- General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
- Risk-based Treatment Assignment
- Treatment Option Overview for Childhood ALL
- Treatment for Newly Diagnosed Childhood ALL
- Postinduction Treatment for Childhood ALL
- CNS-directed Therapy for Childhood ALL
- Postinduction Treatment for Specific ALL Subgroups
- Treatment of Relapsed Childhood ALL
- Changes to this Summary (09 / 10 / 2013)
- About This PDQ Summary
- Get More Information From NCI
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.
Childhood Acute Lymphoblastic Leukemia Treatment
General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
- Primary care physician.
- Pediatric surgical subspecialists.
- Radiation oncologists.
- Pediatric medical oncologists/hematologists.
- Rehabilitation specialists.
- Pediatric nurse specialists.
- Social workers.
- Child life professionals.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. Because treatment of children with ALL entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by pediatric oncologists in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the specialists directing the patient's care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.
Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[3,4] For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to approximately 70% for adolescents aged 15 to 19 years.[1,3,4,5] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Incidence and Epidemiology
ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[3,4] ALL occurs at an annual rate of 35 to 40 cases per 1 million people in the United States.[3,4,6] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[6,7] Over the past 25 years, there has been a gradual increase in the incidence of ALL.[3,4,8]
A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[3,4] The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.[3,4]
The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[3,4,6] The incidence is substantially higher in white children than in black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in white children than in black children.[3,4,6]
Childhood ALL originates in the T- and B-lymphoblasts in the bone marrow (see Figure ).
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:
- M1: Fewer than 5% blast cells.
- M2: 5% to 25% blast cells.
- M3: Greater than 25% blast cells.
Most patients with acute leukemia present with an M3 marrow.
Risk Factors for Developing ALL
Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:
- Prenatal exposure to x-rays.
- Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
- Genetic conditions that include the following:
- Inherited genetic polymorphisms.
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[14,15] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[14,15]
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.[16,17,18] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year), ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[16,17]
Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and hyperdiploidy) and unfavorable (t(9;22) or t(4;11) and hypodiploidy) cytogenetic findings and a near absence of T-cell phenotype.[16,17,18,19] Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of this gene.[20,21,22]CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with B-precursor ALL who do not have Down syndrome.[22,23,24] It does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance. However, IKZF1 gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[20,21,25,26,27] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have CRLF2 genomic alterations.[20,21,22] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[21,26] but more study is needed to address this issue and the prognostic significance of IKZF1 gene deletions.
Inherited genetic polymorphisms
Genome-wide association studies show that some germline (inherited) genetic polymorphisms are associated with the development of childhood ALL. For example, the risk alleles of ARID5B are strongly associated with the development of hyperdiploid B-precursor ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[30,31]
Prenatal origin of childhood ALL
Development of ALL is in most cases a multi-step process, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. Evidence in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[32,33] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients appear to have blood cells carrying at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[32,33,34] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[32,35]
There is also evidence that some children who never develop ALL are born with very rare blood cells carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1 translocation, far exceeding the number of cases of ETV6-RUNX1 ALL in children. Other reports confirm  or do not confirm  this finding. Nonetheless, if confirmed, it would support the hypothesis that additional postnatal genomic changes are needed for the development of this type of ALL and that in most cases in which a leukemia-associated alteration is present at birth, the additional leukemogenic genomic changes do not occur and no leukemia develops.
Overall Outcome for ALL
Among children with ALL, more than 95% attain remission, and approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.[43,44,45,46,47,48]
Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients/families.
Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Risk-based Treatment Assignment
Introduction to Risk-based Treatment
Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2,3]
Certain ALL study groups, such as the Children's Oncology Group (COG), use a more or less intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. Factors used by the COG to determine the intensity of induction include immunophenotype and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification stratifies risk according to age and white blood cell (WBC) count:
- Standard risk—WBC count less than 50,000/μL and age 1 to younger than 10 years.
- High risk—WBC count 50,000/μL or greater and/or age 10 years or older.
All study groups modify the intensity of postinduction therapy based on a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics.
Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which are described below. The factors described are grouped into the following three categories:
- Patient characteristics affecting prognosis.
- Leukemic cell characteristics affecting prognosis.
- Response to initial treatment affecting prognosis.
As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables.[5,6] Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.
A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic (risk) groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)
(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for information about important prognostic factors at relapse.)
Prognostic Factors Affecting Risk-based Treatment
Patient characteristics affecting prognosis
Patient characteristics affecting prognosis include the following:
|1.||Age at diagnosis.|
|2.||WBC count at diagnosis.|
|3.||Central nervous system (CNS) involvement at diagnosis.|
|4.||Testicular involvement at diagnosis.|
|5.||Down syndrome (trisomy 21).|
Age at diagnosis
Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.
|1.||Infants (younger than 1 year)
Approximately 80% of infants with ALL have an MLL gene rearrangement.[10,12,13] The rate of MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL translocations decreases but remains higher than that observed in older children.[10,14] Black infants with ALL are significantly less likely to have MLL translocations than white infants. Infants with leukemia and MLL translocations typically have very high WBC counts and an increased incidence of CNS involvement. Overall survival (OS) is poor, especially in infants younger than 6 months.[10,11] A gene expression profile analysis in infants with MLL-rearranged ALL revealed significant differences between patients younger than 90 days and older infants, suggesting distinctive age-related biological behaviors for MLL-translocation ALL that may relate to the significantly poorer outcome for the youngest infants.
Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[10,11,13,16] Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by MLL translocations.[10,11,13]
|2.||Young children (aged 1 to <10 years)
Young children (aged 1 to <10 years) have a better disease-free survival (DFS) than older children, adolescents, and infants.[1,7,17] The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21), also known as the TEL-AML1 translocation).[7,18]
|3.||Adolescents and young adults (≥10 years)
In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years. However, the outcome for older children, especially adolescents, has improved significantly over time.[19,20,21] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[22,23,24] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[25,26,27] (Refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about adolescents with ALL.)
WBC count at diagnosis
A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis, although the relationship between WBC count and prognosis is a continuous rather than a step function. Patients with B-precursor ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.
The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for B-precursor ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[6,28,29,30,31,32,33,34] One factor that might explain the lack of prognostic effect for WBC count at diagnosis may be the very poor outcome observed for T-cell ALL with the early T-cell precursor phenotype, as patients with this subtype appear to have lower WBC count at diagnosis (median, <50,000/µL) than do other T-cell ALL patients.
CNS involvement at diagnosis
The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence or absence of blasts on cytospin as follows:
- CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
- CNS2: CSF with fewer than 5 WBC/µL and cytospin positive for blasts.
- CNS3 (CNS disease): CSF with 5 or more WBC/µL and cytospin positive for blasts.
Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically) than are patients who are classified as CNS1 or CNS2. Some studies have reported increased risk of CNS relapse and/or inferior event-free survival (EFS) in CNS2 patients, compared with CNS1 patients,[37,38] while others have not.[36,39,40,41]
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,[36,40,42,42] but not others.[37,39] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and MLL gene rearrangements.[36,39,40]
Some clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[36,43]; [Level of evidence: 2A] Other groups have not altered therapy based on CNS2 status.[37,44]
To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.
Testicular involvement at diagnosis
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most commonly in T-cell ALL.
In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[46,47] 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)
The lower EFS and OS of children with Down syndrome appear to be related to higher rates of treatment-related mortality and the absence of favorable biological features such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.[48,49,50,51,52] In a report from the COG, among B-precursor ALL patients who lacked MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome. Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK mutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[53,54,55,56,57] In one study of Down syndrome children with ALL, the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK mutations) was associated with an inferior prognosis.
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[58,59,60] 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.[58,59,60] While some reports describe outcomes for boys as closely approaching those of girls,[43,61] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[22,23,62]
The reason for better outcomes in white and Asian children than in black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, black children have a higher relative incidence of T-cell ALL and lower rates of favorable genetic subtypes of precursor B-cell ALL. Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence to oral 6-mercaptopurine in maintenance therapy. In this study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even when adjusting for other known variables. However, at adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse. Ancestry-related genomic variations may also contribute to racial/ethnic disparities in both the incidence and outcome of ALL. For example, the differential presence of specific host polymorphisms in different racial/ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard.
Leukemic cell characteristics affecting prognosis
Leukemic cell characteristics affecting prognosis include the following:
In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology. However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used.
Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., t(8;14)). Patients with this specific rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of B-cell ALL and Burkitt lymphoma.)
The World Health Organization (WHO) classifies ALL as either:
- B lymphoblastic leukemia.
- T lymphoblastic leukemia.
Either B or T lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.
|1.|| Precursor B-cell ALL (WHO B lymphoblastic leukemia)
Before 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.
Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome.[10,70] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.
The major subtypes of precursor B-cell ALL are as follows:
T-cell ALL is defined by expression of the T cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of clinical features, including the following:[17,28,61]
There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6,28,29,30,31,32,33,34] 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.
Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) fusing to one of the T-cell receptor loci and resulting in aberrant expression of these transcription factors in leukemia cells.[76,78,79,80,81,82] These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction. High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL.[78,79,80,82] Overexpression of TLX3/HOX11L2 resulting from the cryptic t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be associated with increased risk of treatment failure, although not in all studies.
Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL.NOTCH1-activating gene mutations occur in approximately 50% of T-cell ALL cases, and FBXW7 inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases having Notch pathway activation by mutations in at least one of these genes. The prognostic significance of Notch pathway activation by NOTCH1 and FBXW7 mutations in pediatric T-cell ALL is not clear, as some studies have shown a favorable prognosis for mutated cases,[84,85,86] while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.[87,88,89]
A NUP214–ABL1 fusion has been noted in 4% to 6% of T-cell ALL cases and is observed in both adults and children with a male predominance.[90,91,92] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region. T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have therapeutic benefit in this T-cell ALL subtype,[90,91,93] although clinical experience with this strategy is very limited.[94,95,96]
Early T-cell precursor ALL
Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors. The subset of T-cell ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases. Compared with other T-ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells. Retrospective analyses have suggested that this subset has a poorer prognosis than other cases of T-cell ALL.[35,98,99] However, further study in larger patient cohorts is needed.
Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as detected by comparative genomic hybridization and/or quantitative DNA–polymerase chain reaction, was associated with early treatment failure in patients with T-cell ALL.[100,101] ABGD is characteristic of early thymic precursor cells, and many of the T-cell ALL patients with ABGD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.
|3.|| Myeloid antigen expression
Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL translocations and those with the ETV6-RUNX1 gene rearrangement.[102,103] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[102,103]
Leukemia of ambiguous lineage
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[104,105,106] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies. However, most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[107,108,109] In the WHO classification, the presence of myeloperoxidase is required to establish myeloid lineage. This is not the case for the EGIL classification.
Leukemias of mixed phenotype comprise the following two groups:
A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Others are associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).
Prognostically significant chromosomal abnormalities in childhood ALL include the following:
|3.||Other genomic alterations
Numerous new genetic lesions have been discovered by various array comparative hybridization and next-generation sequencing methods. Appreciation of these submicroscopic genomic abnormalities and mutations is redefining the subclassification of ALL:[151,152,153,154,155,156,157]
|4.||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.[170,171,172] For example, patients with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes, although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[174,175]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction minimal residual disease (MRD) and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols. Polymorphic variants involving the reduced folate carrier have been linked to methotrexate metabolism, toxicity, and outcome. While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; whether individualized dose modification based on these findings will improve outcome is unknown.
Response to initial treatment affecting prognosis
The rapidity with which leukemia cells are eliminated 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:
|2.||Day 7 and day 14 bone marrow responses.|
|3.||Peripheral blood response to steroid prophase.|
|4.||Peripheral blood response to multiagent induction therapy.|
|5.||Peripheral blood MRD before end of induction (day 8, day 15).|
Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as polymerase chain reaction assays, which determine unique Ig/T-cell receptor gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[129,180,181,182] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities. Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.[129,179,180,181,184] End-induction MRD is used by almost all groups as a factor determining the intensity of postinduction treatment, with patients found to have higher levels allocated to more intensive therapies. MRD levels at earlier (e.g., day 8 and day 15 of induction) and later time points (e.g., week 12 of therapy) also predict outcome.[129,179,181,183,184,185,186,187,188]
MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS of 97% ± 1%) for patients with B-precursor phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).
There are fewer studies documenting the prognostic significance of MRD in T-cell ALL. In the AIEOP-BFM ALL 2000 trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-cell ALL. Patients with detectable MRD at end-induction who had negative MRD by day 78 did just as well as patients who achieved MRD-negativity at the earlier end-induction time point. Thus, unlike in B-cell precursor ALL, end-induction MRD levels were irrelevant in those patients whose MRD was negative at day 78. A high MRD level at day 78 was associated with a significantly higher risk of relapse.
There are few studies of MRD in the CSF. In one study, MRD was documented in about one-half of children at diagnosis. In this study, CSF MRD was not found to be prognostic when intensive chemotherapy was given.
Although MRD is the most important prognostic factor in determining outcome, there are no data to conclusively show that modifying therapy based on MRD determination significantly improves outcome in newly diagnosed ALL.
Day 7 and day 14 bone marrow responses
Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days 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.[129,191]
Peripheral blood response to steroid prophase
Patients with a reduction in peripheral blast count to less than 1,000/µL after a 7-day induction prophase with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response). Poor prednisone response is observed in fewer than 10% of patients.[17,192] Treatment stratification for protocols of the Berlin-Frankfurt-Münster (BFM) clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately before the initiation of multiagent remission induction).
Peripheral blood response to multiagent induction therapy
Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation. Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.
Peripheral blood MRD before end of induction (day 8, day 15)
MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy has also been evaluated as an early response-to-therapy prognostic factor. In a COG study involving nearly 2,000 children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with adverse prognosis, with increasing MRD levels being associated with a progressively poorer outcome. In multivariate analysis, end of induction therapy MRD was the most powerful prognostic factor, but day 8 peripheral blood MRD maintained its prognostic significance, as did NCI risk group and the presence of favorable trisomies. A smaller study assessed the prognostic significance of peripheral blood MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy. This study also observed multivariate significance for peripheral blood MRD levels after 1 week of multiagent induction therapy. Both studies identified a group of patients who achieved low MRD levels after 1 week of multiagent induction therapy who had a low rate of subsequent treatment failure.
The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts at the end of the induction phase is observed in up to 5% of children with ALL. Patients at highest risk of induction failure have one or more of the following features:[196,197]
- T-cell phenotype (especially without a mediastinal mass).
- B-precursor ALL with very high presenting leukocyte counts.
- 11q23 rearrangement.
- Older age.
- Philadelphia chromosome.
In a large retrospective study, the OS of patients with induction failure was only 32%. However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with B-precursor ALL between the ages of 1 and 5 years without adverse cytogenetics (MLL translocation or BCR-ABL). This group had a 10-year survival exceeding 50%, and HSCT in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to 18 years, or who had the Philadelphia chromosome or MLL rearrangement. B-cell ALL patients younger than 6 years and T-cell ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic HSCT after achieving complete remission than those who received further treatment with chemotherapy alone.
Prognostic (Risk) Groups
For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens based on their estimated risk of treatment failure. Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response (e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate molecular characteristics of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at end of induction (and in some cases at later time points). The risk classification systems of the COG and the BFM groups are briefly described below.
Children's Oncology Group (COG) risk groups
In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) based on a subset of prognostic factors, including the following:
- WBC count at diagnosis.
- Cytogenetics/genomic alterations.
- Presence of extramedullary disease.
- Down syndrome.
- Steroid pretreatment.
EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/μL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 75%.[3,43,192,198,199] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage for patients with Down syndrome and MRD levels in peripheral blood on day 8 and in bone marrow samples at the end of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the presence of extramedullary disease, and steroid pretreatment can identify patient groups for postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.[3,129]
- Infants with MLL translocations.
- Patients with hypodiploidy (<44 chromosomes).
- Patients with initial induction failure.
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:
- Standard risk: Patients who are MRD-negative (i.e., <10-4) at both time points are classified as standard risk.
- Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<10-3) at week 12 are considered intermediate risk.
- High risk: Patients with high MRD (≥10-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD.
Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.
Prognostic (risk) groups under clinical evaluation
COG AALL08B1(Classification of Newly Diagnosed ALL): COG protocol AALL08B1 stratifies four risk groups for patients with B-precursor ALL (low risk, average risk, high risk, and very high risk) based on the following criteria:
- Age and presenting leukocyte count (using NCI risk-group criteria).
- Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
- Genomic alterations in leukemia cells.
- Day 8 peripheral blood MRD.
- Day 29 bone marrow morphologic response and MRD.
- Down syndrome.
- Steroid pretreatment.
Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way.
For patients with B-precursor ALL:
- Favorable genetics are defined as the presence of either hyperdiploidy with trisomies of chromosomes 4 and 10 (double trisomy) or the ETV6-RUNX1 fusion.
- Unfavorable characteristics are defined as CNS3 status at diagnosis, induction failure (M3 marrow at day 29), age 13 years and older, and the following unfavorable genomic alterations: hypodiploidy (<44 chromosomes or DNA index <0.81), MLL rearrangement, and iAMP21. The presence of any of these unfavorable characteristics is sufficient to classify a patient as very high risk, regardless of other presenting features. Infants and children with BCR-ABL (Ph+ ALL) are treated on a separate clinical trial.
- MRD levels at day 8 from peripheral blood and at day 29 from bone marrow are used in risk classification.
The four risk groups for B-precursor ALL are defined in Table .
Table 1. Risk Groups for B-Precursor Acute Lymphoblastic Leukemiaa
|Low Risk||Average Risk||High Risk||Very High Risk|
|EFS = event-free survival; HR = age and WBC count risk group is high risk; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood; SR = age/WBC count risk group is standard risk; WBC = white blood cell.|
|a From the Children's Oncology GroupClassification of Newly Diagnosed ALLprotocol.|
|NCI Risk (Age/WBC)||SR||SR||SR||SR||SR||HR (age <13 y)||SR||HR||HR (age ≥13 y)||SR or HR|
|Day 8 PB MRD||<0.01%||≥0.01%||<1%||Any Level||≥1%||Any Level||Any Level||Any Level||Any Level||Any Level|
|Day 29 Marrow MRD||<0.01%||<0.01%||<0.01%||≥0.01%||<0.01%||<0.01%||≥0.01%||≥0.01%||<0.01%||Any Level|
|% of Patients (Estimated)||15%||36%||25%||24%|
|Anticipated 5-year EFS||>95%||90%–95%||88%–90%||<80%|
AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or T-cell Lymphoblastic Lymphoma): For patients with T-cell ALL, COG uses the following criteria to assign risk category:
- NCI standard risk by age (1.00–9.99 years) and WBC count (initial ≤50,000/μL).
- M1 marrow on day 15 and M1 marrow with MRD <0.1% on day 29.
- CNS1 status and no testicular disease at diagnosis.
- Doesn't meet criteria for low risk.
- M1 marrow with MRD <1% on day 29.
- Any CNS status.
- M2 marrow and/or MRD ≥1% on day 29.
- Any CNS status.
DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase vs. Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): On the current clinical trial conducted by the Dana-Farber Cancer Institute ALL Consortium, patients with B-precursor ALL are initially classified as either standard risk or high risk based on age, presenting leukocyte count, and the presence or absence of CNS disease (CNS3). At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined via polymerase chain reaction assay. Patients with high MRD (≥0.001) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.001) continue to receive treatment based on their initial risk group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<44 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Ph+ patients are removed from study midinduction and are eligible to enroll on the COG protocol for patients with Ph+ ALL.
SJCRH (Total XVI): Patients are classified into one of three categories (low, standard, or high risk) based on the presenting age, leukocyte count, presence or absence of CNS3 status or testicular leukemia, immunophenotype, cytogenetics and molecular genetics, DNA index, and early response to therapy. Hence, definitive risk assignment (for provisional low-risk or standard-risk cases based on presenting features) will be made after completion of remission induction therapy. The criteria and the estimated proportion of patients in each category (based on data from TOTXV study) are provided below.
Criteria for low-risk ALL (approximately 48% of patients)
- B-cell precursor ALL with DNA index ≥1.16, ETV6-RUNX1 fusion, or age 1 to 9.9 years and presenting WBC <50 × 109 /L.
- Must not have:
- CNS3 status (≥5 WBC/µl of cerebrospinal fluid with morphologically identifiable blasts or cranial nerve palsy).
- Overt testicular leukemia (evidenced by ultrasonogram).
- Adverse genetic features—t(9;22) or BCR-ABL1 fusion; t(1;19) with E2A-PBX1 fusion; rearranged MLL (as measured by FISH and/or polymerase chain reaction); or hypodiploidy (<44 chromosomes).
- Poor early response (≥1% lymphoblasts on day 15 of remission induction, ≥0.01% lymphoblasts by immunologic or molecular methods on remission date).
Criteria for standard-risk ALL (approximately 44% of patients)
- All cases of T-cell ALL and those of B-cell precursor ALL that do not meet the criteria for low-risk or high-risk ALL.
Criteria for high-risk ALL (approximately 8% of patients)
- t(9;22) or BCR-ABL fusion.
- Infants with t(4;11) or MLL fusion.
- Induction failure or >1% leukemia lymphoblasts in the bone marrow on remission date.
- >0.1% leukemic lymphoblasts in the bone marrow in week 7 of continuation treatment (i.e., before reinduction 1, about 14 weeks postremission induction).
- Re-emergence of leukemic lymphoblasts by MRD (at any level) in patients previously MRD negative.
- Persistently detectable MRD at lower levels.
- Early T-cell precursor ALL, defined by low expression of T-cell markers together with aberrant expression of myeloid markers. The following features characterize early T-cell precursor ALL:
- Levels of CD5 expression at least tenfold lower than that of normal peripheral blood T-lymphocytes. In the study that identified this subset of T-cell ALL, CD5 expression was tenfold to more than 200-fold lower than that of normal lymphocytes and median percentage of leukemic cells expressing CD5 in the 17 atypical cases was 45%; in contrast to more than 98% for the 122 cases in the typical group.
- Absence (<10%) of CD1a and CD8 expression.
- Expression of cytoplasmic CD3 together with the expression of one or more markers associated with myeloid leukemia such as HLA-Dr, CD34, CD13, CD33, or CD11b, while myeloperoxidase is less than 3% by cytochemistry and/or flow cytometry.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Treatment Option Overview for Childhood ALL
Children with acute lymphoblastic leukemia (ALL) should be cared for at a center with specialized expertise in pediatric cancer. Treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment.
Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, patients must be closely monitored at diagnosis and during treatment.
Adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications.[2,3]
Clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the therapeutic innovations that produced increased survival rates in children with ALL were established through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial.
Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with less intensive therapy and to be spared more toxic treatments, while allowing children with a historically lower probability of long-term survival to receive stronger therapy that may increase their chance of cure. (Refer to the Risk-based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.)
Phases of Therapy
Treatment for children with ALL is typically divided as follows:
|1.||Remission induction (at the time of diagnosis).|
|2.||Postinduction therapy (after achieving complete remission).
Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that are poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL). The two most important sanctuary sites in childhood ALL are the central nervous system (CNS) and the testes. Successful treatment of ALL requires therapy that effectively addresses clinical or subclinical involvement of leukemia in these extramedullary sanctuary sites.
Central nervous system (CNS)
Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid specimen with ≥5 WBC/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. CNS-directed treatments include intrathecal chemotherapy, CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current regimens for ALL. (Refer to the CNS-directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for more information.)
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[4,5] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation. The Children's Oncology Group has also adopted this strategy for boys with testicular involvement that resolves completely during induction chemotherapy.
Treatment for Newly Diagnosed Childhood ALL
Standard Treatment Options for Newly Diagnosed ALL
Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include the following:
Remission induction chemotherapy
The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-precursor ALL achieve CR by the end of this phase, with somewhat lower rates in patients with T-cell ALL or high presenting leukocyte counts.[1,2,3,4,5]
Induction chemotherapy consists of the following drugs, with or without an anthracycline:
- Corticosteroid (prednisone or dexamethasone).
The Children's Oncology Group (COG) protocols do not administer anthracycline during induction to patients with National Cancer Institute standard-risk precursor B-cell ALL.
Patients treated by the following study groups receive an induction regimen with four or more drugs regardless of presenting features:
- Berlin-Frankfurt-Münster Group in Europe.
- St. Jude Children's Research Hospital.
- Dana-Farber Cancer Institute ALL Consortium.
The most common four-drug induction regimen is vincristine, corticosteroid (either dexamethasone or prednisone), L-asparaginase, and either doxorubicin or daunorubicin. Some studies have suggested that this more intensive induction regimen may result in improved event-free survival (EFS) in patients presenting with high-risk features, but it may not be necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[7,8] The COG reserves the use of a four-drug induction for patients with high-risk B-precursor ALL and T-cell ALL.
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy.
|1.||The Children's Cancer Group conducted a randomized trial that compared dexamethasone and prednisone in standard-risk ALL patients.
|2.||Another randomized trial was conducted by the United Kingdom Medical Research Council.
|3.||Other randomized trials did not confirm an EFS advantage with dexamethasone.[11,12]|
The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio was 1:5 to 1:7 have shown a better result for dexamethasone, while studies that used a 1:10 ratio have shown similar outcomes.
While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may be more toxic, especially in the context of more intensive induction regimens and in adolescents. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens.[15,16] The increased risk of infection with dexamethasone during the induction phase has not been noted with three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase). Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone  and has been associated with a higher risk of osteonecrosis, especially in patients aged 10 years and older.a
Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:
- Erwinia L-asparaginase.
- Native E. coli L-asparaginase.
Only PEG-L-asparaginase and Erwinia L-asparaginase are available in the United States. Native E. coli L-asparaginase remains available in other countries.
PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients.
PEG-L-asparaginase may be given either intramuscularly (IM) or intravenously (IV). Pharmacokinetics and toxicity profiles are similar for IM and IV PEG-L-asparaginase administration. There is no evidence that IV administration of PEG-L-asparaginase is more toxic than IM administration.[18,19]
PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion after a single injection.
Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of PEG-L-asparaginase given either IM or IV as part of multiagent induction results in serum enzyme activity (>0.1 IU/mL) in nearly all patients for at least 2 to 3 weeks.[18,19,21]
Evidence (use of PEG-L-asparaginase instead of native E. coli L-asparaginase):
|1.|| A randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase was conducted. Each agent was administered for a 30-week period after the achievement of CR. 
|2.|| Another randomized trial of patients with standard-risk ALL assigned patients to receive either PEG-L-asparaginase or native E. coli asparaginase in induction and each of two delayed intensification courses.
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase.
Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or PEG-L-asparaginase.
The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days). If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration to achieve adequate asparagine depletion.
Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):
|1.||In two studies, newly diagnosed patients were randomly assigned to receive the same schedule and dosage of Erwinia L-asparaginase or E. coli L-asparaginase.[23,24]
|2.||A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with an allergy to PEG L-asparaginase leads to therapeutic serum asparaginase enzyme activity levels (defined as a level ≥0.1 IU/mL). On that trial, 96% of children achieved a level of 0.1 IU/mL or more at 2 days and 85% did so at 3 days.|
Response to remission induction chemotherapy
More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[24,27,28]; [Level of evidence: 3iA]
Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic hematopoietic stem cell transplant (HSCT) once CR is achieved.[30,31,4] In a large retrospective series, the 10-year overall survival for patients with persistent leukemia was 32%. A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and B-precursor patients younger than 6 years. B-precursor ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.
For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, particularly the following:
- Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher relapse risk, and has been used in the past by the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is included, these early marrow findings lose their prognostic significance.[34,35]
- End-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[34,36,37,38] Intensification of postinduction therapy for patients with high levels of end-induction MRD is under investigation by many groups.
- MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance.[34,38,39,40,41]
(Refer to the Response to initial treatment affecting prognosis section of this summary for more information.)
(Refer to the CNS-directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about CNS therapy to prevent CNS relapse in children with newly diagnosed ALL.)
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Postinduction Treatment for Childhood ALL
Standard Postinduction Treatment Options for Childhood ALL
Standard treatment options for consolidation/intensification and maintenance therapy include the following:
Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols (Children's Oncology Group [COG], St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during maintenance, while others (Berlin-Frankfurt-Münster [BFM]) do not. (Refer to the CNS-directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia (ALL) who are receiving postinduction therapy.
Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.
The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:
|1.||An initial consolidation (sometimes referred to as "Induction IB") immediately after the initial induction phase. This phase includes cyclophosphamide, low-dose cytarabine, and a thiopurine (mercaptopurine or thioguanine).|
|2.||An interim maintenance phase, which includes multiple doses of either intermediate-dose or high-dose methotrexate (1–5 g/m2) with leucovorin rescue or escalating doses of methotrexate (starting dose 100 mg/m2) without leucovorin rescue.|
|3.||Reinduction (or delayed intensification), which typically includes the same agents used during the induction and initial consolidation phases.|
|4.||Maintenance, typically consisting of mercaptopurine, low-dose methotrexate, and sometimes, vincristine/steroid pulses.|
This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:
- Intensification for higher-risk patients by including additional interim maintenance and/or reinduction phases and administering additional agents during some phases (e.g., vincristine and L-asparaginase added to interim maintenance phases).
- Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-term toxicity.
Other clincal trial groups utilize a different therapeutic backbone during postinduction treatment phases:
- Pediatric Oncology Group (POG): Protocols conducted by the former POG included intensification with high-dose antimetabolite therapy (e.g., multiple doses of intermediate-dose or high-dose methotrexate with leucovorin rescue), but no reinduction/delayed intensification phase.
- DFCI: The DFCI ALL Consortium protocols include 20 to 30 weeks of L-asparaginase beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, low-dose methotrexate, nightly mercaptopurine). These protocols also do not include a delayed intensification phase, but high-risk patients do receive additional doses of doxorubicin (instead of methotrexate) during intensification.
- SJCRH: SJCRH follows a BFM-backbone, but intensifies maintenance for some patients using rotating drug pairs.
In children with standard-risk ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[5,6,7] For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) and vincristine, have been associated with favorable outcomes. Favorable outcomes for standard-risk patients have also been reported by the POG, utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase),[6,9,10] and by the DFCI ALL Consortium utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[11,12]
Evidence (intensification for standard-risk ALL):
|1.||Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone.[13,14,15] The delayed intensification phase on such regimens, including those of the COG, consists of a 3-week reinduction (including anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after remission is achieved.[13,16,17]|
|2.|| A Children's Cancer Group study (CCG-1991/COG-1991) for standard-risk ALL utilized dexamethasone for induction and a second delayed intensification phase. This study also compared escalating intravenous (IV) methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination including oral methotrexate given during two interim maintenance phases.[Level of evidence: 1iiDi]
In high-risk patients, a number of different approaches have been used with comparable efficacy.[11,18]; [Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.
Evidence (intensification for high-risk ALL):
|1.||The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine and L-asparaginase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, National Cancer Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.
|2.||In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.|
|3.||The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
|4.||The use of the cardioprotectant agent dexrazoxane has been shown to prevent cardiotoxicity without adversely impacting EFS in high-risk ALL patients. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2 /dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[24,25]
Very high-risk ALL
- Patients with adverse cytogenetic abnormalities, including t(9;22), MLL gene rearrangements, and low hypodiploidy (<44 chromosomes).
- Patients who achieve complete remission but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high minimal residual disease (MRD) levels at the end of induction (week 4) or later time points (e.g., week 12).
- Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve complete remission.
COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion is not utilized by other groups.
Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM-backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide. However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,27]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, [27,28,29] although it is not clear whether outcomes are better with transplantation.
Evidence (allogeneic HSCT in first remission for very high-risk patients):
|1.||In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22) or t(4;11), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells [WBC] >100,000/μL) were assigned to receive either an allogeneic HSCT in first remission (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.
|2.||In another study of very high-risk patients that included children with extremely high presenting leukocyte counts and those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow [between 5% and 25% blasts]), allogeneic HSCT in first remission was not associated with either a DFS or OS advantage.|
|3.||In a large retrospective series of patients with initial induction failure, the 10-year OS for patients with persistent leukemia was 32%.
Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally call for the administration of oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy. Nonadherence to treatment with 6-mercaptopurine (6-MP) in the maintenance phase is associated with a significant increase in the risk of relapse.
Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[33,34] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[33,34] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than do patients who are homozygous for the normal allele.
Evidence (maintenance therapy):
|1.||In a meta-analysis of randomized trials comparing thiopurines, 6-thioguanine (6-TG) did not improve the overall EFS, although particular subgroups may benefit from its use. The use of continuous 6-TG instead of 6-MP during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[36,37,38,39,40] Because of the increased toxicity of 6-TG, 6-MP remains the standard drug of choice.|
Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains controversial.
Evidence (vincristine/corticosteroid pulses):
|1.||A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[42,43]|
|2.||A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy.|
|3.||In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.|
|4.||A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[Level of evidence: 1iiA]|
For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents. Dexamethasone has not been associated with an increased frequency of these complications in younger patients.[13,46,47,48,49]
Evidence (dexamethasone vs. prednisone):
|1.||In a CCG study, dexamethasone was compared with prednisone for children aged 1 to younger than 10 years with lower-risk ALL.[13,46]
|2.||In a Medical Research Council trial, dexamethasone was compared with prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients.
|3.||In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.
Duration of maintenance therapy
Maintenance chemotherapy generally continues until 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls; on others, there is no difference in the duration of treatment based on gender.[11,17] It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.
Adherence to maintenance therapy
Nonadherence to treatment with 6-MP in maintenance is associated with a significant increase in the risk of relapse.
Evidence (adherence to treatment):
|1.||The COG studied the impact of non-adherence to 6-MP during maintenance in 327 children and adolescents of different ethnic backgrounds.
Treatment options under clinical evaluation
Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk of treatment failure. The Risk-based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.
Ongoing clinical trials include the following:
COG studies for B-precursor ALL
|1.||COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL):
This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/WBC, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, and BCR-ABL).
All patients will receive a three-drug induction (dexamethasone, vincristine, and IV PEG-L-asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive one of the following:
The objective is not to prove superiority of either regimen, but rather, to determine whether excellent outcomes (at least 95% 5-year DFS) can be achieved.
All average-risk patients will receive a modified BFM-backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.
|1.||COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL):
This protocol is open to patients aged 30 years or younger. Patients treated on this trial are classified as either high risk or very high risk. The presence of any of the following is sufficient to classify a patient as very high risk:
The high-risk group includes patients with NCI high-risk ALL who lack very high-risk features, and two groups of NCI standard-risk patients who otherwise lack very high-risk features: (1) those without favorable genetics (no ETV6-RUNX1 or double trisomies 4 and 10), and with day 8 peripheral blood MRD >1%; and (2) those with favorable cytogenetics and with high marrow MRD at day 29. Patients with BCR-ABL (Philadelphia chromosome–positive) are treated on a separate clinical trial.
Patients on this trial will receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV PEG-L-asparaginase) with intrathecal chemotherapy. Patients younger than 10 years receive dexamethasone during induction, and those aged 10 years and older receive prednisone. Postinduction therapy consists of a modified BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase. Very high-risk patients receive a second interim maintenance phase before beginning more standard maintenance. Only patients with CNS3 status at diagnosis receive cranial radiation. Those with M3 marrow at day 29 or low hypodiploidy are eligible for allogeneic HSCT in first remission.
For high-risk patients, the study will compare, in a randomized fashion, triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS.
For very high-risk patients, the study will test, in a randomized fashion, whether intensified consolidation phases (including either cyclophosphamide/etoposide or clofarabine/cyclophosphamide/etoposide) improves 4-year DFS compared with the standard consolidation phase.
|1.||Total XVI study (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): A study at SJCRH is randomly assigning patients to receive either standard-dose (2,500 u/m2) or high-dose (3,500 u/m2) PEG-L-asparaginase during postremission therapy.|
|2.||DFCI-11-001 (NCT01574274)(SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): A DFCI ALL Consortium protocol is comparing the pharmacokinetics and toxicity of two forms of IV PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
This protocol is also examining the following:
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
CNS-directed Therapy for Childhood ALL
Approximately 3% of patients have detectable central nervous system, (CNS) involvement by conventional criteria at diagnosis (cerebrospinal fluid [CSF] specimen with ≥5 white blood cell [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. Therefore, all children with acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy together with some form of CNS prophylaxis.
Because the CNS is a sanctuary site (i.e., an anatomic space that is poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.
Standard treatment options for CNS-directed therapy include the following:
|2.||CNS-directed systemic chemotherapy.|
All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for selective situations.
The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. Data suggest that the following groups of patients are at increased risk of CNS relapse:
- Patients with five or more WBC/µL and blasts in the CSF (CNS3), obtained at diagnosis.
- Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) may be at increased risk of CNS relapse, although this risk appears to be nearly fully abrogated if they receive more doses of intrathecal chemotherapy, especially during the induction phase.
- Patients with T-cell ALL, especially those with high presenting peripheral blood leukocyte counts.
- Patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis may have an increased risk of CNS relapse. These patients receive more intensive CNS-directed therapy on some treatment protocols.[3,4]
CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table :
Table 2. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL
|Disease Status||Standard Treatment Options|
|ALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with five or more white blood cells/µL, cytospin positive for blasts, or cranial nerve palsies.|
|a The drug itself is not CNS-penetrant, but leads to cerebrospinal fluid asparagine depletion.|
|Standard-risk ALL||Intrathecal chemotherapy|
|Methotrexate with cytarabine and hydrocortisone|
|CNS-directed systemic chemotherapy|
|High-dose methotrexate with leucovorin rescue|
|Escalating-dose intravenous methotrexate (no leucovorin rescue)|
|High-risk ALL||Intrathecal chemotherapy|
|Methotrexate with cytarabine and hydrocortisone|
|CNS-directed systemic chemotherapy|
|High-dose methotrexate with leucovorin rescue|
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:
|2.||Methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy).|
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:
- L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion).
- High-dose methotrexate with leucovorin rescue.
- Escalating dose intravenous (IV) methotrexate without leucovorin rescue.
Evidence (CNS-directed systemic chemotherapy):
|1.||In a randomized Children's Cancer Group (CCG) study of standard-risk patients who all received the same dose and schedule of intrathecal methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.|
|2.||In another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate given during each of two interim maintenance phases.|
|3.||In a randomized clinical trial conducted by the former Pediatric Oncology Group, T-cell ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate than patients who did not receive high-dose methotrexate.|
The proportion of patients receiving cranial radiation has decreased significantly over time. At present, most newly diagnosed children with ALL are treated without cranial radiation. Many groups administer cranial radiation only to those patients considered to be at highest risk of subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/μL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count. In patients who do receive cranial radiation, the dose has been significantly reduced.
Ongoing trials seek to determine whether radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[11,12] A meta-analysis of randomized trials of CNS-directed therapy has confirmed that radiation therapy can be replaced by intrathecal chemotherapy in most patients with ALL. Additional systemic therapy may be required depending on the agents and intensity used.[Level of evidence: 1iDi]
CNS Therapy for Standard-risk Patients
Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[11,12,13,14,15,16]
Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
|1.||The CCG-1952 study for National Cancer Institute (NCI) standard-risk patients compared the relative efficacy and toxicity of triple intrathecal chemotherapy (methotrexate, hydrocortisone, and cytarabine) with methotrexate as the sole intrathecal agent in nonirradiated patients.
CNS Therapy for High-risk Patients
Controversy exists as to which high-risk patients should be treated with cranial radiation. Depending on the protocol, up to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis. Patients receiving cranial radiation on many treatment regimens include the following:
- Patients with T-cell phenotype and high initial WBC count.
- Patients with high-risk precursor B-cell ALL (e.g., extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities and/or CNS3 disease).
Both the proportion of patients receiving radiation and the dose of radiation administered have decreased over the last 2 decades.
Evidence (cranial radiation):
|1.||In a trial conducted between 1990 and 1995, the Berlin-Frankfurt-Münster (BFM) group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients.|
|2.|| In the follow-up trial conducted by the BFM group between 1995 and 2000 (BFM-95), cranial radiation was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.
|3.||Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[11,12,24] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses and intensified dosing of L-asparaginase,[11,12] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine during postinduction treatment phases for CNS3 (CSF with ≥5 WBC/µL and cytospin positive for blasts) patients.
CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis
Therapy for ALL patients with clinically evident CNS disease (≥5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation (usual dose is 18 Gy).[16,18] Spinal radiation is no longer used.
Evidence (cranial radiation):
|1.||SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[11,24] These trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH study also included higher cumulative doses of anthracycline than on Children's Oncology Group (COG) trials, and frequent vincristine/dexamethasone pulses and intensified dosing of L-asparaginase,, while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 (CSF with ≥5 WBC/µL and cytospin positive for blasts) patients.
Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Treatment options under clinical evaluation include the following:
|1.||COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): In the COG protocol (COG-AALL0434) for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-risk features, no evidence of CNS disease, and a rapid response to induction therapy) are treated without cranial radiation, and intermediate-risk and high-risk T-cell patients receive 12 Gy (instead of 18 Gy) cranial radiation. Patients with CNS3 disease at diagnosis continue to receive 18 Gy cranial radiation. All patients are randomly assigned to receive either high-dose methotrexate (5 g/m2 over 24 hours) with leucovorin rescue or escalating-dose methotrexate without leucovorin rescue during the initial interim maintenance phase of therapy. Intermediate-risk and high-risk patients are also randomly assigned to receive or not receive nelarabine, an antipurine with selective activity in T-lymphoblasts.|
|2.||COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy).|
|3.||SJCRH Total XVI (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features, including those with a t(1;19) translocation, receive intensified intrathecal therapy.|
Toxicity of CNS-directed Therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
|1.||Acute/subacute toxicities (e.g., seizures, stroke, somnolence syndrome, and ascending paralysis).|
|2.||Late-developing toxicities (e.g., meningiomas and other second neoplasms; leukoencephalopathy; and a range of neurocognitive, behavioral, and neuroendocrine disturbances).[25,26,27]|
The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of intrathecal chemotherapy will have at least one seizure during therapy. Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to intrathecal chemotherapy.
Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome. Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.
In general, patients who receive intrathecal chemotherapy without cranial radiation appear to have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[30,31,32,33] This modest decline is primarily seen in young children and girls.
A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[Level of evidence: 3iiiC]
Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances. Long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[37,38,39,40,41] At doses of 18 Gy, it does not appear that irradiated patients have more severe neurocognitive impairments than ALL survivors who were treated without radiation. On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose. Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of late effects.
The following groups have been associated with neurocognitive and neuroendocrine sequelae after cranial radiation:
- Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae after cranial radiation.[42,43,44]
- Girls may be at a higher risk than boys of radiation-induced neuropsychologic and neuroendocrine sequelae.[43,44,45]
- Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24–28 Gy) on clinical trials conducted in the 1970s and 1980s.
Evidence (toxicity of cranial radiation):
|1.||In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; cognitive function for both groups was not significantly impaired.|
|2.||In another randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, cognitive function for both groups (assessed at a median of 6 years postdiagnosis) was in the average range, with only subtle differences noted between the groups in cognitive skills.[Level of evidence: 1iiC]|
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas, although high-grade lesions may occur.[27,48,49] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered. In general, systemic methotrexate doses greater than 1 g/m2 should not be given after cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
Postinduction Treatment for Specific ALL Subgroups
Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 10-year overall survival (OS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) DFCI-95001 (NCT00004034) trial was 90.1% compared to 88.7% for patients with B-cell disease. However, in a review of a large number of patients treated on COG trials over a 15-year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis.
|1.||Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL differently from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy regimen for this protocol was based on the DFCI-87001 regimen.
|2.||Protocols of the former Children's Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria.
|3.||In the Children's Oncology Group (COG), children with T-cell ALL are not treated on the same protocols as children with precursor B-cell ALL. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [8,9] in the context of a BFM regimen for patients with newly diagnosed T-cell ALL. The pilot study showed a 5-year EFS rate of 73% for all patients receiving nelarabine and 69% for those patients with a slow early response.|
|4.||The role of prophylactic cranial radiation in the treatment of T-cell ALL is controversial. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation in first-line treatment of ALL, while other groups, such as DFCI, COG, and BFM, use radiation for the majority of patients with T-cell ALL.|
Treatment options under clinical evaluation for T-cell ALL
Treatment options under clinical evaluation for T-cell ALL include the following:
|1.||COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma):
COG-AALL0434 is a phase III trial utilizing a modified augmented BFM regimen for patients aged 1 to 30 years with T-cell ALL. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial include the following:
|2.||DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma):
Patients with T-cell ALL are eligible to enroll on a DFCI ALL Consortium protocol that is comparing the pharmacokinetics and toxicity of two forms of intravenous PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
This protocol is also testing whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase. All T-cell patients are treated on the high-risk arm of this trial, regardless of other presenting characteristics.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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.[12,13,14] Despite intensification of therapy, long-term EFS rates remain below 50%. Infants with congenital leukemia (diagnosed within 1 month of birth) have a particularly poor outcome (17% OS).[Level of evidence: 2A].
For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[12,13,15,16,17][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include the following:; [Level of evidence: 3iDii]
- A very young age (<6 months).
- Extremely high presenting leukocyte count (≥200,000–300,000/μL).
- High levels of MRD at the end of induction and consolidation phases of treatment.
Treatment options for infants withMLLtranslocations
Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients.
Evidence (intensified chemotherapy regimens for infants with MLL translocations):
|1.||The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations.|
|2.||The COG tested intensification of therapy with a regimen including multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide, resulting in a 5-year EFS of 34%.|
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with MLL gene translocations remains controversial.
Evidence (allogeneic HSCT in first remission for infants with MLL translocations):
|1.||On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL-rearrangement were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.
|2.||In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who underwent HSCT in first CR and those who received chemotherapy alone.|
|3.||The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone response) with MLL translocations treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.
Treatment options for infants withoutMLLtranslocations
The optimal treatment for infants without MLL translocations also remains unclear.
|1.||On the Interfant-99 trial, patients without MLL translocations achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%).|
|2.||A favorable outcome for this subset of patients was obtained in a Japanese study using therapy comparable to that used to treat older children with ALL; however, that study was limited by small numbers (n = 22) and a highly unusual gender distribution (91% males).|
Treatment options under clinical evaluation for infants with ALL
Treatment options under clinical evaluation include the following:
|1.||Interfant-06 Study Group trial (DCOG-INTERFANT-06) (Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia): The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC >300,000 /µL) or poor peripheral blood response to steroid prophase. Infants with MLL-rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic HSCT in first remission regardless of other presenting features.|
|2.||COG-AALL0631(Combination Chemotherapy With or Without Lestaurtinib in Treating Infants With Newly Diagnosed ALL): In this COG study of infant ALL, an FLT3 inhibitor, lestaurtinib, is being studied in infants with MLL rearrangement. Infants with MLL rearrangement are known to have a high level of FLT3 mRNA expression and lestaurtinib has been shown to selectively kill MLL-rearranged ALL cells in vitro and in vivo. This study combines lestaurtinib with intensive chemotherapy previously utilized in POG-P9407. An initial safety/activity phase has been completed and the efficacy phase in which children will be randomly assigned to chemotherapy with or without lestaurtinib is now underway. Infants with germline MLL are nonrandomly assigned to less-intensive chemotherapy without lestaurtinib.|
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.[23,24,25] The reasons for this difference include more frequent presentation of adverse prognostic factors at diagnosis, including the following:
- T-cell immunophenotype.
- Philadelphia chromosome–positivity (Ph+).
- Lower incidence of favorable cytogenetic abnormalities.
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.[28,29,30,31,32]; [Level of evidence: 2A] These study results are summarized in Table 3.
Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.
Evidence (pediatric treatment regimen):
|1.||Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study (a pediatric ALL regimen) who showed a 7-year EFS of 63% compared with 124 adolescents and young adults treated on the Cancer and Leukemia Group B (CALGB) study (an adult ALL regimen) with a 7-year EFS of 34%.|
|2.||A study from France of patients aged 15 to 20 years and diagnosed between 1993 and 1999 demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).|
|3.||In the COG high-risk study (CCG-1961), the 5-year EFS rate for 262 patients aged 16 to 21 years was 71.5%.[Level of evidence: 1iiDi] For rapid responders randomly assigned to early intensive postinduction therapy on the augmented intensity arms of this study, the 5-year EFS rate was 82% (n = 88).|
|4.||The DFCI ALL Consortium reported that a study of 51 adolescents aged 15 to 18 years in a pediatric trial had a 5-year EFS of 78%.|
|5.||In an SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% ± 5%.|
|6.||In a Spanish study, 35 adolescents (aged 15–18 years) and 46 young adults (aged 19–30 years) with standard-risk ALL were treated with a pediatric-based regimen.[Level of evidence: 2A]
The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following: 
- Treatment setting (i.e., site experience in treating ALL).
- Adherence to protocol therapy.
- The components of protocol therapy.
Table 3. Outcome According to Treatment Protocol for Adolescents and Young Adults with ALL
|Site and Study Group||Adolescent and Young Adult Patients (No.)||Median age (y)||Survival (%)|
|ALL = acute lymphoblastic leukemia; EFS = event-free survival; OS = overall survival.|
|AEIOP = Associazione Italiana Ematologia Oncologia Pediatrica; CALGB = Cancer and Leukemia Group B; CCG = Children's Cancer Group; DCOG = Dutch Childhood Oncology Group; FRALLE = French Acute Lymphoblastic Leukaemia; GIMEMA = Gruppo Italiano Malattie e Matologiche dell'Adulto; HOVON = Dutch-Belgian Hemato-Oncology Cooperative Group; LALA = France-Belgium Group for Lymphoblastic Acute Leukemia in Adults; MRC = Medical Research Council (United Kingdom); NOPHO = Nordic Society for Pediatric Hematology and Oncology; UKALL = United Kingdom Acute Lymphoblastic Leukaemia.|
|CCG (Pediatric)||197||16||67, OS 7 y|
|FRALLE 93 (Pediatric)||77||16||67 EFS|
|AEIOP (Pediatric)||150||15||80, OS 2 y|
|DCOG (Pediatric)||47||12||71 EFS|
|NOPHO 92 (Pediatric)||36||16||74, OS 5 y|
|MRC ALL (Pediatric)||61||15–17||71, OS 5 y|
|UKALL XII (Adult)||67||15–17||56|
Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[30,38] Before the use of postinduction intensification for treatment of ALL, osteonecrosis was infrequent. The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.
The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative interventions are needed for management of symptoms and impaired mobility in more than 40% of cases. The majority of the cases are diagnosed within the first 2 years of therapy and often the symptoms are recognized during maintenance.
|1.||In the CCG-1961 high-risk ALL study, alternate-week dosing of dexamethasone was compared with standard continuous dexamethasone during delayed intensification to see if the osteonecrosis risk could be reduced.
Treatment options under clinical evaluation for adolescent and young adult patients with ALL
Treatment options under clinical evaluation include the following:
|1.||COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): This is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and MRD level at day 29. The following are objectives of the trial: (1) to determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients, (2) to determine the relative safety and efficacy of high-dose versus Capizzi methotrexate during interim maintenance, and (3) to test the efficacy of treating low-risk T-cell ALL patients without cranial radiation.|
|2.||COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Patients with very high-risk disease include those who, at diagnosis:
These patients are eligible for a three-arm study designed to assess the efficacy of either clofarabine/etoposide/cyclophosphamide versus cyclophosphamide/etoposide versus the standard cyclophosphamide/thioguanine/cytarabine combination during the consolidation and late intensification phases.
Philadelphia Chromosome–positive ALL
Philadelphia chromosome–positive (Ph+) ALL is seen in about 3% of pediatric ALL cases, increases in adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as extremely difficult to treat with poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS of 25%, with an OS of 36%. In 2010, the same group reported a 7-year EFS of 31% and an overall survival of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors. Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow transplantation, and currently to combination therapy using chemotherapy plus tyrosine kinase inhibitor.
Pre-tyrosine kinase inhibitor era
Before the use of imatinib mesylate, HSCT from a matched sibling donor was the treatment of choice for patients with Ph+ ALL.[41,42,43] Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome than standard (pre-imatinib mesylate) chemotherapy. In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib mesylate era), transplantation with matched-related or matched-unrelated donors were equivalent. DFS at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and OS was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.
Factors significantly associated with favorable prognosis in the pre-tyrosine kinase inhibitor era included the following:
- Younger age at diagnosis.
- Lower leukocyte count at diagnosis.
- Early response measures.[40,44,45]
- Ph+ ALL with a rapid morphologic response or rapid peripheral blood response to induction therapy.[40,44]
Tyrosine kinase inhibitor era
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[49,50]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[51,52,53] Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[54,55,56,57]
Evidence (imatinib mesylate):
|1.||The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.
|2.||A nonrandomized study reported the outcome in 16 pediatric patients with Ph+ ALL who were treated with chemotherapy, imatinib, and allogeneic HSCT.
|3.||The EsPhALL trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improves outcome for pediatric Ph+ ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk based on early response measures and remission status at the end of induction. Good risk patients (N = 90) were randomly assigned to receive imatinib or not; poor risk patients (N = 70) were directly assigned to imatinib. Interpretation of this study is limited due to the high noncompliance rate with randomized assignment in good risk patients and early closure before reaching goal accrual due to publication of the results of the COG AALL1131 trial on which imatinib had been given continuously with chemotherapy. The overall DFS of patients treated on this trial appeared to be better than historic controls, and when analyzed as-treated (and not by intent-to-treat), good risk patients who received imatinib had a superior DFS. The EsPhALL trial has since been amended to test continuous dosing of imatinib; results are pending.|
Dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial treatment of Ph+ ALL. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.
Treatment options under clinical evaluation for Philadelphia chromosome–positive ALL
Treatment options under clinical evaluation include the following:
|1.||COG-AALL1122 (NCT01460160) (Pediatric Ph+ ALL): In this international collaborative study, patients receive dasatinib, which has increased affinity for BCR/ABL1, in conjunction with a chemotherapy backbone based on the European EsPhALL regimen. Allogeneic HSCT in first remission is reserved for those patients with suboptimal early response to therapy, as measured by morphology and MRD techniques. The goals of this study include the following:
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Treatment of Relapsed Childhood ALL
Prognostic Factors After First Relapse of Childhood ALL
The two most important prognostic risk factors after first relapse of childhood ALL are the following:
- Site of relapse.
- Time from diagnosis to relapse.
Other prognostic factors include the following:
- Patient characteristics (e.g., age and peripheral blast count at time of relapse).
- Risk group classification at initial diagnosis.
- Response to reinduction therapy.
- Cytogenetics/genomic alterations.
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 have a better prognosis than those with a marrow relapse.[5,13]
Time from diagnosis to relapse
For patients with relapsed B-precursor ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For example, survival rates range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to 40% to 50% for those whose relapses occur more than 36 months from diagnosis.[5,13]
For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early relapse (<18 months from diagnosis) are 40% to 50% and 75% to 80% for those with late relapses (>18 months from diagnosis).[13,16] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.
Age 10 years and older at diagnosis has been reported as an independent predictor of poor outcome. A Children's Oncology Group (COG) study further showed that although patients aged 10 to 15 years at initial diagnosis do worse than patients aged 1 to 9 years (35% vs. 48%, 3-year postrelapse survival), those older than age 15 years did much worse (3-year OS, 15%; P = .001).
The Berlin-Frankfurt-Münster (BFM) group has also reported that high peripheral blast counts (>10,000/μL) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.
Children with Down syndrome with relapse of ALL had inferior outcomes as reported in a BFM report before 2000, primarily due to increased induction deaths and treatment-related mortality. However, since 2000, there was no difference in outcome between patients with Down syndrome and patients without Down syndrome.
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.[Level of evidence: 2Di]; [Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[20,22,23,24]; [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.
TP53 alterations (mutations and/or copy number alterations) are observed in approximately 11% of patients with ALL at first relapse and have been associated with an increased likelihood of induction failure (38.5% TP53 alteration vs. 12.5% TP53 wild-type) and poor event-free survival (EFS) (9% TP53 alteration vs. 49% TP53 wild-type). Approximately half of the alterations were present at initial diagnosis and half were newly observed at time of relapse.
Boys with ETV6-RUNX1–positive ALL at diagnosis who relapse are more likely to have a testicular relapse than are boys without ETV6-RUNX1 ALL. Relapse, most commonly occurs more than 36 months after diagnosis. Of patients who relapsed at any site more than 36 months after diagnosis, the presence of ETV6-RUNX1 is associated with an improved survival outcome (5-year OS, 81% vs. 50%; P = .015).
Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any time during treatment or posttreatment are less likely to achieve a second remission and long-term EFS than are patients with B-cell ALL.[5,20]
Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL
Standard treatment options for first bone marrow relapse include the following:
|2.||Postreinduction therapy for patients achieving a second complete remission.|
Initial treatment of relapse consists of reinduction therapy to achieve a CR2. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a CR2 at the end of the first month of treatment.; [Level of evidence: 2A]; [Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) than do those with late marrow relapses (approximately 95%).[20,28]
|1.||A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination including doxorubicin followed by two intensive consolidation blocks before either hematopoietic stem cell transplantation or chemotherapy continuation.
|2.||A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone. [Level of evidence: 1iiA]
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
|3.||Investigators from the ALL-REZ BFM group used a six-drug reinduction approach, including high-dose methotrexate. A randomized comparison of 1 g/m2 of methotrexate versus 5 g/m2 of methotrexate with reinduction showed no advantage at the higher dose.|
|4.||The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 42% to 56% of patients with refractory or multiply relapsed disease.[31,32]; [Level of evidence: 2A]|
|5.||The combination of bortezomib plus vincristine, dexamethasone, peg-asparaginase, and doxorubicin was reported to induce complete response (with or without platelet recovery) in 80% of multiply relapsed patients with B-precursor ALL.[Level of evidence: 3iiiDiv] Notably, this trial did not include patients who were refractory to reinduction.|
Patients with relapsed T-cell ALL have much lower rates of achieving second complete remission with standard reinduction regimens than do patients with B-precursor phenotype. Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%. The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.
Postreinduction therapy for patients achieving a second complete remission
Early-relapsing B-precursor ALL
For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in higher leukemia-free survival than a chemotherapy approach.[7,25,37,38,39,40,41,42,43,44,45] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%. (Refer to the Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse section of this summary for more information.)
Late-relapsing B-precursor ALL
For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of second complete remission has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[5,9,29,46,47,48]; [Level of evidence: 3iiA] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no HSCT) in second complete remission. Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction requires further study.
Evidence (MRD-based risk stratification for late-relapse of B-precursor ALL):
|1.||In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in second complete remission, the 2-year cumulative incidence of relapse was 49% for the 12 patients who were MRD-positive at the end of reinduction and 0% for the 11 patients who were MRD-negative.|
|2.|| In BFM studies, patients are considered to be intermediate risk if they have a late isolated marrow relapse or an early or late combined marrow/extramedullary relapse. In a study from this group of 61 children with intermediate-risk relapsed B-cell ALL treated with chemotherapy alone in second complete remission (no HSCT), end-reinduction MRD (assessed by a polymerase chain reaction–based assay) significantly predicted outcome.
For patients with T-cell ALL who achieved remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor, and these patients are usually treated with allogeneic HSCT in second complete remission, regardless of time to relapse.
Standard Treatment for Second and Subsequent Bone Marrow Relapse
Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant is generally considered a reasonable approach for those achieving remission. Long-term survival for all patients after a second relapse is particularly poor, in the range of less than 10% to 20%. One of the main reasons for this is failure to obtain a third remission. In spite of numerous attempts at novel combination approaches, only about 40% of children with second relapse are able to achieve remission. If these patients achieve CR, HSCT has been shown to cure 20% to 35%, with failures occurring due to high rates of relapse and transplant-related mortality.[51,52,53,54,55][Level of evidence: 3iiA]
Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
Components of the transplantation process
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:
|1.||Total-body irradiation (TBI)-containing transplant preparative regimens.|
|2.||MRD detection just before transplant.|
|3.||Donor type and HLA match.|
|4.||Immune modulation after transplant to prevent relapse.|
TBI-containing transplant preparative regimens
For patients proceeding to allogeneic HSCT, TBI appears to be an important component of the conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant conditioning regimens that include TBI produce higher cure rates than do chemotherapy-only preparative regimens.[37,56,57] 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,[58,59] although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary. Many standard regimens include cyclophosphamide with TBI dosing between 1.32 and 1.4 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 1.2 Gy resulted in worse survival due to excessive toxicity.
MRD detection just before transplant
Disease status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates. Several studies have also demonstrated that the level of MRD at the time of transplant is a key risk factor in children with ALL in CR undergoing allogeneic HSCT.[23,62,63,64,65] 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. Several study groups are attempting to answer this question.
Donor type and HLA match
Survival rates after matched unrelated donor and umbilical cord blood transplantations have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.[41,66,67,68,69]; [Level of evidence: 2A]; [Level of evidence: 3iiiA]; [Level of evidence: 3iiiDii] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related mortality remain higher after unrelated donor transplantation compared with matched sibling donor transplants.[42,51,66] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and Center for International Blood and Marrow Transplant Research (CIBMTR) analyses have demonstrated that rates of GVHD, treatment-related mortality, and OS have improved over time.; [74,75][Level of evidence: 3iiA]
Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor. In certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered. For T cell-depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells may have a better outcome than those who receive paternal stem cells.[Level of evidence: 3iiA]
Immune modulation after transplant to prevent relapse
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. Trials in Europe and the United States have shown that patients defined as having a high risk of relapse based upon increasing recipient chimerism (i.e., increased percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression without excessive toxicity. One study showed that in 46 patients with increasing recipient chimerism, the 31 patients who underwent immune suppression withdrawal, donor lymphocyte infusion, or both therapies had a 3-year EFS of 37% versus 0% in the nonintervention group (P < .001).
Intrathecal medication after HSCT to prevent relapse
Relapse after allogeneic HSCT for relapsed ALL
For patients relapsing after an allogeneic HSCT for ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure because of failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy. Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term EFS.[86,87,88]; [55,89][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.[87,88,90] In addition, one study showed an improvement in survival after second HSCT if acute GVHD occurred, especially if it had not occurred after the first transplant.
Reduced-intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a CR confirmed by flow cytometry.[Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.; [Level of evidence: 3iiiA]
Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is unknown, and a small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[Level of evidence: 3iA]
Treatment of Isolated Extramedullary Relapse
With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5%, and testicular relapse is less than 1% to 2%.[96,97,98] As with bone marrow and mixed relapses, time from initial diagnosis to relapse is a key prognostic factor in isolated extramedullary relapses. In addition, age older than 6 years at diagnosis was noted to be an adverse prognostic factor for patients with an isolated extramedullary relapse in one study. Of note, in the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques, and successful treatment strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis (5-year EFS, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS, 60%).
Standard treatment options for childhood ALL that has recurred in the CNS include the following:
|1.||Systemic and intrathecal chemotherapy.|
|2.||Cranial or craniospinal radiation.|
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.[16,99,102,103]
Evidence (chemotherapy and radiation therapy):
|1.||In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or longer had a 4-year EFS rate of approximately 80% compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.|
|2.||In a follow-up POG study, children who had not previously received radiation therapy and who had initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only. The 4-year EFS was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS of 52%.|
A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.[104,105] The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.
|1.||In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above, 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses.
The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.
Standard treatment options in North America for childhood ALL that has recurred in the testes include the following:
The standard approach for treating isolated testicular relapse in North America is to administer intensive chemotherapy that includes high-dose methotrexate. Patients who do not respond with a CR after induction also receive local radiation therapy.
In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control (surgical removal or radiation) is to be performed. A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes is being tested in clinical trials.
Evidence (treatment of testicular relapse [case reports]):
|1.||Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation. All five boys were long-term survivors.|
|2.||In a small series of boys who had an isolated testicular relapse after a HSCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second HSCT.[Level of evidence: 3iA]|
Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
Treatment options under clinical evaluation include the following:
COG trials for ALL in first relapse
The COG has divided patients with first relapse into three risk categories as outlined in Table . Clinical trials in some risk categories are available.
Table 4. Children's Oncology Group ALL Relapse Risk Stratification for B-Precursor ALLa
|Isolated CNS or Testicular Relapse||Bone Marrow or Combined Relapse|
|ALL = acute lymphoblastic leukemia; CNS = central nervous system.|
|a All relapsed T-cell ALL is considered high risk.|
|<18 months from diagnosis||Intermediate risk||High risk|
|18–36 months from diagnosis||Low risk||High risk|
|>36 months from diagnosis||Low risk||Intermediate risk|
|1.||COG-AALL07P1 (Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed ALL or Lymphoblastic Lymphoma): Patients with marrow relapse of T-cell ALL and early marrow relapse (<36 months) of B-precursor ALL are eligible for this study. This is a phase II pilot study to determine the feasibility and safety of adding bortezomib to intensive reinduction chemotherapy. Bortezomib is a proteasome inhibitor that has been shown to sensitize leukemic cells to apoptosis induced by chemotherapy.|
Other trials for ALL in first relapse
|1.||TACL 2008-002 (NCT00981799) (Trial of Nelarabine, Etoposide, and Cyclophosphamide in Relapsed T-cell ALL and T-cell Lymphoblastic Lymphoma): This trial, conducted by the Therapeutic Advances in Childhood Leukemia & Lymphoma clinical trials group, is testing the feasibility of administering nelarabine in combination with cyclophosphamide and etoposide as reinduction for patients with T-cell ALL in first relapse (as well as those who failed primary induction therapy). Doses of nelarabine and cyclophosphamide will be escalated in successive cohorts of patients to determine the maximum tolerated doses of these drugs when given in combination.|
|2.||DFCI-11-237 (NCT01523977) (Everolimus With Multiagent Reinduction Chemotherapy in Pediatric Patients With ALL): Patients in first relapse are eligible to enroll on a Dana-Farber Cancer Institute ALL Consortium trial testing the feasibility of administering everolimus, an oral mTOR inhibitor, in combination with multiagent reinduction (vincristine, prednisone, doxorubicin, intravenous PEG-L-asparaginase, and intrathecal chemotherapy).|
Trials for ALL in second or subsequent relapse
|1.||NCT01471782 (Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-Precursor ALL): This is a phase I and II trial evaluating the safety and efficacy of blinatumomab, the CD3-CD19 binding molecule, in recruiting autologous T-cells to treat relapsed B-cell ALL.|
|2.||COG-ADVL1114 (NCT01403415) (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed ALL or Non-Hodgkin Lymphoma [NHL]): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALL R3 induction regimen for patients with relapsed ALL and NHL.|
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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Changes to this Summary (09 / 10 / 2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:
- Robert J. Arceci, MD, PhD (Phoenix Children's Hospital)
- Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Michael A. Pulsipher, MD (Primary Children's Medical Center)
- Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
- Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Malcolm A. Smith, MD, PhD (National Cancer Institute)
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National Cancer Institute: PDQ® Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-09-10
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