32,33,34] 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, but more studies are needed to address this issue.[29,31]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[30,31,35,36,37] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[30,31,32] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival (EFS) in children with Down syndrome and ALL,[31,36] but more study is needed to address this issue.
A genome-wide association study found that four susceptibility loci associated with B-ALL in the non-Down syndrome population (IKZF1, CDKN2A, ARID5B, and GATA3) were also associated with susceptibility to ALL in children with Down syndrome.CDKN2A risk allele penetrance appeared to be higher for children with Down syndrome.
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.[31,40]
Low- and high-penetrance inherited genetic variants
Genetic predisposition to ALL can be divided into several broad categories, as follows:
Genetic risk factors for T-ALL share some overlap with the genetic risk factors for B-ALL, but unique risk factors also exist. A genome-wide association study identified a risk allele near USP7 that was associated with an increased risk of developing T-ALL (odds ratio, 1.44) but not B-ALL. The risk allele was shown to be associated with reduced USP7 transcription, which is consistent with the finding that somatic loss-of-function mutations in USP7 are observed in patients with T-ALL. USP7 germline and somatic mutations are generally mutually exclusive and are most commonly observed in T-ALL patients with TAL1 alterations.
Genetic risk factors that have similar impact for developing both B-ALL and T-ALL include CDKN2A/B and 8q24.21 (cis distal enhancer region variants for MYC).
Prenatal origin of childhood ALL
Development of ALL is a multistep process in most cases, 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.[58,59] 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.[58,59,60] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[58,61]
Evidence also exists that some children who never develop ALL are born with rare blood cells carrying a genomic alteration associated with ALL. Initial studies focused on the ETV6-RUNX1 translocation and used reverse transcriptase (RT)–polymerase chain reaction (PCR) to identify RNA transcripts indicating the presence of the gene fusion. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1 translocation. While subsequent reports generally confirmed the presence of the ETV6-RUNX1 translocation at birth in some children, rates and extent of positivity varied widely.
To more definitively address this question, a highly sensitive and specific DNA-based approach (genomic inverse PCR for exploration of ligated breakpoints [GIPFEL]) was applied to DNA from 1,000 cord blood specimens and found that 5% of specimens had the ETV6-RUNX1 translocation. When the same method was applied to 340 cord blood specimens to detect the TCF3-PBX1 fusion, two cord specimens (0.6%) were positive for its presence. For both ETV6-RUNX1 and TCF3-PBX1, the percentage of cord blood specimens positive for one of the translocations far exceeds the percentage of children who will develop either type of ALL (<0.01%).
The typical and atypical symptoms and clinical findings of childhood ALL have been published.[65,66,67]
The evaluation needed to definitively diagnose childhood ALL has been published.[65,66,67,68,69]
Among children with ALL, approximately 98% attain remission. 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.[70,71,72,73] Cytogenetic and genomic findings combined with minimal residual disease (MRD) results can define subsets of ALL with EFS rates exceeding 95% and, conversely, subsets with EFS rates of 50% or lower (refer to the Cytogenetics/Genomics of Childhood ALL and Prognostic Factors Affecting Risk-Based Treatment sections of this summary for more information).
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.
The 2016 revision to the WHO classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:
2016 WHO Classification of B-Lymphoblastic Leukemia/Lymphoma
2016 WHO Classification of T-Lymphoblastic Leukemia/Lymphoma
2016 WHO Classification of Acute Leukemias of Ambiguous Lineage
For acute leukemias of ambiguous lineage, the group of acute leukemias that have characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the WHO classification system is summarized in Table 1.[2,3] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.
Leukemias of mixed phenotype may be seen in various presentations, including the following:
Biphenotypic cases represent the majority of mixed phenotype leukemias. Patients with B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have lower rates of complete remission (CR) and significantly worse event-free survival (EFS) rates compared with patients with B-ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[5,6,7,8]; [Level of evidence: 3iiiA] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.
Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/Genomics of Childhood ALL section of this summary.
Genomics of childhood ALL
The genomics of childhood ALL has been extensively investigated, and multiple distinctive subtypes have been defined on the basis of cytogenetic and molecular characterizations, each with its own pattern of clinical and prognostic characteristics. Figure 2 illustrates the distribution of ALL cases by cytogenetic/molecular subtype.
Figure 2. Subclassification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL. Reprinted from Seminars in Hematology, Volume 50, Charles G. Mullighan, Genomic Characterization of Childhood Acute Lymphoblastic Leukemia, Pages 314–324, Copyright (2013), with permission from Elsevier.
The genomic landscape of B-ALL is typified by a range of genomic alterations that disrupt normal B-cell development and, in some cases, by mutations in genes that provide a proliferation signal (e.g., activating mutations in RAS family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3-PBX1 and ETV6-RUNX1), point mutations (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).
The genomic alterations in B-ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3-PBX1, ETV6-RUNX1, and KMT2A [MLL]-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within distinctive biological subtypes:
Activating point mutations in kinase genes are uncommon in high-risk B-ALL. JAK genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with Ph-like ALL that have CRLF2 abnormalities, although JAK2 mutations are also observed in approximately 15% of children with Down syndrome ALL.[4,8,9] Several kinase genes and cytokine receptor genes are activated by translocations, as described below in the discussion of Ph+ ALL and Ph-like ALL. FLT3 mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and KMT2A-rearranged ALL, and are rare in other subtypes.
Understanding of the genomics of B-ALL at relapse is less advanced than the understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise. Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in NT5C2 are not found at diagnosis, whereas specific mutations in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-ALL with early relapse that were evaluated for this mutation in two studies.[11,12]NT5C2 mutations are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine (6-MP) and thioguanine. Another gene that is found mutated only at relapse is PRSP1, a gene involved in purine biosynthesis. Mutations were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[11,14] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing mutations early and intervene before a frank relapse.
A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-ALL. Some chromosomal alterations are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Other alterations historically have been associated with a poorer prognosis, including the Ph chromosome (t(9;22)(q34;q11.2)), rearrangements of the 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 B-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 B-ALL, but very rarely in cases of T-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 an independent favorable prognostic factor.[17,18,19] 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.[21,22]
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 on the basis of the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Ph 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-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 (hyperdiploidy with two and four copies of chromosomes rather than three copies). 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.[28,29,30] 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.[28,30]
The genomic landscape of hyperdiploid ALL is characterized 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.
B-ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying on the basis of 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.[27,32] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells. A number of studies have shown that patients with high minimal residual disease (MRD) (≥0.01%) after induction do very poorly, with 5-year event-free survival (EFS) rates ranging from 25% to 47%. Although hypodiploid patients with low MRD after induction fare better (5-year EFS, 64%–75%), their outcomes are still inferior to most children with other types of ALL.[33,34,35]
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. Approximately two-thirds of patients with ALL and germline pathogenic TP53 variants have hypodiploid ALL.
Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in 20% to 25% of cases of B-ALL but is rarely observed in T-ALL. The t(12;21)(p13;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.[38,39] Hispanic children with ALL have a lower incidence of t(12;21)(p13;q22) than do white children.
Reports generally indicate favorable 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:[41,42,43,44,45]
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.[45,46]
There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusions compared with other relapsed B-ALL patients.[41,47] 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).[50,51]
The Ph chromosome t(9;22)(q34.1;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 3). Figure 3. The Philadelphia chromosome is a translocation between the ABL1 oncogene (on the long arm of chromosome 9) and the BCR gene (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 B-ALL and high WBC count, with the incidence of the t(9;22)(q34.1;q11.2) increasing to about 25% in young adults with ALL.
Historically, the Ph chromosome t(9;22)(q34.1;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.[25,52,53,54] 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.[56,57]
Rearrangements involving the 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.[58,59,60,61] The t(4;11)(q21;q23) is the most common rearrangement involving the KMT2A gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[59,62]
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.[58,59] Irrespective of the type of KMT2A gene rearrangement, infants with leukemia cells that have KMT2A gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have a KMT2A gene rearrangement.[58,59]
Whole-genome sequencing has determined that cases of infant ALL with KMT2A gene rearrangements have few additional genomic alterations, none of which have clear clinical significance. Deletion of the KMT2A gene has not been associated with an adverse prognosis.
Of interest, the t(11;19)(q23;p13.3) involving KMT2A and MLLT1/ENL occurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-ALL. Outcome for infants with the t(11;19) is poor, but outcome appears relatively favorable in older children with T-ALL and 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.[66,67] 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 immunoglobulin 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.[67,71] 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.[72,73]
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 with disseminated intravascular coagulation and hypercalcemia at diagnosis. 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 B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[5,6] 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.DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with focal deletions in ERG,[75,76,77,78] and one-half to more than two-thirds of these cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes.[5,75]ERG deletions often appear to be clonal, but using sensitive detection methodology, it appears that most cases are polyclonal.IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[5,6]
ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.[76,77,78] While DUX4-rearranged ALL has an overall favorable prognosis, there is uncertainty as to whether this applies to both ERG-deleted and ERG-intact cases. In a study of 50 patients with DUX4-rearranged ALL, patients with ERG deletion detected by genomic polymerase chain reaction (PCR) (n = 33) had a more favorable EFS rate of approximately 90% than did patients with intact ERG (n = 17), with an EFS rate of approximately 70%.
Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 4% of childhood ALL cases.[79,80] Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[79,81] 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 Ph-like gene expression profile.[79,82]
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.[79,80] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS rate 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-ALL cases.[79,83,84] 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.[79,83,84]ZNF384 rearrangement does not appear to confer independent prognostic significance.[79,83,84] The immunophenotype of B-ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[83,84] Cases of mixed phenotype acute leukemia (MPAL) (B/myeloid) that have ZNF384 gene fusions have been reported, [85,86] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.
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.[88,89] The joining of the IGH locus to the promoter region of the IL3 gene 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. Diagnosis of cases of IL3-IGH ALL may be delayed because it can present with hypereosinophilia in the absence of cytopenias and circulating blasts.
iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome). It occurs in approximately 2% of B-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 MRD.[92,93,94]
The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) 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 HSCT in first remission.
Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, termed PAX5alt and PAX5 p.Pro80Arg. The alterations in the PAX5alt subtype included rearrangements, sequence mutations, and focal intragenic amplifications.
PAX5alt. PAX5 rearrangements have been reported to represent 2% to 3% of pediatric ALL. More than 20 partner genes for PAX5 have been described, with PAX5-ETV6, the primary genomic alteration in dic(9;12)(p13;p13), being the most common gene fusion.
Intragenic amplification of PAX5 was identified in approximately 1% of B-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-ALL subtype.
PAX5 p.Pro80Arg. PAX5 with a p.Pro80Arg mutation shows a gene expression profile distinctive from that of other cases with PAX5 alterations. Cases with PAX5 p.Pro80Arg appear to be more common in the adolescent and young adult (AYA) and adult populations (3%–4% frequency) than in children with NCI standard-risk or high-risk ALL (0.4% and 1.9% frequency, respectively). Outcome for the pediatric patients with PAX5 p.Pro80Arg and PAX5alt treated on a COG clinical trial appears to be intermediate (5-year EFS, approximately 75%).
BCR-ABL1–negative patients with a gene expression profile similar to BCR-ABL1–positive patients have been referred to as Ph-like.[99,100,101] This occurs in 10% to 20% of pediatric ALL patients, increasing in frequency with age, and has been associated with an IKZF1 deletion or mutation.[8,99,100,102,103]
Retrospective analyses have indicated that patients with Ph-like ALL have a poor prognosis.[4,99] In one series, the 5-year EFS for NCI high-risk children and adolescents with Ph-like ALL was 58% and 41%, respectively. While it is more frequent in older and higher-risk patients, the Ph-like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-ALL patients were found to have Ph-like ALL; these patients had an inferior EFS compared with non–Ph-like standard-risk patients (82% vs. 91%), although no difference in OS (93% vs. 96%) was noted. In one study of 40 Ph-like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.
The hallmark of Ph-like ALL is activated kinase signaling, with 50% containing CRLF2 genomic alterations [101,106] and half of those cases containing concomitant JAK mutations.
Many of the remaining cases of Ph-like ALL have been noted to have a series of translocations with a common theme of involvement of kinases, including ABL1, ABL2, CSF1R, JAK2, and PDGFRB.[4,102] 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. The prevalence of targetable kinase fusions in Ph-like ALL is lower in NCI standard-risk patients (3.5%) than in NCI high-risk patients (approximately 30%). Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL cases.
Approximately 9% of Ph-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.
CRLF2. Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-ALL; they represent approximately 50% of cases of Ph-like ALL.[109,110,111] 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.[8,106,109,110] These two genomic alterations are associated with distinctive clinical and biological characteristics.
The P2RY8-CRLF2 fusion is observed in 70% to 75% of pediatric patients with CRLF2 genomic alterations, and it occurs in younger patients (median age, approximately 4 years vs. 14 years for patients with IGH-CRLF2).[112,113]P2RY8-CRLF2 occurs not infrequently with established chromosomal abnormalities (e.g., hyperdiploidy, iAMP21, dic(9;20)), while IGH-CRLF2 is generally mutually exclusive with known cytogenetic subgroups. CRLF2 genomic alterations are observed in approximately 60% of patients with Down syndrome ALL, with P2RY8-CRLF2 fusions being more common than IGH-CRLF2 (approximately 80% vs. 20%).[110,112]
IGH-CRLF2 and P2RY8-CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence. However, in some cases they appear to be a late event and show subclonal prevalence. Loss of the CRLF2 genomic abnormality in some cases at relapse confirms the subclonal nature of the alteration in these cases.[112,115]
CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions. Other recurring genomic alterations found in association with CRLF2 alterations include deletions in genes associated with B-cell differentiation (e.g., PAX5, BTG1, EBF1, etc.) and cell cycle control (CDKN2A), as well as genomic alterations activating JAK-STAT pathway signaling (e.g., IL7R and JAK mutations).[4,106,107,110,116]
Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance in univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[106,109,110,117,118] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and Ph-like expression signatures were associated with unfavorable outcome. Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed on the basis of CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[117,118]
IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of B-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.[2,100,116,119] A high proportion of Ph-like cases have a deletion of IKZF1,[3,116] 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 ALL.[76,99,116]
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 in multivariate analyses.[76,99,100,103,116,121,122,123,124,125,126,127]; [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.[76,77,78] Similarly, the prognostic significance of the IKZF1 deletion also appeared to be minimized in a cohort of COG patients with DUX4-rearranged ALL and with ERG transcriptional dysregulation that frequently occurred by ERG deletion. The Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)–Berlin-Frankfurt-Münster (BFM) group reported that IKZF1 deletions were significant adverse prognostic factors only in B-ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.
There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[Level of evidence: 2A]
T-ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with mutations in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway. In contrast to B-ALL, the prognostic significance of T-ALL genomic alterations is less well-defined. Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-ALL.[132,133]
Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-ALL, and these are the most commonly mutated genes in pediatric T-ALL.[131,134]NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-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 NOTCH1/FBXW7 mutations may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia groups reported that patients having mutated NOTCH1/FBXW7 and wild-type PTEN/RAS constituted a favorable-risk group while patients with PTEN or RAS mutations, regardless of NOTCH1/FBXW7 status, have a significantly higher risk of treatment failure.[136,137] In the FRALLE study, 5-year cumulative incidence of relapse and disease-free survival (DFS) were 50% and 46% for patients with mutated NOTCH1/FBXW7 and mutated PTEN/RAS versus 13% and 87% for patients with mutated NOTCH1/FBXW7 and wild-type PTEN/RAS. The overall 5-year DFS in the FRALLE study was 73%, and additional research is needed to determine whether the same prognostic significance for NOTCH1/FBXW7 and PTEN/RAS mutations will apply to current treatment regimens, which produce overall 5-year DFS rates that approach 90%.
Multiple chromosomal translocations have been identified in T-ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1/TAL2, LMO1 and LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[131,132,139,140,141,142,143] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including FISH or PCR. Mutations in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-ALL.
Translocations resulting in chimeric fusion proteins are also observed in T-ALL.
Early T-cell precursor ALL cytogenetics/genomics
Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases. Compared with other T-ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.
Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL.[154,155] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.
Mixed phenotype acute leukemia (MPAL) cytogenetics/genomics
For acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 3.[156,157] The criteria for lineage assignment for a diagnosis of MPAL are provided in Table 4.
The classification system for MPAL includes two entities that are defined by their primary molecular alteration: MPAL with BCR-ABL1 translocation and MPAL with KMT2A rearrangement. The genomic alterations associated with the MPAL, B/myeloid, NOS (B/M MPAL) and MPAL, T/myeloid, NOS (T/M MPAL) entities are distinctive, as described below:
Gene polymorphisms in drug metabolic pathways
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[158,159,160]
Patients with mutant phenotypes of TPMT (a gene involved in the metabolism of thiopurines such as mercaptopurine) appear to have more favorable outcomes, although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[162,163] 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.[164,165]
Germline variants in NUDT15 that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[164,166] 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.[164,167]
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 interleukin-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.[170,171] 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 on the basis of these findings will improve outcome.
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 cure 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 the following:
The NCI risk group classification for B-ALL stratifies risk according to age and white blood cell (WBC) count, as follows:
All study groups modify the intensity of postinduction therapy on the basis of a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics and genomic alterations. Detection of the Philadelphia chromosome (i.e., Philadelphia chromosome–positive [Ph+] ALL) 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 a KMT2A gene rearrangement.[9,11,13,14] The most common rearrangement is KMT2A-AFF1 (t(4;11)(q21;q23)), but KMT2A rearrangements with many other translocation partners are observed.
The rate of KMT2A gene rearrangements is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of KMT2A rearrangements decreases but remains higher than that observed in older children.[9,15] Black infants with ALL are significantly less likely to have KMT2A rearrangements than are white infants.
Infants with leukemia and 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 KMT2A-rearranged ALL.[9,10,11] A comparison of the landscape of somatic mutations in infants and children with KMT2A-rearranged ALL revealed significant differences between the two groups, suggesting distinctive age-related biological behaviors for KMT2A-rearranged ALL that may relate to the significantly poorer outcome for infants.[16,17]
Blasts from infants with KMT2A rearrangements are often CD10 negative and express high levels of FLT3.[9,10,14,18] Conversely, infants whose leukemic cells show a germline KMT2A gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by KMT2A 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 fusion (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 function rather than a step function. Patients with B-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-ALL (>50,000/µL) than for B-ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-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-ALL phenotype, and KMT2A gene rearrangements.[42,46,47]
Most clinical trial groups have approached the treatment of CNS2 and traumatic lumbar puncture patients by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[42,51,52]; [Level of evidence: 2A]; [Level of evidence: 1iiA]
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,[55,56] with its frequency being higher in patients with T-ALL than in patients with B-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.[55,56] 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)
Outcomes in children with Down syndrome and ALL have generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome.[57,58,59,60,61,62] 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.[57,58,59,60,63,64] The inferior anti-leukemic outcome may be due, in part, to the decreased prevalence of favorable biological features such as ETV6-RUNX1 or hyperdiploidy (51–65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.[63,64]
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[71,72,73] 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.[71,72,73] While some reports describe outcomes for boys as closely approaching those of girls,[22,51,74] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[21,28,29,75]
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.[76,77,78,79]
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 patients who were not underweight (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with a decrease in BMI 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:
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.[93,94] (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 B-ALL (precursor B-cell ALL).
B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is usually associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[9,95] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.
The major immunophenotypic subtypes of B-ALL are as follows:
Approximately three-quarters of patients with B-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 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 the TCF3-PBX1 (previously known as E2A-PBX1) fusion.[97,98]
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 B-ALL.
Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with French-American-British criteria 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 the treatment for B-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 mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia.)
A small number of cases of IG-MYC-translocated leukemias with precursor B-cell immunophenotype (e.g., absence of CD20 expression and surface Ig expression) have been reported. These cases presented in both children and adults. Like Burkitt lymphoma/leukemia, they had a male predominance and most patients showed L3 morphology. The cases lacked mutations in genes recurrently altered in Burkitt lymphoma (e.g., ID3, CCND3, or MYC), whereas mutations in RAS genes (frequently altered in B-ALL) were common. The clinical significance of IG-MYC–translocated leukemias with precursor B-cell phenotype and molecular characteristics requires further study.
T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[20,36,74]
While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-lineage ALL.[20,36,39,40,74,101]
There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[35,36,37,38,39,40,41,102] 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.
Early T-cell precursor ALL
Early T-cell precursor ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors. The subset of T-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).
Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other patients with T-ALL.[104,105,106] However, another study indicated that the early T-cell precursor ALL subgroup had nonsignificantly inferior 5-year EFS rates compared with non–early T-cell precursor patients (76% vs. 84%). Similarly, the COG AALL0434 trial observed similar 5-year EFS rates for early T-cell precursor patients and non-early T-cell precursor patients, 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 on the basis of early T-cell precursor status.
Up to one-third of childhood ALL patients have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with KMT2A rearrangements, ETV6-RUNX1, and BCR-ABL1.[109,110,111] Patients with B-ALL who have gene rearrangements involving ZNF384 also commonly show myeloid antigen expression.[112,113] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[109,110]
(Refer to the 2016 WHO Classification of Acute Leukemias of Ambiguous Lineage section of this summary for information about leukemia of ambiguous lineage.)
(Refer to the Cytogenetics/Genomics of Childhood ALL section of this summary for information about B-ALL and T-ALL cytogenetics/genomics and gene polymorphisms in drug metabolic pathways.)
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. In order to detect lower levels of leukemic cells in either blood or marrow, specialized techniques are required; such techniques include polymerase chain reaction (PCR) assays, which determine unique Ig/T-cell receptor gene rearrangements and fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes. 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. Newer techniques involving high-throughput sequencing (HTS) of Ig/T-cell receptor gene rearrangements can increase sensitivity of MRD detection to 1 in 1 million cells (10-6 or 0.001%).
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[117,118,119] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities. In general, patients with higher levels of end-induction MRD have a poorer prognosis than do those with lower or undetectable levels.[115,117,118,119] However, the absolute risk of relapse associated with specific MRD levels varies by genetic subtype. For example, at any given level of detectable end-induction MRD, patients with favorable cytogenetics, such as ETV6-RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients. This observation may have important implications when MRD is used to develop risk classification plans.
End-induction MRD is used by almost all groups as a factor in determining the intensity of postinduction treatment; patients found to have higher MRD levels (typically >0.1% to 0.01%) are allocated to more intensive therapies.[115,118,122]; [Level of evidence: 2A]
A study of 619 children with ALL compared the prognostic utility of MRD by flow cytometry with the more sensitive HTS assay. Using an end-induction MRD cutpoint level of 0.01%, high-throughput sequencing identified approximately 30% more cases as positive (i.e., >0.01%). Patients identified as positive by HTS, but negative by flow cytometry, had an intermediate prognosis compared with patients categorized as either positive or negative by both methods. Patients meeting the criteria for standard-risk ALL with undetectable MRD by HTS had an especially good prognosis (5-year EFS rate, 98.1%).
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.[119,120]
Another study also indicated that MRD at a later time point may be more prognostically significant in T-ALL. In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-ALL. Patients with detectable MRD at end-induction who had negative MRD by day 78 generally had a favorable prognosis, similar to that of patients who achieved MRD-negativity at the earlier end-induction time point.
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 rate, 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 were sustained for more than 10 years from diagnosis.
Modifying therapy on the basis of MRD determination has been shown to improve outcome.
Compared with previous trials conducted by the same group, therapy was less intensive for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS rate (87%) and OS rate (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.[118,129]
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.[20,130] 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.
Persistent leukemia 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 by morphological assessment at the end of the induction phase is observed in 1% to 2% of children with ALL.[21,22,133,134,135]
Features associated with a higher risk of induction failure include the following:[135,136,137]
In a large retrospective study, the OS rate of patients with induction failure was only 32%. However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with B-ALL between the ages of 1 and 5 years without adverse cytogenetics (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 Ph chromosome or KMT2A rearrangement. B-ALL patients younger than 6 years and T-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.
Flow cytometry versus morphology
MRD is now being integrated with morphological assessment into the response to induction therapy, on the basis of studies that showed that patients with MRD levels above 5%, despite morphologic complete remission, had outcomes similar to patients with morphologic induction failure.
Prognostic (Risk) Groups
For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens on the basis of 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) on the basis of 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%.[4,51,130,140,141] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., 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%.[4,118]
Patients who are at very high risk of treatment failure include the following:[142,143,144,145]
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. 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
Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way.
For patients with B-ALL, the definitions of favorable, unfavorable, and neutral cytogenetics are as follows:
NCI standard-risk patients are divided into a highly favorable group (standard-risk favorable; 5-year DFS rate, >95%), a group with favorable outcome (standard-risk average; 5-year DFS rate, 90%–95%), and a group with a 5-year DFS rate below 90% (standard-risk high). Patients classified as standard-risk high receive backbone chemotherapy as per high-risk B-ALL regimens with intensified consolidation, interim maintenance, and reinduction therapy. Criteria for these three groups are provided in Table 6, Table 7, and Table 8 below.
High-risk favorable B-ALL is defined by the characteristics in Table 9. These patients have an EFS rate higher than 90% on past COG clinical trials for high-risk patients.
High-risk B-ALL is defined by the characteristics in Table 10. NCI standard-risk patients are elevated to high-risk status based on steroid pretreatment and CNS and/or testicular involvement.
NCI high-risk patients with end-of-consolidation marrow MRD ≥0.01% are classified as very high risk and are eligible for a chimeric antigen receptor (CAR) T-cell clinical trial in first remission (NCT03792633).
Patients with B-ALL and Down syndrome are classified into risk groups similar to other children, but Down syndrome patients classified as high risk receive a treatment regimen that is modified to reduce toxicity.
Very high risk.
Criteria for low-risk (approximately 42% of patients).
Criteria for standard-risk (approximately 48% of patients).
Criteria for high-risk (approximately 10% of patients).
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 acute lymphoblastic leukemia (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 the remission induction phase and another 1% to 3% die after having achieved complete 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 into the following phases:
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 Induction 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 induction phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-ALL achieve CR by the end of this phase, with somewhat lower rates in infants and in noninfant patients with T-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-ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-ALL and all T-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:
Pegaspargase is a form of L-asparaginase in which the E. coli–derived enzyme is modified by the covalent attachment of polyethylene glycol. It 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] In one randomized study, higher doses of pegaspargase (3,500 U/m2) did not improve outcome when compared with standard doses (2,500 U/m2).[Level of evidence: 1iiA]
Evidence (use of pegaspargase versus 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.[18,19]
Several studies have identified a subset of patients who experience silent inactivation of asparaginase, defined as absence of therapeutic SAA levels without overt allergy.[20,21] 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%).[13,20] Determination of the optimal frequency of pharmacokinetic monitoring for pegaspargase-treated patients, and whether such screening impacts outcome, awaits further investigation.
Another formulation of pegylated asparaginase, calaspargase pegol, is also available for the treatment of children and adolescents with ALL. This formulation is similar in structure to pegaspargase, except with a different linker between the L-asparaginase enzyme and the PEG moiety, resulting in a longer half-life.[23,24]
Erwinia L-asparaginase is typically used in patients who have experienced an 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 use during induction
The COG protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to NCI standard-risk B-ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus an anthracycline) to NCI high-risk B-ALL and all T-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 used. 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).[28,29,30]; [Level of evidence: 3iA]
Most patients with persistence of morphologically detectable 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.[4,32,33] In a large retrospective series, the 10-year OS rate for such patients was 32%. A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and B-ALL patients older than 6 years. B-ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A [MLL] 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 (postinduction 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:
An interim maintenance phase, which includes four doses of high-dose methotrexate (typically 5 g/m2) with leucovorin rescue.
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, as follows:
In children with standard-risk B-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.[50,51,52] 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 were also reported in trials that utilized a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase).[51,54,55] The DFCI ALL Consortium study utilized multiple doses of pegaspargase (30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[56,57]
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.[36,38,39,58,59] 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.[56,67]; [Level of evidence: 2Di] Treatment for high-risk patients is generally 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:[63,75]
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.[32,63]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.[32,76,77,78] 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. 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 among various racial and socioeconomic groups. Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase has been associated with a significant increase in the risk of relapse.[82,83]
In the past, clinical practice generally called for the administration of oral mercaptopurine in the evening, on the basis of evidence from older studies that this practice may improve EFS. However, in a study conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) group, in which details of oral intake were prospectively captured, timing of mercaptopurine administration (nighttime vs. other times of day) was not of prognostic significance. In a COG study, taking mercaptopurine at varying times of day rather than consistently at nighttime was associated with higher rates of nonadherence; however, among adherent patients (i.e., those who took >95% of prescribed doses), there was no association between timing of mercaptopurine ingestion and relapse risk.
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.[87,88] These patients are able to tolerate mercaptopurine only in much lower dosages than those conventionally used.[87,88] Patients who are heterozygous for the mutation 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.[89,90,91]
Evidence (maintenance therapy):
On the basis of these findings, SJCRH 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.[6,7,21,60,106] Compared with prednisone, dexamethasone has also been associated with a higher frequency of behavioral problems. In a randomized study of 50 patients aged 3 to 16 years who received maintenance chemotherapy, concurrent administration of hydrocortisone (at physiologic dosing) during dexamethasone pulses reduced the frequency of behavioral difficulties, emotional lability, and sleep disturbances.
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.[68,106]
Duration of maintenance therapy
Maintenance chemotherapy generally continues for 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.[56,63] 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 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 B-ALL
All patients receive a three-drug induction (no anthracycline). After completion of induction, patients are classified into one of three groups on the basis of biology and early response measures:
Standard-risk favorable patients will be treated with standard therapy.
All standard-risk average patients will have MRD evaluated at day 29 of induction using high-throughput sequencing (HTS)-MRD assay. HTS-MRD undetectable patients will be treated with standard therapy, while patients with HTS-MRD detectable disease (or if HTS-MRD is indeterminate or unavailable), as well as those with double trisomies and day 29 marrow MRD of ≥0.01% to <0.1% will be eligible to participate in a randomization of standard therapy or standard therapy plus the addition of two cycles of blinatumomab.
Standard-risk high patients will be treated with the augmented BFM (NCI high risk) backbone. Any patients with end-consolidation MRD of >1% are removed from protocol therapy. Those with end-consolidation MRD of <0.1% will be eligible to participate in a randomization of either the NCI high-risk backbone alone or this therapy plus two cycles of blinatumomab. Those with end-consolidation MRD of ≥0.1% and <1% will be directly assigned to receive NCI high-risk backbone therapy plus two cycles of blinatumomab.
NCI standard-risk Down syndrome patients who meet definition of standard-risk average will be treated in the same way as non-Down syndrome standard-risk average patients, as detailed above. All other Down syndrome patients, including NCI high-risk Down syndrome patients, those with unfavorable biology, and those with high day 29 MRD will be considered Down syndrome-high, and will be nonrandomly assigned to receive two cycles of blinatumomab added to a deintensified chemotherapy regimen that omits intensive elements of the augmented BFM treatment backbone. Omitted elements include anthracyclines during induction and cyclophosphamide/cytarabine-based chemotherapy during the second half of delayed intensification.
All patients, regardless of risk group, will receive the same duration of therapy (2 years from the start of interim maintenance 1 phase). This represents a reduction in treatment duration by 1 year for boys compared with standard treatment.
High-risk and very high-risk ALL
Patients enrolled on this trial will undergo leukapheresis to collect autologous T cells, which will then be sent for manufacturing of tisagenlecleucel. While awaiting completion of manufacturing, patients will proceed with interim maintenance phase 1 (high-dose methotrexate); this phase may be interrupted as soon as product is available. Once available, patients will then receive lymphodepleting chemotherapy and infusion of tisagenlecleucel. No further anti-leukemic treatment is to be administered after tisagenlecleucel. Marrow samples will be obtained at regular intervals postinfusion, beginning at day 29 after tisagenlecleucel administration to assess disease status; tests of peripheral blood will also be sent to screen for evidence of B-cell aplasia.
Patients must have evidence of CD19-positivity at diagnosis to enroll on trial. Patients with M3 marrow at end of induction, M2/M3 marrow at end of consolidation, hypodiploidy (<44 chromosomes), Ph+ ALL, or previous treatment with tyrosine kinase inhibitors are excluded from enrollment.
For patients with B-ALL, the protocol is testing whether the addition of two blocks of inotuzumab ozogamicin to a modified-BFM backbone will improve DFS and whether reducing duration of treatment in boys (from 3 years from the start of interim maintenance 1 phase to 2 years from the start of that phase) does not adversely impact DFS. The study also aims to determine the EFS of patients with MPAL and disseminated B-lymphoblastic lymphoma who are treated with a standard high-risk ALL chemotherapy regimen.
All patients receive a four-drug induction (including daunorubicin). After completion of induction, subsequent therapy depends on age, biology, and response to therapy.
All patients will receive the same duration of therapy (2 years from the start of interim maintenance 1 phase). This represents a reduction in treatment duration by 1 year for boys, compared with standard treatment. NCI high-risk B-ALL patients with EOC MRD of ≥0.01% are removed from protocol therapy and are eligible to enroll on the COG-AALL1721 trial (see above). NCI standard-risk patients with EOC MRD of ≥1% are removed from protocol therapy and are not eligible for enrollment on the COG-AALL1721 trial.
This trial has the following four main objectives:
This trial has the following two main objectives:
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, KMT2A gene rearrangement, TCF3-HLF fusion (t(17;19)), 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-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 an anthracycline).
Final risk group, which determines the intensity of postinduction therapy, is assigned on the basis of 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.
Overview of CNS-Directed Treatment Regimens
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 select 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 11.
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):
Cranial Radiation Therapy
The proportion of patients receiving cranial radiation therapy has decreased significantly over time. At present, most newly diagnosed children with ALL are treated without cranial radiation therapy. Many groups administer cranial radiation therapy 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 therapy, the cranial radiation dose has been significantly reduced and administration of spinal irradiation is not standard.
Ongoing trials seek to determine whether radiation therapy can be eliminated from the treatment of all children with newly diagnosed 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 newly diagnosed 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 therapy, 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 therapy 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 Without CNS Involvement
Controversy exists as to whether high-risk and very high-risk patients should be treated with cranial radiation therapy, although there is a growing consensus that cranial radiation therapy may not be necessary for most of these patients. Indications for cranial radiation therapy on some treatment regimens have included the following:
Both the proportion of patients receiving radiation therapy and the dose of radiation administered has decreased over the last two decades.
Evidence (cranial radiation therapy):
CNS Therapy for Patients With CNS3 Disease at Diagnosis
Therapy for ALL patients with clinically evident CNS disease (≥5 WBC/high-power field with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation therapy (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 therapy 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 12 courses of intermediate-dose intravenous (IV) methotrexate (1 g/m2) given every 2 weeks with intrathecal chemotherapy. Intrathecal and high-dose IV 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 therapy. 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 patients with ALL 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 therapy 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 of 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 of 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-acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with B-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-ALL are now approaching those achieved for children with B-ALL. For example, the 10-year overall survival (OS) rate for children with T-ALL treated on the Dana-Farber Cancer Institute (DFCI) DFCI-95001 (NCT00004034) trial was 90.1%, compared with 88.7% for patients with B-ALL. Another example is the COG trial for T-ALL (AALL0434 [NCT00408005]) that resulted in a 5-year event-free survival (EFS) rate of 83.8% and an OS rate of 89.5%.
Treatment options for T-ALL
Treatment options for T-ALL include the following:
Evidence (chemotherapy and prophylactic radiation therapy):
The use of prophylactic cranial radiation therapy in the treatment of patients with T-ALL is declining. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation therapy in first-line treatment of ALL, and other groups, such as DFCI, COG, and BFM, are now limiting radiation therapy to patients with very high-risk features or CNS3 disease.
Treatment options under clinical evaluation for T-ALL
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.[17,18,19]
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 rate for infants diagnosed at younger than 90 days was 16%.[Level of evidence: 2A]
For infants with KMT2A (MLL) gene rearrangements, the EFS rates at 4 to 5 years continue to be in the 35% range.[17,18,19,21][Level of evidence: 2A] Factors predicting poor outcome for infants with KMT2A rearrangements include the following:[18,19]; [Level of evidence: 3iDii]; [Level of evidence: 2A]
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.[18,19] 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 withKMT2Arearrangements
Infants with 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 KMT2A rearrangements):
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with KMT2A gene rearrangements remains controversial.
Evidence (allogeneic HSCT in first remission for infants with KMT2A rearrangements):
For infants with ALL who undergo transplantation in first CR, outcomes appear to be similar with non–total-body irradiation (TBI) regimens and TBI-based regimens.[26,28]
Treatment options for infants withoutKMT2Arearrangements
The optimal treatment for infants without KMT2A rearrangements also remains unclear, in part because of the paucity of data on the use of standard ALL regimens used in older children.
Treatment options under clinical evaluation for infants with ALL
The following is an example of a 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]
Treatment options for adolescents and young adults with ALL
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 12.
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):
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.[37,50,51] 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 were needed for management of symptoms and impaired mobility in more than 40% of cases. Most cases are diagnosed within the first 2 years of therapy and the symptoms are often recognized during maintenance.
Treatment options under clinical evaluation for adolescent and young adult patients with ALL
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 a poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS rate of 25%, with an OS rate of 36%. In 2010, the same group reported a 7-year EFS rate of 31% and an OS rate 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.
Treatment options for patients with Ph+ ALL
Standard therapy for patients with Ph+ ALL includes the use of a tyrosine kinase inhibitor (e.g., imatinib or dasatinib) in combination with cytotoxic chemotherapy, with or without allogeneic HSCT in first CR.
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and phase II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[55,56]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[57,58,59] Patients with Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[60,61,62,63,64] Clinical trials have also demonstrated that many pediatric patients with Ph+ ALL will have a comparable EFS using chemotherapy and a tyrosine kinase inhibitor than with transplant.[64,65]
Dasatinib, a second-generation inhibitor of tyrosine kinases, has also been studied in the 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 grade 4 adverse events.
Evidence (tyrosine kinase inhibitor):
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 following two important risk factors after first relapse of childhood ALL are key to determining prognosis and treatment approach:
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 only relapse; however, other studies have not confirmed this finding.[5,13,16]
Time from diagnosis to relapse
For patients with relapsed B-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 higher than 60% for those whose relapses occur more than 36 months from diagnosis.[5,13,17]
For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates are 40% to 50% for early relapse (<18 months from diagnosis) and 75% to 80% for those with late relapses (>18 months from diagnosis).[13,18] 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 rate, 15%; P = .001).
For patients with B-ALL who were diagnosed at age 18 years or younger and experienced a late relapse, age was not a significant predictor of subsequent outcome when analyzed by quartiles. However, the outcome for patients aged 18 years and older at time of relapse was significantly inferior to the outcome for patients relapsing at age younger than 18 years (39.5% vs. 68.7%; P = .0001).
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 and ALL who relapse 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.[21,24,26,27,28]; [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.[30,31] 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.[30,32,33]
TP53 alterations (mutations and/or copy number alterations) are observed in approximately 10% of patients with ALL at first relapse and have been associated with an increased likelihood of persistent leukemia after initial reinduction and poor event-free survival (EFS) rates.[21,34] In one study, approximately one-half of the TP53 alterations were present at initial diagnosis and half were newly observed at time of relapse.
IKZF1 deletions have also been reported to be associated with a poor prognosis in patients with B-ALL in first bone marrow relapse. However, in a BFM study of patients with B-ALL who experienced a late first marrow relapse, IKZF1 deletions were not prognostically significant.
RAS pathway mutations (KRAS, NRAS, FLT3, and PTPN11) are common at relapse in B-ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children.[30,36] 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.[35,37]
Immunophenotype is an important prognostic factor at relapse. Patients with T-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-ALL.[5,24]
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%).[24,38]
Evidence (reinduction chemotherapy):
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
Patients with relapsed T-ALL have much lower rates of achieving second CR with standard reinduction regimens than do patients with B-cell phenotype. Treatment of children with first relapse of T-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 also been used in patients with relapsed/refractory T-ALL.
Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT, especially if MRD becomes low or nondetectable (refer to the Late-relapsing B-ALL section of this summary for more information on MRD risk stratification). 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. Because studies of chimeric antigen receptor (CAR) T cells, blinatumomab, and inotuzumab have been shown to lead to high rates of remission in multiply relapsed and chemotherapy-refractory B-ALL patients, trials testing these agents after initial relapse are underway (refer to the Immunotherapeutic Approaches for Refractory ALL section of this summary for more information).
Postreinduction therapy for patients achieving a second complete remission
For B-ALL patients with an early marrow relapse, allogeneic transplant from an 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.[7,29,49,50,51,52,53,54,55,56,57] 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.)
Previous studies of late marrow relapse in patients with B-ALL showed that a primary chemotherapy approach after achievement of second CR resulted in survival rates of approximately 50%, and it was not clear whether allogeneic transplantation was associated with a superior cure rate.[5,9,39,58,59,60]; [Level of evidence: 3iiA] Subsequent data have shown that the presence of end-reinduction MRD identifies patients with a high risk of ensuing relapse if treated with chemotherapy alone (no HSCT) in second CR. A number of studies have shown that patients with a late marrow relapse who have high end-reinduction MRD have better outcomes if they receive an allogeneic HSCT in second CR after achieving low or nondetectable MRD status.[17,62]
Evidence (MRD-based risk stratification for late-relapse of B-ALL):
For patients with T-ALL who achieve 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, the OS rate after allogeneic transplant for T-ALL in second remission was reported to be 48%, and the DFS rate 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 has generally been 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% CR 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 because of high rates of relapse and transplant-related mortality.[65,66,67,68,69][Level of evidence: 3iiA]
Given the poor outcomes for multiply relapsed B-ALL patients who are treated with chemotherapy followed by HSCT, CAR T-cell therapy has been tested in this population and has resulted in high rates of remission and improved short-term survival (long-term follow-up pending; refer to the CAR T-cell therapy section of this summary for more information). Immune therapies such as blinatumomab and inotuzumab have also greatly facilitated the achievement of remission, which has generally been followed by HSCT.[70,71] Comparative studies of immune and cell therapy approaches have yet to be performed in this population, so data to inform optimal approaches to first therapy or sequence of therapies are lacking.
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 registry studies and a small randomized trial showed that transplant conditioning regimens that include TBI resulted in higher cure rates than chemotherapy-only preparative regimens.[49,73,74] An international study (United States, Europe, and Australia) that combined data sets from prospective trials and single-center data showed that the use of non-TBI regimens was an independent risk factor for poor outcome. TBI for all but the youngest children (age <3 or 4 years) remains standard of care in most centers in North America and Europe.[63,68,75]
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,[76,77,78] 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.
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.[27,81,82,83,84,85,86,87,88][Level of evidence: 3iiA]; [Level of evidence: 3iiB]; [21,75] 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.[88,90,91,92,93] For patients with MRD that is detectable pre-HSCT, the detection of any level of MRD post-HSCT puts that patient at very high risk of failure (>90%). The accuracy of MRD for predicting relapse increases as time from HSCT elapses and relapse risk is 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.[53,94,95,96,97]; [98,99][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.[54,65,94] 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.[102,103,104]; [105,106][Level of evidence: 3iiA]
Another CIBMTR study suggested 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. Improved approaches to haploidentical HSCT using alpha-beta T-cell receptor (TCR)/CD19 depletion or posttransplant cyclophosphamide have shown survival rates that are similar to those in studies using other stem cell sources. A large multicenter trial from Italy showed similar outcomes using alpha-beta TCR/CD19–depleted haploidentical donors compared with matched unrelated donors, with lower rates of GVHD.
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.[94,111,112,113]
To harness 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.[114,115] Trials in Europe and the United States have shown that patients defined as having a high risk of relapse based on increasing recipient chimerism (i.e., increased percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression without excessive toxicity.[116,117]
Intrathecal medication after HSCT to prevent relapse
The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial.[120,121,122,123]
Relapse after allogeneic HSCT for relapsed ALL
For patients with B-ALL who relapse after allogeneic HSCT and can be successfully weaned from immune suppression and have no GVHD, tisagenlecleucel and other 4-1BB CAR T-cell approaches have resulted in EFS rates exceeding 50% at 12 months. For patients with T-ALL who relapse or for patients with B-ALL who are unable to undergo CAR T-cell therapy, 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.[125,126,127,128,129,130]; [69,131][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.[127,128,132] 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 for the treatment of refractory ALL include monoclonal antibody therapy and CAR T-cell therapy.
Monoclonal antibody therapy
The following two immunotherapeutic agents have been studied for the treatment of patients with refractory B-ALL:
In a phase I/II trial of children younger than 18 years with relapsed/refractory B-ALL, 27 of 70 patients (39%) treated at the recommended phase II dose achieved a CR with single-agent blinatumomab; 52% of those achieving CR were MRD negative.
In trials of adult patients with relapsed/refractory B-ALL, CR was achieved in approximately 80% of patients.[139,140]
In a retrospective study of 51 heavily pretreated children with relapsed/refractory B-ALL who received inotuzumab, CR occurred in 67% of patients, with MRD-negative CR occurring in 71% of those patients. Of patients proceeding to HSCT after therapy, 11 of 21 developed veno-occlusive disease (VOD), with an increased risk in patients undergoing a second HSCT. Expert panel recommendations for the prevention of VOD associated with HSCT after inotuzumab include limiting inotuzumab to two doses, avoiding dual-alkylator HSCT regimens, avoiding hepatotoxic agents, and considering VOD prophylactic agents.
CAR T-cell therapy
Chimeric antigen receptor (CAR) T-cell therapy is a therapeutic strategy for pediatric B-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.
Toxicities associated with CAR T-cell therapy
Treatment with CAR T cells has been associated with cytokine release syndrome, which can be life-threatening.[143,144] Cytokine release syndrome presents as fever, headache, myalgias, hypotension, capillary leak, hypoxia, and renal dysfunction. Severe cytokine release syndrome has been effectively treated with tocilizumab, an anti–interleukin-6 receptor (IL-6R) antibody. Long-term persistence of CAR T cells can lead to B-cell aplasia, necessitating immunoglobulin replacement.
Neurotoxicity, including aphasia, altered mental status, and seizures, has also been observed with CAR T-cell therapy, and the symptoms usually resolve spontaneously. CNS symptoms have not responded to IL-6R–targeting agents or other approaches.
Other CAR T-cell therapy side effects include coagulopathy, hemophagocytic lymphohistiocytosis–like laboratory changes, and cardiac dysfunction. Between 20% and 40% of patients require treatment in the intensive care unit, mostly pressor support, with 10% to 20% of patients requiring intubation and/or dialysis.[142,143,146]
CD19-targeted CAR T-cell therapy
Several clinical trials of CAR T cells targeting CD19 in relapsed/refractory ALL have been conducted, with encouraging results. Published trials have involved the use of two types of costimulatory molecules, 4-1BB and CD28. CD28-based approaches have led to high rates of remission, but CAR T cells in these trials rarely persist longer than 1 to 2 months, necessitating HSCT for long-term survival. Many of the trials that used 4-1BB costimulation have resulted in persistence of CAR T cells for extended periods and long-term responses.[124,146]
Evidence (CD19-targeted CAR T-cell therapy):
CD22-targeted CAR T-cell therapy
At least 50% of relapses after CD19-targeted CAR T-cell therapy have occurred because of antigen escape, which has been shown to be related to mutations in the CD19 protein that delete the binding sites used by CAR T-cell constructs. Salvage after antigen escape has been documented with cell and immune therapy approaches targeting a second lymphoid antigen, CD22. Studies looking specifically at inotuzumab rescue of CD19-negative relapse have not been published, but two groups have reported high rates of subsequent achievement of remission and survival, generally when CD22 CAR T-cell therapy is followed by HSCT therapy.[150,151] Because the CD22 antigen can be downregulated, there is concern about targeting CD22 alone for long-term CAR T-cell response; consequently, this approach is often paired with HSCT.
Evidence (CD22-targeted 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%.[152,153,154] 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.[16,156] Of note, in most 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 rate, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS rate, 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.[18,155,158,159]
Evidence (chemotherapy and radiation therapy):
A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.[160,161] 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 rate 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:
Standard approaches for treating isolated testicular relapse in North America include local radiation therapy along with intensive chemotherapy. 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.
There are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy. Treatment protocols that have tested this approach have incorporated intensified dosing of chemotherapy agents (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes.
Evidence (treatment of testicular relapse):
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. Multiple clinical trials investigating new agents, new combinations of agents, and immunotherapeutic approaches are available. (Refer to the ClinicalTrials.gov website for more information.)
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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.
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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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