jueves, 31 de octubre de 2019

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 4/9 –Health Professional Version - National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

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 cure varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2]
Certain ALL study groups, such as the Children’s Oncology Group (COG), use a more- or less-intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. Factors used by the COG to determine the intensity of induction include immunophenotype, the presence or absence of extramedullary disease, steroid pretreatment, the presence or absence of Down syndrome, and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification for B-ALL stratifies risk according to age and white blood cell (WBC) count, as follows:[3]
  • 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 on the basis of a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics and genomic alterations.[4] Detection of the Philadelphia chromosome (i.e., Philadelphia chromosome–positive [Ph+] ALL) leads to immediate changes in induction therapy.[5]
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.[6] Factors affecting prognosis are grouped into the following three categories:
As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables. Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.
A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic [risk] groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)
(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for information about important prognostic factors at relapse.)

Prognostic Factors Affecting Risk-Based Treatment

Patient and clinical disease characteristics

Patient and clinical disease characteristics affecting prognosis include the following:
Age at diagnosis
Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7]
  1. Infants (younger than 1 year)
    Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in the following groups:
    • Infants younger than 6 months (with an even poorer prognosis for those aged ≤90 days).[8-12]
    • Infants with extremely high presenting leukocyte counts (>200,000–300,000 × 109/L).[9]
    • Infants with a poor response to a prednisone prophase.[9]
    • Infants with a KMT2A (MLL) gene rearrangement.[8-11]
    Up to 80% of infants with ALL have a translocation of 11q23 with numerous chromosome partners generating a KMT2A gene rearrangement.[9,11,13,14] The most common rearrangement is KMT2A-AFF1 (t(4;11)(q21;q23)), but KMT2A rearrangements with many other translocation partners are observed.
    The rate of KMT2A gene rearrangements is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of KMT2A rearrangements decreases but remains higher than that observed in older children.[9,15] Black infants with ALL are significantly less likely to have KMT2A rearrangements than are white infants.[15]
    Infants with leukemia and KMT2A rearrangements typically have very high WBC counts and an increased incidence of CNS involvement. Event-free survival (EFS) and overall survival (OS) are poor, with 5-year EFS and OS rates of only 35% to 40% for infants with KMT2A-rearranged ALL.[9-11] A comparison of the landscape of somatic mutations in infants and children with KMT2A-rearranged ALL revealed significant differences between the two groups, suggesting distinctive age-related biological behaviors for KMT2A-rearranged ALL that may relate to the significantly poorer outcome for infants.[16,17]
    Blasts from infants with KMT2A rearrangements are often CD10 negative and express high levels of FLT3.[9,10,14,18] Conversely, infants whose leukemic cells show a germline KMT2A gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by KMT2A rearrangements.[9,10,14,19]
    (Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)
  2. Young children (aged 1 to <10 years)
    Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants.[3,7,20-22] The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts, including hyperdiploidy with 51 to 65 chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 fusion (t(12;21)(p13;q22), also known as the TEL-AML1 translocation).[7,23,24]
  3. Adolescents and young adults (aged ≥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.[25-27] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[28-30]
    Multiple retrospective studies have established that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[31-33] (Refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about adolescents with ALL.)
WBC count at diagnosis
A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[3] although the relationship between WBC count and prognosis is a continuous rather than a step function. Patients with B-ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.[34]
The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for B-ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[34-41]
CNS involvement at diagnosis
The presence or absence of CNS leukemia at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence or absence of blasts on cytospin as follows:
  • 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.[42,43] Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 patients,[44,45] while others have not.[42,46-48]
A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies,[42,47,49] but not others.[45,46,50] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and KMT2A gene rearrangements.[42,46,47]
Most clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[42,51,52]; [46][Level of evidence: 2A]
To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.[53]
Testicular involvement at diagnosis
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males,[54,55] with its frequency being higher in patients with T-cell ALL than in patients with B-ALL.[55]
In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[54,55] For example, the European Organization for Research and Treatment of Cancer (EORTC [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[55]
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.[54] The COG has also adopted this strategy for boys with testicular involvement that resolves completely by the end of induction therapy. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.
Down syndrome (trisomy 21)
Outcome in children with Down syndrome and ALL has generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome.[56-61] In some studies, the lower EFS and OS of children with Down syndrome appear to be related to increased frequency of treatment-related mortality, as well as higher rates of induction failure and relapse in patients with Down syndrome.[56-59,62,63] The inferior anti-leukemic outcome may be due, in part, to the decreased prevalence of favorable biological features such as ETV6-RUNX1 or hyperdiploidy (51–65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.[62,63]
  • In a large retrospective study that included 653 patients with Down syndrome and ALL, Down syndrome patients had a lower CR rate (97% vs. 99%, P < .001), higher cumulative incidence of relapse (26% vs. 15%, P < .001) and higher treatment-related mortality (7% vs. < 1%, P < .001) compared with non-Down syndrome patients.[63] Among the patients with Down syndrome, age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6-RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS.
  • In a report from the COG, among patients with B-ALL who lacked KMT2A rearrangements, BCR-ABL1ETV6-RUNX1, and hyperdiploidy with trisomies of chromosomes 4 and 10, the EFS and OS rates were similar in children with and without Down syndrome.[62]
  • 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.[64-68] Studies of children with Down syndrome and ALL suggest that the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK mutations) is associated with an inferior prognosis.[63,68,69]
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[70-72] 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.[70-72] While some reports describe outcomes for boys as closely approaching those of girls,[22,51,73] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[21,28,29,74]
Race and ethnicity
Over the last several decades in the United States, survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[75-78]
The following factors associated with race and ethnicity influence survival:
  • ALL subtype. 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 B-ALL.
  • Treatment adherence. Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence to oral mercaptopurine (6-MP) in maintenance therapy. In the first report from the 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, even with adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse.[79] In the second report from the study, adherence rates were shown to be significantly lower in Asian American and African American patients than in non-Hispanic white patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.[80]
  • Ancestry-related genomic variations. Ancestry-related genomic variations may also contribute to racial and ethnic disparities in both the incidence and outcome of ALL.[81] For example, the differential presence of specific host polymorphisms in different racial and 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.[82]
Weight at diagnosis and during treatment
Studies of the impact of obesity on the outcome of ALL have had variable results. In most of these studies, obesity is defined as weight above the 95th percentile for age and height.
  • Three studies have not demonstrated an independent effect of obesity on EFS.[83][Level of evidence: 2Dii]; [84,85][Level of evidence: 3iiDi]
  • Two studies have shown obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[86,87][Level of evidence: 3iiDi]
  • The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial (CCG-1961 [NCT00002812]).[88][Level of evidence: 2Di] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS rates, 64% vs. 74%; P = .002.) However, obese patients at diagnosis who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.
  • In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease (MRD) at the end of induction and an inferior EFS.[89][Level of evidence: 3iiDi]
  • In a different retrospective study of 373 patients treated at a single institution, body mass index (BMI) at diagnosis was not associated with MRD at days 19 and 46, cumulative incidence of relapse, or EFS. OS was lower in patients with a high BMI, primarily resulting from treatment-related mortality and inferior salvage after relapse.[90][Level of evidence: 3iiA]
In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (8% of the population) had an almost twofold higher risk of relapse compared with patients who were not underweight (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with loss of BMI during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.[91]

Leukemic characteristics

Leukemic cell characteristics affecting prognosis include the following:
The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics.[92,93] (Refer to the Diagnosis section of this summary for more information.)
Either B- or T-lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.
  1. B-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 B-ALL (precursor B-cell ALL).
    B-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 B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[9,94] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[95]
    The major immunophenotypic subtypes of B-ALL are as follows:
    • Common B-ALL (CD10 positive and no surface or cytoplasmic immunoglobulin [Ig])
      Approximately three-quarters of patients with B-ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.
    • Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig)
      Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with KMT2A gene rearrangements.
    • Pre-B ALL (presence of cytoplasmic Ig)
      The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19)(q21;p13) translocation with the TCF3-PBX1 (previously known as E2A-PBX1) fusion.[96,97]
      Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for B-ALL.[98]
    • Mature B-ALL
      Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with French-American-British criteria L3 morphology and an 8q24 translocation involving MYC), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from the treatment for B-ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with MYC gene translocations should also be treated as mature B-cell leukemia.[98] (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with B-ALL and Burkitt lymphoma.)
      A small number of cases of IG-MYC-translocated leukemias with precursor B-cell immunophenotype (e.g., absence of CD20 expression and surface Ig expression) have been reported.[99] These cases presented in both children and adults. Like Burkitt lymphoma/leukemia, they had a male predominance and most patients showed L3 morphology. The cases lacked mutations in genes recurrently altered in Burkitt lymphoma (e.g., ID3CCND3, or MYC), whereas mutations in RAS genes (frequently altered in B-ALL) were common. The clinical significance of IG-MYC–translocated leukemias with precursor B-cell phenotype and molecular characteristics requires further study.
  2. T-cell ALL
    T-cell ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of clinical features, including the following:[20,36,73]
    • Male sex.
    • Older age.
    • Leukocytosis.
    • Mediastinal mass.
    While not true historically, with appropriately intensive therapy, children with T-cell ALL now have an outcome approaching that of children with B-lineage ALL.[20,36,39,40,73,100]
    There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[35-41,101] 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.[102]
    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.[103] 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).
    Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other patients with T-cell ALL.[103-105] However, another study indicated that the early T-cell precursor ALL subgroup had nonsignificantly inferior 5-year EFS rates compared with non–early T-cell precursor patients (76% vs. 84%).[106] Similarly, the COG AALL0434 trial observed similar 5-year EFS rates for early T-cell precursor patients and non-early T-cell precursor patients, with both at approximately 87%.[107] Further study in additional patient cohorts is needed to firmly establish the prognostic significance of early T-cell precursor ALL, but most ALL treatment groups do not change patient treatment on the basis of early T-cell precursor status.
  3. Myeloid antigen expression
    Up to one-third of childhood ALL patients have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with KMT2A rearrangements, ETV6-RUNX1, and BCR-ABL1.[108-110] Patients with B-ALL who have gene rearrangements involving ZNF384 also commonly show myeloid antigen expression.[111,112] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[108,109]
    (Refer to the 2016 WHO Classification of Acute Leukemias of Ambiguous Lineage section of this summary for information about leukemia of ambiguous lineage.)
Cytogenetics/genomic alterations
(Refer to the Cytogenetics/Genomics of Childhood ALL section of this summary for information about B-ALL and T-cell ALL cytogenetics/genomics and gene polymorphisms in drug metabolic pathways.)

Response to initial treatment

The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual disease at the end of induction are associated with long-term outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[113] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:
MRD determination
Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. In order to detect lower levels of leukemic cells in either blood or marrow, specialized techniques are required; such techniques include polymerase chain reaction (PCR) assays, which determine unique Ig/T-cell receptor gene rearrangements and fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.[114] Newer techniques involving high-throughput sequencing (HTS) of Ig/T-cell receptor gene rearrangements can increase sensitivity of MRD detection to 1 in 1 million cells (10-6).[115]
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[116-118] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[119] In general, patients with higher levels of end-induction MRD have a poorer prognosis than do those with lower or undetectable levels.[114,116-118] However, the absolute risk of relapse associated with specific MRD levels varies by genetic subtype. For example, at any given level of detectable end-induction MRD, patients with favorable cytogenetics, such as ETV6-RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients.[120] This observation may have important implications when MRD is used to develop risk classification plans.
End-induction MRD is used by almost all groups as a factor in determining the intensity of postinduction treatment; patients found to have higher MRD levels (typically >10-3 to 10-4) are allocated to more intensive therapies.[114,117,121]; [122][Level of evidence: 2A]
A study of 619 children with ALL compared the prognostic utility of MRD by flow cytometry with the more sensitive HTS assay. Using an end-induction MRD cutpoint level of 10-4, high-throughput sequencing identified approximately 30% more cases as positive (i.e., >10-4). Patients identified as positive by HTS, but negative by flow cytometry, had an intermediate prognosis compared with patients categorized as either positive or negative by both methods. Patients meeting the criteria for standard-risk ALL with undetectable MRD by HTS had an especially good prognosis (5-year EFS rate, 98.1%).[115]
MRD levels obtained 10 to 12 weeks after the start of treatment (end-consolidation) have also been shown to be prognostically important; patients with high levels of MRD at this time point have a significantly inferior EFS compared with other patients.[118,119]
  • B-ALL: For patients with B-ALL, evaluating MRD at two time points (end-induction and end-consolidation) can identify the following three prognostically distinct patient subsets:[119]
    1. Low or undetectable end-induction MRD—best prognosis.
    2. Detectable or high MRD at end-induction but low or negative end-consolidation MRD—intermediate prognosis.
    3. Detectable or high MRD at end-consolidation (week 12 of therapy)—worst prognosis.
  • T-cell ALL: There are fewer studies documenting the prognostic significance of MRD in patients with T-cell ALL. The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) group reported that T-cell ALL patients with nondetectable end-induction MRD had excellent outcomes, while those with very high MRD levels (>5%) at the end of induction had a poor prognosis; however, for all other T-cell ALL patients, an association between end-induction MRD level and relapse risk was not found.[120] Another study also indicated that MRD at a later time point may be more prognostically significant in T-cell ALL.[123] In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-cell ALL.[123] Patients with detectable MRD at end-induction who had negative MRD by day 78 generally had a favorable prognosis, similar to that of patients who achieved MRD-negativity at the earlier end-induction time point.[123]
MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS rate, 97% ± 1%) for patients with precursor B-cell phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).[117] The excellent outcomes in patients with low MRD at the end of induction is sustained for more than 10 years from diagnosis.[124]
Modifying therapy on the basis of MRD determination has been shown to improve outcome.
  • The UKALL2003 (NCT00222612) study demonstrated that reduction of therapy (i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-high–risk patients with favorable end-induction MRD.[21][Level of evidence: 1iiDii] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if end-induction MRD was greater than 0.01% (5-year EFS rates, 89.6% for augmented therapy vs. 82.8% for standard therapy).[125]
  • The Dutch AAL10 trial stratified patients into the following three risk groups on the basis of MRD after the first month of treatment and after the second cycle of chemotherapy:[126][Level of evidence: 2A]
    • Standard risk (low MRD after the first month of treatment).
    • Moderate risk (high MRD after the first month of treatment, low MRD after the second cycle of chemotherapy).
    • High risk (high MRD after the second cycle of chemotherapy).
    Compared with previous trials conducted by the same group, therapy was less intensive for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS rate (87%) and OS rate (92%) were superior to the previous Dutch studies.
Day 7 and day 14 bone marrow responses
Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days after the initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[127] 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.[117,128]
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).[20] Poor prednisone response is observed in fewer than 10% of patients.[20,129] 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.[130] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[130]
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.[117]
  • 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.[131] 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.
Persistent leukemia at the end of induction (induction failure)
The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts by morphological assessment at the end of the induction phase is observed in 1% to 2% of children with ALL.[21,22,132-134]
Features associated with a higher risk of induction failure include the following:[134-136]
  • T-cell phenotype.
  • Higher WBC at diagnosis for patients with B-ALL.
  • Unfavorable cytogenetics (e.g., KMT2A rearrangement).
  • Older age.
  • Presence of the Ph chromosome (Ph+ ALL) (before the use of tyrosine kinase inhibitors).
  • Rearrangement of PDGFRB (most commonly EBF1-PDGFRB), commonly associated with the Ph-like subtype.[134,137] These patients represent less than 1% of B-ALL cases in children, but account for as much as 10% of induction failure cases.[134] Among 13 patients who were EBF1-PDGFRB positive, eight patients had end-of-induction MRD greater than 10%.[137]
In a large retrospective study, the OS rate of patients with induction failure was only 32%.[132] However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with B-ALL between the ages of 1 and 5 years without adverse cytogenetics (KMT2A rearrangement or BCR-ABL1). This group had a 10-year survival exceeding 50%, and HSCT in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to 18 years, or who had the Ph chromosome or KMT2A rearrangement. B-ALL patients younger than 6 years and T-cell ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic HSCT after achieving CR than those who received further treatment with chemotherapy alone.
Some investigators have suggested that the definition of induction failure should be expanded to include end-of-induction MRD of more than 5%, regardless of morphologic findings. In the UKALL2003 (NCT00222612) study, 59 of 3,113 patients (1.9%) had morphologic induction failure; the 5-year EFS was 51%, and the OS was 58%. However, 2.3% of patients had a morphologic remission, with MRD of 5% or more measured by real-time quantitative IgH-T-cell receptor (TCR) PCR; this group had a 5-year EFS of 47%, similar to those with morphologic induction failure. The authors suggest that using both morphologic and MRD criteria to define induction failure more precisely identifies patients with poor outcomes.[134]

Prognostic (Risk) Groups

For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens on the basis of their estimated risk of treatment failure. Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response (e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single-agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate cytogenetics and genomic lesions of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at end of induction (and in some cases at later time points).[123] The risk classification systems of the COG and the BFM groups are briefly described below.

Children’s Oncology Group (COG) risk groups

In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) on the basis of a subset of prognostic factors, including the following:
  • Age.
  • WBC count at diagnosis.
  • Immunophenotype.
  • 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%.[4,51,129,138,139] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., MRD levels in peripheral blood on day 8 and in bone marrow samples at the end of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the presence of extramedullary disease, and steroid pretreatment can identify patient groups for postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.[4,117]
Patients who are at very high risk of treatment failure include the following: [140-143]
  • Infants with KMT2A rearrangements.
  • 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:[119]
  • 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)(q34;q11.2) or the t(4;11)(q21;q23) are considered high risk, regardless of early response measures.

Prognostic (risk) groups under clinical evaluation

COG AALL1731 (NCT03914625) standard-risk and AALL1732 (NCT03959085) high-risk clinical trials: The COG classifies patients into six risk groups for patients with B-ALL (standard-risk favorable, standard-risk average, standard-risk high, high-risk favorable, high risk, and very high risk) on the basis of the following:
  • Age and presenting leukocyte count (using NCI risk-group criteria).[3]
    • NCI standard (low) risk: Includes children aged 1 year to <10 years with WBC <50,000/µL at the time of diagnosis.
    • NCI high risk: Includes children ≥10 years and/or children who have WBC ≥50,000/µL at the time of diagnosis.
  • Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
    • CNS1: Absence of blasts on CSF cytospin preparation, regardless of the number of WBCs.
    • CNS2: Presence of <5 WBC/μL in CSF and cytospin positive for blasts; or traumatic LP, ≥5 WBC/μL, cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.
    • CNS3 is divided and defined as follows:
      • CNS3a: <10 RBC/μL; ≥5 WBC/μL and cytospin positive for blasts.
      • CNS3b: ≥10 RBC/μL; ≥5 WBC/μL and positive by Steinherz/Bleyer algorithm.
      • CNS3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome).
  • Genomic alterations in leukemia cells.
  • Day 8 peripheral blood MRD.
  • Day 29 bone marrow morphologic response and MRD.
  • End of consolidation MRD.
  • 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-ALL, the definitions of favorable, unfavorable, and neutral cytogenetics are as follows:
  • Favorable cytogenetic features include the following:
    • Hyperdiploidy with double trisomies of chromosomes 4 and 10 (double trisomy); or
    • ETV6-RUNX1 fusion.
  • Unfavorable cytogenetic features include the following:
    • Hypodiploidy (<44 chromosomes or DNA index <0.81).
    • KMT2A rearrangements.
    • t(17;19)(q21-q22;p13.3) or resultant E2A-HLF fusion transcript.
    • Intrachromosomal amplification of chromosome 21 (iAMP21); and
    • Ph+ ALL (BCR-ABL1 fusion transcript or t(9;22)(q34;q11)). Patients with Ph+ ALL are treated on a separate clinical trial.
  • Neutral cytogenetics: Lacking favorable and unfavorable cytogenetic features.
  • MRD levels at day 8 from peripheral blood and at day 29 from bone marrow are used in risk classification.
NCI standard-risk patients are divided into a highly favorable group (standard-risk favorable; 5-year DFS rate, >95%), a group with favorable outcome (standard-risk average; 5-year DFS rate, 90%–95%), and a group with a 5-year DFS rate below 90% (standard-risk high). Patients classified as standard-risk high receive backbone chemotherapy as per high-risk B-ALL regimens with intensified consolidation, interim maintenance, and reinduction therapy. Criteria for these three groups are provided in Table 5Table 6, and Table 7 below.
Table 5. Standard-Risk (SR) Favorable B-ALL (Non-Down Syndrome and Down Syndrome)
NCI Risk GroupCNS StageSteroid PretreatmentaFavorable Genetics (ETV6-RUNX1 or DT)PB MRD Day 8BM MRD Day 29
BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood.
aWithin one month prior to diagnosis.
SR1, 2NoneYes<1%<0.01%
Table 6. Standard-Risk (SR) Average B-ALL (Non-Down Syndrome and Down Syndrome)
NCI Risk GroupCNS StageETV6-RUNX1DTNeutral CytogeneticsPB MRD Day 8BM MRD Day 29
BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood.
SR1, 2Yes to eitherNo≥1%<0.01%
SR1, 2NoYesNoAny≥0.01 to <0.1%
Table 7. Standard-Risk (SR) High B-ALL
NCI Risk GroupCNS StageETV6-RUNX1DTNeutral CytogeneticsUnfavorable CytogeneticsPB MRD Day 8BM MRD Day 29
BM = bone marrow; CNS = central nervous system; DT = double trisomy; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood.
SR1, 2YesNoNoNoAny≥0.01%
SR1, 2NoYesNoNoAny≥0.1%
SR1, 2NoNoNoYesAnyAny
High-risk favorable B-ALL is defined by the characteristics in Table 8. These patients have an EFS higher than 90% on past COG clinical trials for high-risk patients.
Table 8. Characteristics of High-Risk (HR) Favorable B-ALL Patients
NCI Risk GroupAge (y)CNS StatusTesticular LeukemiaSteroid PretreatmentFavorable Genetics (ETV6-RUNX1 or DT)Bone marrow MRD EOI
HR<101None≤24 hoursaYes<0.01%
CNS = central nervous system; DT = double trisomy; EOI = end of induction; MRD = minimal residual disease; NCI = National Cancer Institute.
aWithin two weeks of diagnosis.
High-risk B-ALL is defined by the characteristics in Table 9. NCI standard-risk patients are elevated to high-risk status based on steroid pretreatment and CNS and/or testicular involvement.
Table 9. Characteristics of High-Risk (HR) B-ALL Patients
NCI Risk GroupAge (y)CNS and/or Testicular LeukemiaSteroid PretreatmentCytogeneticsBone marrow MRD EOIBone marrow MRD EOC
CNS = central nervous system; EOC = end of consolidation; EOI = end of induction; MRD = minimal residual disease; N/A = not applicable; NCI = National Cancer Institute; SR = standard risk.
bPhiladelphia chromosome–positive (Ph+) ALL is excluded.
cOnly subjects with EOI bone marrow MRD ≥0.01% will have a bone marrow MRD assessment at EOC.
dWithin 2 weeks of diagnosis.
eCNS2 or CNS3.
SR<10No>24 hoursdAnybAny<1%c
HR<10No>24 hoursdAnyb<0.01%N/A
HR<10No≤24 hoursdNeutral/unfavorableb<0.01%N/A
NCI high-risk patients with end-of-consolidation marrow MRD ≥0.01% are classified as very high risk and are eligible for a chimeric antigen receptor (CAR) T-cell clinical trial in first remission (NCT03792633).
Patients with B-ALL and Down syndrome are classified into risk groups similar to other children, but Down syndrome patients classified as high risk receive a treatment regimen that is modified to reduce toxicity.
NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II-IV T-Cell Lymphoblastic Lymphoma): For patients with T-cell ALL, COG uses the following criteria to assign risk category:
Standard risk
  • M1 marrow with MRD <0.01% on day 29.
  • CNS1 status and no testicular disease at diagnosis.
  • No steroid therapy pretreatment.
Intermediate risk
  • M1 or M2 marrow at day 29 with MRD ≥0.01%.
  • MRD <0.1% at end of consolidation.
  • Any CNS status at diagnosis.
Very high risk
  • M3 marrow at day 29 or MRD ≥0.1% at end of consolidation.
  • Any CNS status.
SJCRH Total 17 study (NCT03117751) (Total Therapy XVII for Newly Diagnosed Patients With ALL and Lymphoma): The overarching objective of this study is to use novel precision medicine strategies based on inherited and leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with ALL and acute lymphoblastic lymphoma.
Criteria for low-risk (approximately 42% of patients)
  • B-ALL with DNA index ≥1.16, ETV6-RUNX1 fusion, OR age 1 to 9.9 years and presenting WBC count <50 x 109/L.
  • Patients must not have the following:
    • CNS3 status (≥5 WBC/μL of CSF with leukemic blasts or cranial nerve palsy).
    • Overt testicular leukemia (evidenced by ultrasonography).
    • Adverse genetic features: BCR-ABL1 fusion; TCF3-PBX1 fusion; rearranged KMT2A (by FISH, PCR, and/or transcriptome or whole-genome sequencing); hypodiploidy (defined by <0.95 DNA index, <44 chromosomes, or genome-wide DNA copy-number alterations and gene expression); iAMP21; or MEF2D fusion.
    • Poor early response (≥1% lymphoblasts on Day 15 of remission induction or ≥0.01% lymphoblasts on remission date [end of remission induction] by immunologic or molecular methods).
Criteria for standard-risk (approximately 48% of patients)
  • Patients with T-cell ALL or B-ALL who do not meet the criteria for low-risk or high-risk ALL.
Criteria for high-risk (approximately 10% of patients)
  • MRD ≥1% at the end of remission induction.
  • MRD ≥0.1% at the end of early intensification and inadequate decrease in MRD levels after 1 to 2 courses of consolidation treatment.
  • Increasing MRD level at ≥0.01% after remission induction.
  • Hypodiploid (defined by <0.95 DNA index, <44 chromosomes or genome-wide analysis) and MRD ≥0.01% at the end of remission induction.
  • Re-emergence of leukemic lymphoblasts by MRD at ≥0.01% in patients previously MRD negative.
  • Persistently detectable MRD at ≥0.01% after reinduction II (week 17 of continuation).
DFCI ALL 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL): Patients are assigned an initial risk group by day 10 of therapy on the basis of presenting features and leukemia biology:
  • Initial low risk: All of the following criteria are met: B-cell ALL, age 1 to younger than 15 years, WBC count less than 50 x 109/L, CNS1 or CNS2, no iAMP21, no very high-risk features.
  • Initial high risk: Any of the following criteria are met: Aged 15 years or older, WBC count greater than 50 x 109/L, T-cell ALL, CNS3, presence of iAMP21. Very high-risk features must be absent.
  • Initial very high risk: Any of the following criteria are met: IKZF1 deletion, MLL gene-rearrangement, low hypodiploidy (<40 chromosomes).
Patients with BCR-ABL1 are removed from protocol therapy at day 15. The final risk group is based on the initial risk group and MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 of therapy (second time point):
  • Final low risk: Initial low risk and MRD less than 10-4 at the first time point.
  • Final high risk: Initial low risk with MRD greater than 10-4 at the first time point and less than 10-3 at the second time point or initial high risk with MRD less than 10-3 at the second time point.
  • Final very high risk: Initial very high-risk patients or any patient with MRD greater than 10-3 at the second time point.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
  1. Hunger SP, Loh ML, Whitlock JA, et al.: Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer 60 (6): 957-63, 2013. [PUBMED Abstract]
  2. Hunger SP, Mullighan CG: Acute Lymphoblastic Leukemia in Children. N Engl J Med 373 (16): 1541-52, 2015. [PUBMED Abstract]
  3. Smith M, Arthur D, Camitta B, et al.: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14 (1): 18-24, 1996. [PUBMED Abstract]
  4. Schultz KR, Pullen DJ, Sather HN, et al.: Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG). Blood 109 (3): 926-35, 2007. [PUBMED Abstract]
  5. Jeha S, Coustan-Smith E, Pei D, et al.: Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 120 (10): 1514-9, 2014. [PUBMED Abstract]
  6. Vrooman LM, Silverman LB: Childhood acute lymphoblastic leukemia: update on prognostic factors. Curr Opin Pediatr 21 (1): 1-8, 2009. [PUBMED Abstract]
  7. Möricke A, Zimmermann M, Reiter A, et al.: Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr 217 (6): 310-20, 2005 Nov-Dec. [PUBMED Abstract]
  8. Reaman GH, Sposto R, Sensel MG, et al.: Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. J Clin Oncol 17 (2): 445-55, 1999. [PUBMED Abstract]
  9. Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007. [PUBMED Abstract]
  10. Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006. [PUBMED Abstract]
  11. Dreyer ZE, Hilden JM, Jones TL, et al.: Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer 62 (3): 419-26, 2015. [PUBMED Abstract]
  12. Chessells JM, Harrison CJ, Watson SL, et al.: Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987-1999. Br J Haematol 117 (2): 306-14, 2002. [PUBMED Abstract]
  13. Isoyama K, Eguchi M, Hibi S, et al.: Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Br J Haematol 118 (4): 999-1010, 2002. [PUBMED Abstract]
  14. Nagayama J, Tomizawa D, Koh K, et al.: Infants with acute lymphoblastic leukemia and a germline MLL gene are highly curable with use of chemotherapy alone: results from the Japan Infant Leukemia Study Group. Blood 107 (12): 4663-5, 2006. [PUBMED Abstract]
  15. Sam TN, Kersey JH, Linabery AM, et al.: MLL gene rearrangements in infant leukemia vary with age at diagnosis and selected demographic factors: a Children's Oncology Group (COG) study. Pediatr Blood Cancer 58 (6): 836-9, 2012. [PUBMED Abstract]
  16. Kang H, Wilson CS, Harvey RC, et al.: Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 119 (8): 1872-81, 2012. [PUBMED Abstract]
  17. Andersson AK, Ma J, Wang J, et al.: The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat Genet 47 (4): 330-7, 2015. [PUBMED Abstract]
  18. Stam RW, Schneider P, de Lorenzo P, et al.: Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia. Blood 110 (7): 2774-5, 2007. [PUBMED Abstract]
  19. De Lorenzo P, Moorman AV, Pieters R, et al.: Cytogenetics and outcome of infants with acute lymphoblastic leukemia and absence of MLL rearrangements. Leukemia 28 (2): 428-30, 2014. [PUBMED Abstract]
  20. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000. [PUBMED Abstract]
  21. Vora A, Goulden N, Wade R, et al.: Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 14 (3): 199-209, 2013. [PUBMED Abstract]
  22. Place AE, Stevenson KE, Vrooman LM, et al.: Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol 16 (16): 1677-90, 2015. [PUBMED Abstract]
  23. Forestier E, Schmiegelow K; on behalf of the Nordic Society of Paediatric Haematology and Oncology NOPHO: The incidence peaks of the childhood acute leukemias reflect specific cytogenetic aberrations. J Pediatr Hematol Oncol 28 (8): 486-95, 2006. [PUBMED Abstract]
  24. Dastugue N, Suciu S, Plat G, et al.: Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood 121 (13): 2415-23, 2013. [PUBMED Abstract]
  25. Nachman JB, La MK, Hunger SP, et al.: Young adults with acute lymphoblastic leukemia have an excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a report from the children's oncology group. J Clin Oncol 27 (31): 5189-94, 2009. [PUBMED Abstract]
  26. Pulte D, Gondos A, Brenner H: Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood 113 (7): 1408-11, 2009. [PUBMED Abstract]
  27. Pui CH, Pei D, Campana D, et al.: Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 29 (4): 386-91, 2011. [PUBMED Abstract]
  28. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013, Section 28. Also available online. Last accessed August 09, 2019.
  29. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, 2013, Section 29. Also available online. Last accessed August 09, 2019.
  30. Smith MA, Ries LA, Gurney JG, et al.: Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 17-34. Also available online. Last accessed October 04, 2019.
  31. de Bont JM, Holt B, Dekker AW, et al.: Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia 18 (12): 2032-5, 2004. [PUBMED Abstract]
  32. Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003. [PUBMED Abstract]
  33. Stock W, La M, Sanford B, et al.: What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 112 (5): 1646-54, 2008. [PUBMED Abstract]
  34. Hastings C, Gaynon PS, Nachman JB, et al.: Increased post-induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (≥200 × 10(9) /l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group. Br J Haematol 168 (4): 533-46, 2015. [PUBMED Abstract]
  35. Pullen J, Shuster JJ, Link M, et al.: Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study. Leukemia 13 (11): 1696-707, 1999. [PUBMED Abstract]
  36. Goldberg JM, Silverman LB, Levy DE, et al.: Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 21 (19): 3616-22, 2003. [PUBMED Abstract]
  37. Silverman LB, Stevenson KE, O'Brien JE, et al.: Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia 24 (2): 320-34, 2010. [PUBMED Abstract]
  38. Pui CH, Pei D, Sandlund JT, et al.: Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24 (2): 371-82, 2010. [PUBMED Abstract]
  39. Gaynon PS, Angiolillo AL, Carroll WL, et al.: Long-term results of the children's cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children's Oncology Group Report. Leukemia 24 (2): 285-97, 2010. [PUBMED Abstract]
  40. Möricke A, Zimmermann M, Reiter A, et al.: Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 24 (2): 265-84, 2010. [PUBMED Abstract]
  41. Vaitkevičienė G, Forestier E, Hellebostad M, et al.: High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL-92 and ALL-2000 studies. Eur J Haematol 86 (1): 38-46, 2011. [PUBMED Abstract]
  42. Bürger B, Zimmermann M, Mann G, et al.: Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 21 (2): 184-8, 2003. [PUBMED Abstract]
  43. Vora A, Andreano A, Pui CH, et al.: Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy. J Clin Oncol 34 (9): 919-26, 2016. [PUBMED Abstract]
  44. Mahmoud HH, Rivera GK, Hancock ML, et al.: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329 (5): 314-9, 1993. [PUBMED Abstract]
  45. Winick N, Devidas M, Chen S, et al.: Impact of Initial CSF Findings on Outcome Among Patients With National Cancer Institute Standard- and High-Risk B-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group. J Clin Oncol 35 (22): 2527-2534, 2017. [PUBMED Abstract]
  46. Sirvent N, Suciu S, Rialland X, et al.: Prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. Eur J Cancer 47 (2): 239-47, 2011. [PUBMED Abstract]
  47. te Loo DM, Kamps WA, van der Does-van den Berg A, et al.: Prognostic significance of blasts in the cerebrospinal fluid without pleiocytosis or a traumatic lumbar puncture in children with acute lymphoblastic leukemia: experience of the Dutch Childhood Oncology Group. J Clin Oncol 24 (15): 2332-6, 2006. [PUBMED Abstract]
  48. Gilchrist GS, Tubergen DG, Sather HN, et al.: Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: a Childrens Cancer Group report. J Clin Oncol 12 (12): 2594-600, 1994. [PUBMED Abstract]
  49. Gajjar A, Harrison PL, Sandlund JT, et al.: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96 (10): 3381-4, 2000. [PUBMED Abstract]
  50. Matloub Y, Bostrom BC, Hunger SP, et al.: Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 118 (2): 243-51, 2011. [PUBMED Abstract]
  51. Pui CH, Campana D, Pei D, et al.: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360 (26): 2730-41, 2009. [PUBMED Abstract]
  52. Levinsen M, Taskinen M, Abrahamsson J, et al.: Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 61 (8): 1416-21, 2014. [PUBMED Abstract]
  53. Cherlow JM, Sather H, Steinherz P, et al.: Craniospinal irradiation for acute lymphoblastic leukemia with central nervous system disease at diagnosis: a report from the Children's Cancer Group. Int J Radiat Oncol Biol Phys 36 (1): 19-27, 1996. [PUBMED Abstract]
  54. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005. [PUBMED Abstract]
  55. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007. [PUBMED Abstract]
  56. Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005. [PUBMED Abstract]
  57. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005. [PUBMED Abstract]
  58. Whitlock JA, Sather HN, Gaynon P, et al.: Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 106 (13): 4043-9, 2005. [PUBMED Abstract]
  59. Arico M, Ziino O, Valsecchi MG, et al.: Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 113 (3): 515-21, 2008. [PUBMED Abstract]
  60. Lundin C, Forestier E, Klarskov Andersen M, et al.: Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries. J Hematol Oncol 7 (1): 32, 2014. [PUBMED Abstract]
  61. Athale UH, Puligandla M, Stevenson KE, et al.: Outcome of children and adolescents with Down syndrome treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 and 05-001. Pediatr Blood Cancer 65 (10): e27256, 2018. [PUBMED Abstract]
  62. Maloney KW, Carroll WL, Carroll AJ, et al.: Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group. Blood 116 (7): 1045-50, 2010. [PUBMED Abstract]
  63. Buitenkamp TD, Izraeli S, Zimmermann M, et al.: Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood 123 (1): 70-7, 2014. [PUBMED Abstract]
  64. Mullighan CG, Collins-Underwood JR, Phillips LA, et al.: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 41 (11): 1243-6, 2009. [PUBMED Abstract]
  65. Bercovich D, Ganmore I, Scott LM, et al.: Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 372 (9648): 1484-92, 2008. [PUBMED Abstract]
  66. Gaikwad A, Rye CL, Devidas M, et al.: Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 144 (6): 930-2, 2009. [PUBMED Abstract]
  67. Kearney L, Gonzalez De Castro D, Yeung J, et al.: Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 113 (3): 646-8, 2009. [PUBMED Abstract]
  68. Buitenkamp TD, Pieters R, Gallimore NE, et al.: Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 26 (10): 2204-11, 2012. [PUBMED Abstract]
  69. Hanada I, Terui K, Ikeda F, et al.: Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. Genes Chromosomes Cancer 53 (11): 902-10, 2014. [PUBMED Abstract]
  70. Pui CH, Boyett JM, Relling MV, et al.: Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 17 (3): 818-24, 1999. [PUBMED Abstract]
  71. Shuster JJ, Wacker P, Pullen J, et al.: Prognostic significance of sex in childhood B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study. J Clin Oncol 16 (8): 2854-63, 1998. [PUBMED Abstract]
  72. Chessells JM, Richards SM, Bailey CC, et al.: Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol 89 (2): 364-72, 1995. [PUBMED Abstract]
  73. Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001. [PUBMED Abstract]
  74. Hunger SP, Lu X, Devidas M, et al.: Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol 30 (14): 1663-9, 2012. [PUBMED Abstract]
  75. Bhatia S: Influence of race and socioeconomic status on outcome of children treated for childhood acute lymphoblastic leukemia. Curr Opin Pediatr 16 (1): 9-14, 2004. [PUBMED Abstract]
  76. Kadan-Lottick NS, Ness KK, Bhatia S, et al.: Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 290 (15): 2008-14, 2003. [PUBMED Abstract]
  77. Tai EW, Ward KC, Bonaventure A, et al.: Survival among children diagnosed with acute lymphoblastic leukemia in the United States, by race and age, 2001 to 2009: Findings from the CONCORD-2 study. Cancer 123 (Suppl 24): 5178-5189, 2017. [PUBMED Abstract]
  78. Kahn JM, Cole PD, Blonquist TM, et al.: An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001. Pediatr Blood Cancer 65 (3): , 2018. [PUBMED Abstract]
  79. Bhatia S, Landier W, Shangguan M, et al.: Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group. J Clin Oncol 30 (17): 2094-101, 2012. [PUBMED Abstract]
  80. Bhatia S, Landier W, Hageman L, et al.: 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 124 (15): 2345-53, 2014. [PUBMED Abstract]
  81. Yang JJ, Cheng C, Devidas M, et al.: Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet 43 (3): 237-41, 2011. [PUBMED Abstract]
  82. Xu H, Cheng C, Devidas M, et al.: ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 30 (7): 751-7, 2012. [PUBMED Abstract]
  83. Aldhafiri FK, McColl JH, Reilly JJ: Prognostic significance of being overweight and obese at diagnosis in children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 36 (3): 234-6, 2014. [PUBMED Abstract]
  84. Baillargeon J, Langevin AM, Lewis M, et al.: Obesity and survival in a cohort of predominantly Hispanic children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 28 (9): 575-8, 2006. [PUBMED Abstract]
  85. Hijiya N, Panetta JC, Zhou Y, et al.: Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia. Blood 108 (13): 3997-4002, 2006. [PUBMED Abstract]
  86. Butturini AM, Dorey FJ, Lange BJ, et al.: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25 (15): 2063-9, 2007. [PUBMED Abstract]
  87. Gelelete CB, Pereira SH, Azevedo AM, et al.: Overweight as a prognostic factor in children with acute lymphoblastic leukemia. Obesity (Silver Spring) 19 (9): 1908-11, 2011. [PUBMED Abstract]
  88. Orgel E, Sposto R, Malvar J, et al.: Impact on survival and toxicity by duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia: A report from the Children's Oncology Group. J Clin Oncol 32 (13): 1331-7, 2014. [PUBMED Abstract]
  89. Orgel E, Tucci J, Alhushki W, et al.: Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia. Blood 124 (26): 3932-8, 2014. [PUBMED Abstract]
  90. Eissa HM, Zhou Y, Panetta JC, et al.: The effect of body mass index at diagnosis on clinical outcome in children with newly diagnosed acute lymphoblastic leukemia. Blood Cancer J 7 (2): e531, 2017. [PUBMED Abstract]
  91. den Hoed MA, Pluijm SM, de Groot-Kruseman HA, et al.: The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia. Haematologica 100 (1): 62-9, 2015. [PUBMED Abstract]
  92. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. Lyon, France: International Agency for Research on Cancer, 2017.
  93. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
  94. Pui CH, Chessells JM, Camitta B, et al.: Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17 (4): 700-6, 2003. [PUBMED Abstract]
  95. Möricke A, Ratei R, Ludwig WD, et al.: Prognostic factors in CD10 negative precursor b-cell acute lymphoblastic leukemia in children: data from three consecutive trials ALL-BFM 86, 90, and 95. [Abstract] Blood 104 (11): A-1957, 540a, 2004.
  96. Hunger SP: Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood 87 (4): 1211-24, 1996. [PUBMED Abstract]
  97. Uckun FM, Sensel MG, Sather HN, et al.: Clinical significance of translocation t(1;19) in childhood acute lymphoblastic leukemia in the context of contemporary therapies: a report from the Children's Cancer Group. J Clin Oncol 16 (2): 527-35, 1998. [PUBMED Abstract]
  98. Koehler M, Behm FG, Shuster J, et al.: Transitional pre-B-cell acute lymphoblastic leukemia of childhood is associated with favorable prognostic clinical features and an excellent outcome: a Pediatric Oncology Group study. Leukemia 7 (12): 2064-8, 1993. [PUBMED Abstract]
  99. Wagener R, López C, Kleinheinz K, et al.: IG-MYC+ neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas. Blood 132 (21): 2280-2285, 2018. [PUBMED Abstract]
  100. Winter SS, Dunsmore KP, Devidas M, et al.: Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization. J Clin Oncol 36 (29): 2926-2934, 2018. [PUBMED Abstract]
  101. Slack JL, Arthur DC, Lawrence D, et al.: Secondary cytogenetic changes in acute promyelocytic leukemia--prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. J Clin Oncol 15 (5): 1786-95, 1997. [PUBMED Abstract]
  102. Attarbaschi A, Mann G, Dworzak M, et al.: Mediastinal mass in childhood T-cell acute lymphoblastic leukemia: significance and therapy response. Med Pediatr Oncol 39 (6): 558-65, 2002. [PUBMED Abstract]
  103. Coustan-Smith E, Mullighan CG, Onciu M, et al.: Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10 (2): 147-56, 2009. [PUBMED Abstract]
  104. Ma M, Wang X, Tang J, et al.: Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia. Front Med 6 (4): 416-20, 2012. [PUBMED Abstract]
  105. Inukai T, Kiyokawa N, Campana D, et al.: Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15. Br J Haematol 156 (3): 358-65, 2012. [PUBMED Abstract]
  106. Patrick K, Wade R, Goulden N, et al.: Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol 166 (3): 421-4, 2014. [PUBMED Abstract]
  107. Wood BL, Winter SS, Dunsmore KP, et al.: T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) study AALL0434. [Abstract] Blood 124 (21): A-1, 2014. Also available onlineExit Disclaimer. Last accessed October 18, 2019.
  108. Pui CH, Rubnitz JE, Hancock ML, et al.: Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia. J Clin Oncol 16 (12): 3768-73, 1998. [PUBMED Abstract]
  109. Uckun FM, Sather HN, Gaynon PS, et al.: Clinical features and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 90 (1): 28-35, 1997. [PUBMED Abstract]
  110. Corrente F, Bellesi S, Metafuni E, et al.: Role of flow-cytometric immunophenotyping in prediction of BCR/ABL1 gene rearrangement in adult B-cell acute lymphoblastic leukemia. Cytometry B Clin Cytom 94 (3): 468-476, 2018. [PUBMED Abstract]
  111. Hirabayashi S, Ohki K, Nakabayashi K, et al.: ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica 102 (1): 118-129, 2017. [PUBMED Abstract]
  112. Qian M, Zhang H, Kham SK, et al.: Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Res 27 (2): 185-195, 2017. [PUBMED Abstract]
  113. Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1 (2): 99-108, 2001. [PUBMED Abstract]
  114. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998. [PUBMED Abstract]
  115. Wood B, Wu D, Crossley B, et al.: Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood 131 (12): 1350-1359, 2018. [PUBMED Abstract]
  116. Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 110 (5): 1607-11, 2007. [PUBMED Abstract]
  117. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 111 (12): 5477-85, 2008. [PUBMED Abstract]
  118. Borowitz MJ, Wood BL, Devidas M, et al.: Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232. Blood 126 (8): 964-71, 2015. [PUBMED Abstract]
  119. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010. [PUBMED Abstract]
  120. O'Connor D, Enshaei A, Bartram J, et al.: Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia. J Clin Oncol 36 (1): 34-43, 2018. [PUBMED Abstract]
  121. Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27 (31): 5168-74, 2009. [PUBMED Abstract]
  122. Pui CH, Pei D, Coustan-Smith E, et al.: Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol 16 (4): 465-74, 2015. [PUBMED Abstract]
  123. Schrappe M, Valsecchi MG, Bartram CR, et al.: Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 118 (8): 2077-84, 2011. [PUBMED Abstract]
  124. Bartram J, Wade R, Vora A, et al.: Excellent outcome of minimal residual disease-defined low-risk patients is sustained with more than 10 years follow-up: results of UK paediatric acute lymphoblastic leukaemia trials 1997-2003. Arch Dis Child 101 (5): 449-54, 2016. [PUBMED Abstract]
  125. Vora A, Goulden N, Mitchell C, et al.: Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 15 (8): 809-18, 2014. [PUBMED Abstract]
  126. Pieters R, de Groot-Kruseman H, Van der Velden V, et al.: Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 34 (22): 2591-601, 2016. [PUBMED Abstract]
  127. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997. [PUBMED Abstract]
  128. Borowitz MJ, Wood BL, Devidas M, et al.: Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study. [Abstract] J Clin Oncol 31 (Suppl 15): A-10001, 2013. Also available onlineExit Disclaimer. Last accessed October 18, 2019.
  129. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008. [PUBMED Abstract]
  130. Griffin TC, Shuster JJ, Buchanan GR, et al.: Slow disappearance of peripheral blood blasts is an adverse prognostic factor in childhood T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Leukemia 14 (5): 792-5, 2000. [PUBMED Abstract]
  131. Volejnikova J, Mejstrikova E, Valova T, et al.: Minimal residual disease in peripheral blood at day 15 identifies a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with superior prognosis. Haematologica 96 (12): 1815-21, 2011. [PUBMED Abstract]
  132. Schrappe M, Hunger SP, Pui CH, et al.: Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 366 (15): 1371-81, 2012. [PUBMED Abstract]
  133. Möricke A, Zimmermann M, Valsecchi MG, et al.: Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood 127 (17): 2101-12, 2016. [PUBMED Abstract]
  134. O'Connor D, Moorman AV, Wade R, et al.: Use of Minimal Residual Disease Assessment to Redefine Induction Failure in Pediatric Acute Lymphoblastic Leukemia. J Clin Oncol 35 (6): 660-667, 2017. [PUBMED Abstract]
  135. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85 (6): 1395-404, 1999. [PUBMED Abstract]
  136. Oudot C, Auclerc MF, Levy V, et al.: Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 26 (9): 1496-503, 2008. [PUBMED Abstract]
  137. Schwab C, Ryan SL, Chilton L, et al.: EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood 127 (18): 2214-8, 2016. [PUBMED Abstract]
  138. Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007. [PUBMED Abstract]
  139. Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009. [PUBMED Abstract]
  140. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004. [PUBMED Abstract]
  141. Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26. [PUBMED Abstract]
  142. Schrauder A, Reiter A, Gadner H, et al.: Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24 (36): 5742-9, 2006. [PUBMED Abstract]
  143. Ribera JM, Ortega JJ, Oriol A, et al.: Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25 (1): 16-24, 2007. [PUBMED Abstract]

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