INTRODUCTION — Acute leukemia is the most common form of cancer in children, comprising approximately 30 percent of all childhood malignancies [1]. Of the acute leukemias, acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) occurs five times more commonly than acute myeloid leukemia (AML). Survival rates for ALL/LBL have improved dramatically since the 1980s, with a current five-year overall survival rate estimated at greater than 85 to 90 percent [1-5]. This improvement in survival is due to treatment of a large number of children on sequential standardized research protocols usually in a cooperative group setting. Approximately 75 to 80 percent of children with newly diagnosed ALL/LBL participate in such trials, the goals of which are to improve clinical outcomes while minimizing acute toxicities and late-occurring adverse events.
Leukemia and lymphoma are overlapping clinical presentations of the same disease (ie, B-ALL/LBL); diagnosis and classification do not distinguish between these entities. The risk group stratification for ALL/LBL in children will be reviewed here. The presentation, classification, treatment, and outcome of childhood ALL/LBL are discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Overview of the treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
OVERVIEW — Current treatment protocols for ALL/LBL in children emphasize risk-based therapy in order to reduce toxicity in low risk patients while ensuring appropriate, more aggressive therapy for those with a high risk of relapse. The development of such risk-based therapy regimens and the introduction of preventive central nervous system (CNS) therapy have helped to improve survival rates for children with ALL/LBL.
Certain clinical and laboratory features have been historically correlated with prognosis (table 1). Features that continue to be used in risk stratification include:
●Initial white blood cell (WBC) count
●Age
●Cytogenetics and ploidy
●Immunologic subtype
●Rapidity and degree of cytoreduction
As treatment regimens become more intense and successful, the association between the following features and outcome has become less or is no longer significant [6,7]:
●Sex
●FAB morphology
●Mediastinal mass
●Organomegaly and lymphadenopathy
●Hemoglobin level
●Race
●Platelet count
●Serum immunoglobulins
Risk stratification — Cases of ALL/LBL are usually first categorized by immunophenotyping and include the early B cell, mature B cell and T cell lineages. (See 'Immunophenotype' below.)
Early B cell lineage is the most common subgroup, and within this lineage, the following four risk groups with different outcomes have been identified based upon initial clinical and biological risk factors. (See 'Cytogenetics' below.)
●Low risk – Children with favorable age, low WBC count and favorable cytogenetic changes, such as hyperdiploidy, including extra copies of 4, 10, and often 17, or the presence of the ETV6-RUNX1 rearrangement (formerly known as TEL-AML1), along with rapid response to treatment, are in the low risk group and have the best prognosis, with reported four to five year, event-free survival (EFS) rates over 95 percent [8-10]. (See 'Cytogenetics' below.)
●Standard risk – Patients with favorable age and low WBC count and favorable response to treatment, but without favorable cytogenetic changes, are considered to have standard risk ALL/LBL.
●High risk – Patients older than 10 years of age (10 to 13 years in the United States), those with unfavorable cytogenetic changes, and those with measurable residual disease (MRD; also referred to as minimal residual disease) >0.01 percent at day 28 to 36 of induction therapy are considered to have high risk ALL/LBL. Patients with otherwise high risk disease at the start of therapy who then have a poor response to initial therapy (positive MRD at the end of induction) are considered very high risk.
●Very high risk – Children in the very high risk group include those with extreme hypodiploidy (44 or fewer chromosomes), t(9;22) (Philadelphia chromosome) BCR/ABL1 rearrangement, t(4;11) KMT2A (MLL) rearrangement, iAMP21 (intrachromosomal amplification of chromosome 21) amplification, those over 13 years of age in the United States, and/or failure to achieve complete remission at the end of induction therapy (>5 percent lymphoblasts in day 28 bone marrow or the presence of MRD). In the past, this group of patients had a poor prognosis, but subsets of these patients can be successfully treated with aggressive chemotherapy, often in combination with hematopoietic stem cell transplant. Patients older than 13 years of age are in this category (United States).
Support of risk stratification was illustrated in a retrospective review of 6238 children with ALL/LBL from the Children's Oncology Group [8]. Risk stratification was based upon age, WBC count, sex, extramedullary disease, blast cytogenetics and ploidy, and early response to therapy (table 1). Four year, event-free survival rates based upon the risk groups above were as follows:
●Low risk – >95 percent
●Standard risk – 90 to 95 percent
●High risk – 88 to 90 percent
●Very high risk – <80 percent
WBC COUNT AND AGE — White blood cell (WBC) count and age at the time of diagnosis remain independent predictors of prognosis. They have been established by the National Cancer Institute (NCI) as the standard criteria for risk assignment at diagnosis in precursor B cell ALL/LBL [11], but are less predictive of outcome in T cell ALL/LBL [12].
Several studies have demonstrated a linear relationship between initial WBC and outcome [13,14]. Children with initial WBC >50,000/microL have a worse prognosis and are stratified into a higher risk group (table 1) [11]. Patients older than 10 years, or younger than one year, also have less favorable outcomes and are assigned to higher risk groups (table 1) [14-19].
Infant ALL/LBL — Infant ALL/LBL appears to have distinct biological characteristics. Most infants with ALL/LBL (60 to 80 percent) have translocations involving 11q23 [20-23]. These translocations involve the KMT2A (formerly known as MLL [myeloid/lymphoid, or mixed-lineage, leukemia], ALL1, and HRX) [21-25]. The cytogenetic rearrangements create a fusion protein within the KMT2A gene. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)
Leukemias with KMT2A translocations have a characteristic gene expression profile, suggesting that they constitute a distinct disease, characterized by a high rate of early treatment failure and a very poor outcome [21,22,26], even when treated with more aggressive chemotherapy regimens [27]. Infants diagnosed within the first three months of life have a particularly guarded prognosis [28,29].
●In a recent series of 147 infants, the estimated five-year event-free survival (EFS) rate in infants with ALL/LBL and a KMT2A rearrangement was 19 percent compared with 46 percent for patients with non-rearranged KMT2A [30].
●Survival was directly proportional to age at diagnosis. Those over 90 days of age with rearranged KMT2A had a five-year EFS of 44 versus 69 percent for those without the KMT2A rearrangement. However, outcomes for those less than 90 days at diagnosis with rearranged KMT2A were poor, with a five-year EFS of only 15 percent.
●In an older Children’s Oncology Group study, 115 infants with ALL/LBL were treated with a more aggressive regimen, estimated five-year EFS was 34 versus 60 percent for those with or without KMT2A rearrangement, respectively [28].
Infants with ALL/LBL are typically treated with more aggressive chemotherapy regimens because they have poor responses to conventional therapy [28,31-33]. However, in one retrospective analysis of 106 infants with ALL/LBL, most (74 percent) responded to prednisone during the induction phase [34]. These infants received conventional therapy and had better outcomes than did those who failed to respond to prednisone and received intensified therapy, with an estimated probability for EFS at 6 years of age of 53 versus 15 percent, respectively. A European retrospective analysis noted that 277 of 297 infants with ALL/LBL and a KMT2A rearrangement were able to attain a first complete remission [35]. This study also suggested an improvement in disease-free survival with allogeneic hematopoietic cell transplantation in a subgroup of infants with a particularly poor prognosis. However, a similar study by the Children’s Oncology Group (COG) was not able to duplicate these findings [36].
CYTOGENETICS — Cytogenetic features play an important role in the risk stratification in childhood ALL/LBL [37], and are important components of the World Health Organization (WHO) classification of ALL/LBL (table 2). Abnormalities involving both chromosome number and chromosome structure, such as gene rearrangements and fusions (translocations), have an impact on prognosis. Cytogenetic findings that affect risk-group stratification in current clinical trials from the United States include ETV6-RUNX1; hyperdiploidy and trisomies including extra copies of chromosomes 4, 10, and often 17; BCR-ABL1; iAMP21; hypodiploidy; and the KMT2A translocation.
This was illustrated in a study that analyzed cytogenetic data from 1725 children with B cell precursor ALL/LBL [38]. The following findings were noted:
●Two chromosomal abnormalities, ETV6-RUNX1 (the t[12;21] translocation formerly known as TEL-AML1) and high hyperdiploidy, were associated with a favorable outcome.
●Five abnormalities were associated with an increased risk of relapse. These included the following structural defects: iAMP21, t(9;22) (the Philadelphia chromosome) associated with BCR-ABL1, KMT2A translocations, abnormal 17p, and loss of 13q.
Numeric abnormalities — Numerical abnormalities may involve the whole chromosome set (ploidy changes), or the gain or loss of individual chromosomes (aneuploidy changes). The following chromosomal numeric abnormalities are prognostic indicators in patients with ALL/LBL.
●"High hyperdiploidy" (50 or more chromosomes) is a favorable prognostic feature [6,39-42]. High hyperdiploidy has been uniformly associated with good prognosis in ALL/LBL. Of patients with high hyperdiploidy, those with the best outcomes in clinical trials from the United States include those with either double trisomies of chromosomes 4 and 10, or triple trisomies of chromosomes 4, 10 and 17 [43]. Lower intensity therapy is frequently targeted in patients with trisomies [43].
●Hypodiploidy (fewer than 44 chromosomes) is a poor prognostic indicator. The likelihood of a poor outcome increases with a decrease in chromosomal numbers. Thus, hypodiploid cases lacking only a single chromosome have a similar prognosis to diploid cases, whereas cases that are near-haploid (24 to 28 chromosomes) have the worst outcome [39,44,45].
●Although rare cases with near triploidy (68 to 80 chromosomes) or near tetraploidy (>80 chromosomes) generally are associated with very poor outcome [46], a large series has reported favorable outcome in B-lineage cases [47]. Care must be used to assure that near triploidy or near tetraploidy are not near-haploid or diploid, which have a very poor prognosis [48].
Structural abnormalities — Structural gene abnormalities include translocations, deletions, insertions, and inversion. The following structural chromosomal abnormalities are prognostic indicators in patients with ALL/LBL.
●The t(12;21) translocation creates the ETV6-RUNX1 fusion gene (formerly known as TEL-AML1). This structural change is the most common translocation found in pediatric ALL/LBL (25 percent incidence) and is associated with a favorable prognosis, and patients with this finding are assigned to low risk treatment. Late relapses are more common in this group, but these patients have an excellent response rate to chemotherapy following relapse [49,50].
●The t(9;22) translocation (also referred to as the Philadelphia chromosome or Ph) is one of two structural rearrangements associated with poor prognosis (the other is KMT2A gene rearrangement, which is discussed below). t(9;22) translocation is found in 4 percent of ALL/LBL cases and can be seen with either B cell or T cell ALL/LBL [51]. Patients with this abnormality receive higher intensity treatments, including the use of a tyrosine kinase inhibitor (TKI), and as a result have significantly improved outcomes.
The t(9;22) translocation creates the BCR-ABL1 fusion, which encodes a constitutively active tyrosine kinase. TKIs have been used successfully to treat chronic myeloid leukemia (CML) in adults, a disease that is linked to the presence of the Ph chromosome. Although imatinib and related TKIs induce an initial response in many adults with ALL/LBL and the t(9:22) translocation, some patients develop drug resistance and relapse [52]. However, leukemias with this translocation respond favorably to a combination of TKIs and conventional chemotherapy [53]. (See "Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults", section on 'TKI plus chemotherapy'.)
●BCR-ABL1-like (Ph like) genotype: There are 15 percent of high-risk patients that have similar outcomes and gene expression profiles to BCR-ABL1, but do not express the BCR-ABL1 fusion. These patients are three- to four-fold more common than Ph+ ALL/LBL and have a significantly worse outcome than other high-risk patients [54]. Ph like ALL/LBL usually has multiple genetic alterations that activate cytokine receptor genes and kinase signaling pathways, and are often amenable to treatment with tyrosine kinase inhibitors (TKI) [55]. Half of these patients have CRLF2 overexpression, and one half of these are associated with JAK mutations; these are being treated with JAK inhibitors such as ruxolitinib on an experimental basis. Others have ABL1 rearrangements (responsive to TKI therapy), EPOR (erythropoietin receptor) rearrangements and other genetic alterations of known kinase domains [55]. Patients that respond to TKI with chemotherapy have a substantially increased event free survival.
●Rearrangements involving the KMT2A gene (MLL) at 11q23 are associated with a poor prognosis [56]. The incidence is approximately 10 percent in children, but is at least 70 percent in infants. The leukemia cells are pro-lymphocytes and lack CD10 expression. These immature cells are often drug resistant, particularly to steroids and asparaginase [57]. Relapse is common, and often involves a lineage switch to AML, a phenomenon that has become more common with the use of B cell-directed immunotherapies [58].
●Although the t(1;19) translocation associated with the E2A-PBX1 fusion product, seen in 25 percent of pediatric ALL/LBL, was initially identified as a poor prognostic feature, it does not appear to have prognostic significance based upon data from clinical trials [59]. It encodes a chimeric protein that affects both histone acetylation and HDM2 ubiquitination, and is now considered prognostically neutral. Targeted agents have been tested, but outcome to date is similar to other standard risk ALL/LBL groups [60].
●Intrachromosomal amplification of chromosome 21 (iAMP21) is identified in approximately 2 percent of children with B cell precursor ALL/LBL and is associated with a high risk of relapse [38,61,62]. A benefit from treatment intensification in this population was demonstrated in a retrospective comparison of patients treated on one of two prospective trials [61]. In one trial (MRC ALL97), iAMP21 was identified retrospectively and iAMP21 status did not impact treatment. In a subsequent trial (UK ALL2003), iAMP21 status was determined prospectively, and patients with iAMP21 were assigned to more intensive therapy. Those patients had superior event-free survival (78 versus 29 percent), fewer relapses (16 versus 70 percent), and improved overall survival rates (89 versus 67 percent) at five years.
Genome-wide association studies — Genome-wide association studies (GWAS) have shown the predictive value of using gene expression profiling based upon the chromosomal abnormalities on ALL/LBL prognosis [63,64]. Studies using germline single-nucleotide polymorphisms (SNPs) have shown that several SNPs have been associated with measurable residual disease at the end of induction therapy, increased likelihood of relapse, altered antileukemic drug pharmacokinetics, and immunophenotype [65-68]. Recent studies have also defined the specific molecular changes found in Ph-like ALL/LBL [69], information that has both treatment and prognostic significance.
GWAS has also provided insight into the origin of relapsed ALL/LBL. For patients with T cell ALL/LBL, recurrences more than 2.5 years from diagnosis may represent a second leukemia rather than a relapse of the original leukemia, while late relapses in children with pre-B ALL/LBL are more likely to represent clonal evolution of the original disease [70].
IMMUNOPHENOTYPE — Precursor T cell ALL/LBL and mature B cell ALL/LBL have historically been associated with poor prognosis. Patients with these types of ALL/LBL are treated according to different protocols.
T cell ALL/LBL — Whether the outcomes in T cell ALL/LBL are directly related to immunophenotype or due to the increased incidence of elevated initial WBC counts in older patients is not clear [71-75]. Some institutions treat T cell ALL/LBL as high risk ALL/LBL (table 1) [75]. Younger patients with the T cell immunophenotype who do not have high WBC counts or bulky disease have done well with either T cell specific or higher risk ALL/LBL treatment protocols [74,76,77].
In a series of 125 children with T cell ALL/LBL who were treated the same as high risk Precursor B cell ALL/LBL, there were no significant differences based on age, presenting white blood cell (WBC) count, sex, central nervous system (CNS) involvement, or presence of a mediastinal mass, which identify those children with T cell ALL/LBL at higher risk for induction failure or early relapse [75]. Gene expression profiling holds promise for being able to prospectively detect patients with T cell ALL/LBL at risk for induction failure, relapse, and/or shortened overall survival [78-80]. Although one small study suggests that DNA methylation subgroups may correlate with T cell ALL/LBL survival [81], to date there have not been sufficient evidence to aid with risk stratification in T cell ALL/LBL.
As an example, several groups have associated the early thymocyte precursor (ETP) phenotype with an unusually poor outcome. Patients with the ETP phenotype have increased expression of myeloid markers more typical of acute myeloid leukemia (AML) and are thought to contain a more "stem-like" gene expression signature [80]. The incidence of this T-ALL/LBL subtype is approximately 12 to 15 percent [82,83]. In a single-institution study that included 38 children with ETP T-ALL/LBL, the ETP phenotype was associated with a higher rate of relapse (HR 11.6) and poor event-free survival [83]. However, a cooperative group study from the United Kingdom that included 35 cases of ETP T-ALL/LBL suggested that ETP T-ALL/LBL patients had a non-inferior five-year event-free and overall survival compared with non-ETP T-ALL/LBL [84]. Further studies are needed to clarify the clinical significance of the ETP phenotype, particularly in adolescents and adults where the outcomes are not well defined [85].
Mature B cell ALL/LBL — Mature B cell ALL/LBL has a different biology and a poorer prognosis than precursor B ALL/LBL. Almost all cases of mature B cell ALL/LBL demonstrate FAB L3 morphology and are associated with the t(8;14) translocation. The similarity between the molecular mechanisms associated with these translocations and those that occur in Burkitt lymphoma supports the hypothesis that mature B cell ALL/LBL represents a disseminated form of Burkitt lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)
Patients with mature B cell ALL/LBL respond poorly to conventional ALL/LBL treatment but have a better response to therapy designed for Burkitt lymphoma [86]. This therapy includes several courses of intensive therapy with a large number of chemotherapeutic agents [87]. (See "Treatment of Burkitt leukemia/lymphoma in adults" and "Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults", section on 'Burkitt-type ALL-L3'.)
RATE OF RESPONSE — One of the most important factors in assigning a final risk group in ALL/LBL is initial response to therapy [6,88-90]. In one controlled trial, 2090 children with ALL/LBL were randomly assigned, independent of risk factors, to receive either standard or intensified therapy [6]. In multivariate analysis, after controlling for age, sex, and presenting white blood cell (WBC) count, the bone marrow blast percentage on day eight of induction therapy, remission status at the end of induction therapy, and blast karyotype were the only significant predictors of outcome. The effects of these risk factors were similar in both groups. Other studies support early response to therapy (eg, day 8 in peripheral blood measurable residual disease) as an independent prognostic factor [88-93].
MEASURABLE RESIDUAL DISEASE — Although response rate is an important factor in predicting prognosis, improved methods of assessing treatment response are desirable. Most bone marrow aspirates performed at the end of induction therapy show histologic evidence of "complete" remission (CR), defined as less than 5 percent lymphoblasts in a bone marrow with evidence of hematopoietic recovery.
Many patients in clinical CR, however, continue to have small numbers of leukemic lymphoblasts in their bone marrow. The presence of such measurable residual disease (MRD) can be detected by flow cytometry or polymerase chain reaction at various points in the treatment course [94-97]. A detailed discussion of this issue is presented separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)
Large, prospective MRD monitoring studies in pediatric ALL/LBL confirm that the probability of long-term, relapse-free survival is directly related to the level of residual disease, both early in the course of treatment [91,98-105] and at later time points [100,106-108]. In a semi-quantitative MRD study of 246 children with ALL/LBL, multivariate analysis indicated that PCR detection of >0.01 percent residual blasts (ie, more than one leukemic cell per 10,000 nucleated cells) after intensive induction and especially end-consolidation chemotherapy was the most powerful independent predictor of early relapse [100,104]. A large study from the Children's Oncology Group, confirmed that residual blasts >0.01 percent at the end of induction was associated with a lower event-free survival [107].
When later time points were analyzed, a MRD burden of >0.01 percent (ie, more than one leukemic cell per 10,000 nucleated cells) was associated with significantly higher relapse rates. Other studies have confirmed the significance of serial, quantitative measurements of residual disease, indicating that the timing of disappearance and reappearance of marrow blasts is crucial in predicting relapse [100,104,109].
The European pediatric cooperative group, I-BFM-SG, and the Children's Oncology Group (COG) have begun prospective trials in which results of a semiquantitative MRD assay are used to stratify postremission treatment in childhood ALL/LBL. There are also efforts to use next-generation sequencing to more accurately assess MRD [110], and these efforts will be validated in the next series of clinical trials in both Europe and the United States. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)
DRUG METABOLISM AND RESISTANCE — In vitro resistance of the malignant cells to commonly employed agents (eg, glucocorticoids, vincristine, etoposide, L-asparaginase, daunorubicin, methotrexate) has been shown to be an independent adverse prognostic factor in children with low risk ALL/LBL who are treated on a number of protocols [111-113]. Ongoing studies, such as the use of gene expression profiling techniques, are engaged in methods for documenting the mechanisms underlying this resistance [114-124] and adapting treatment based on these patients' drug resistance profile. There is also evidence that genetic polymorphisms of drug metabolism enzymes [120,125-129], as well as the switch from prednisolone to dexamethasone [130,131], might influence response to therapy in some children with ALL/LBL.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)
SUMMARY
●Important risk stratification criteria for acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) in children include white blood cell (WBC) count, age at the time of diagnosis, cytogenetics, immunophenotype, and response to induction therapy (table 1). (See 'Overview' above.)
●Children with initial WBC >50,000/microL are assigned to the high risk group. (See 'WBC count and age' above.)
●Children older than 10 years are assigned to the high risk group. Those younger than one year and those older than 13 years (in the United States) are assigned to the very high risk group. (See 'WBC count and age' above.)
●Cytogenetic characteristics of ALL/LBL lymphoblasts affect risk stratification as follows:
•Lesser risk – Hyperdiploid (50 to 67 chromosomes) (Europe), trisomies 4 or 10, and translocation (12;21) encoding the ETV-RUNX1 protein (United States)
•Very high risk – Translocations (9;22), many of the 11q23 (MLL) mutations, the iAMP21 amplification, and hypodiploid (<44 chromosomes) (see 'Cytogenetics' above)
•Precursor T cell ALL/LBL may be associated with a lower prognosis, although recent clinical trials suggest that outcome for precursor T cell ALL/LBL is equal to non-precursor T cell ALL/LBL in more modern trials with more intense chemotherapy.
●Mature B cell ALL/LBL are associated with poorer prognosis. (See 'Immunophenotype' above.)
●Prognosis is directly related to the level of measurable residual disease following induction chemotherapy. (See 'Measurable residual disease' above.)
1 : SEER Cancer Statistic Review, 1973-1999. National Cancer Institute, Bethesda, MD, 2000. p.467.
2 : Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital.
3 : Childhood cancer survival trends in Europe: a EUROCARE Working Group study.
4 : Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths.
5 : Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia.
6 : Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol.
7 : Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol.
8 : 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).
9 : Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia.
10 : Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia.
11 : Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.
12 : Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994.
13 : Initial features and prognosis in 363 children with acute lymphocytic leukemia.
14 : Age at diagnosis in childhood acute lymphoblastic leukemia.
15 : Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01.
16 : Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children's Cancer Study Group.
17 : Biology and treatment of infant leukemias.
18 : Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials. Report from the Medical Research Council Working Party on Childhood Leukaemia.
19 : Acute lymphoid leukemia in adolescents: clinical and biologic features predict a poor prognosis--a Pediatric Oncology Group Study.
20 : Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome.
21 : Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study.
22 : Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4; 11)(q21; q23).
23 : ALL-1 gene at chromosome 11q23 is consistently altered in acute leukemia of early infancy.
24 : Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.
25 : A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias.
26 : MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.
27 : Cancer statistics, 2008.
28 : Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group.
29 : Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study.
30 : Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3).
31 : Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia.
32 : Towards targeted therapy for infant acute lymphoblastic leukaemia.
33 : 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.
34 : Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia.
35 : Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study.
36 : Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group.
37 : Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia.
38 : Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.
39 : Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (>50 chromosomes).
40 : Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201.
41 : Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study.
42 : Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results.
43 : High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative.
44 : Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia.
45 : Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis.
46 : Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood.
47 : Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome.
48 : Masked Hypodiploidy: Hypodiploid Acute Lymphoblastic Leukemia (ALL) in Children Mimicking Hyperdiploid ALL: A Report From the Children's Oncology Group (COG) AALL03B1 Study [Abstract 1580]
49 : TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis.
50 : Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse.
51 : Philadelphia positive acute lymphoblastic leukaemia of childhood.
52 : Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children's Cancer Group.
53 : Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031.
54 : Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project.
55 : Ph-like acute lymphoblastic leukemia.
56 : Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.
57 : In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype.
58 : MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches.
59 : 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.
60 : Molecular processes involved in B cell acute lymphoblastic leukaemia.
61 : Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials.
62 : Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children's oncology group studies: a report from the children's oncology group.
63 : Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected].
64 : Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.
65 : Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.
66 : A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
67 : Germline genomic variants associated with childhood acute lymphoblastic leukemia.
68 : Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia.
69 : Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics.
70 : Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia.
71 : Immunologically defined subclasses of acute lymphoblastic leukaemia in children: their relationship to presentation features and prognosis.
72 : Clinical relevance of lymphoblast biological features in children with acute lymphoblastic leukemia.
73 : Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report.
74 : Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.
75 : Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.
76 : Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group.
77 : Favorable outcome after 1-year treatment of childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia.
78 : Identification of novel molecular prognostic markers for paediatric T-cell acute lymphoblastic leukaemia.
79 : Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group.
80 : Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.
81 : An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression.
82 : Early T-cell precursor acute lymphoblastic leukaemia.
83 : Early T-cell precursor leukemia/lymphoma in adults and children.
84 : Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003.
85 : Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype.
86 : Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia.
87 : Non-Hodgkin's lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage--a report of the Berlin-Frankfurt-Münster Group.
88 : Prognostic value of karyotypic analysis in children and adults with high-risk acute lymphoblastic leukemia included in the PETHEMA ALL-93 trial.
89 : Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster.
90 : Prognostic value of day 14 blast percentage and the absolute blast index in bone marrow of children with acute lymphoblastic leukemia.
91 : Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia.
92 : Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial.
93 : Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow.
94 : Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia.
95 : Polymerase chain reaction (PCR)- and reverse transcription PCR-based minimal residual disease detection in long-term follow-up of childhood acute lymphoblastic leukaemia.
96 : Importance of minimal residual disease testing during the second year of therapy for children with acute lymphoblastic leukemia.
97 : Minimal residual disease detection in childhood precursor-B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children's Oncology Group study.
98 : Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood.
99 : Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction.
100 : Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group.
101 : Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome.
102 : Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.
103 : Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study.
104 : Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.
105 : Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels.
106 : Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia.
107 : Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study.
108 : Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.
109 : Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL.
110 : The predictive strength of next-generation sequencing MRD detection for relapse compared with current methods in childhood ALL.
111 : Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia.
112 : The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype.
113 : Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia.
114 : Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
115 : Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.
116 : A genome-wide view of the in vitro response to l-asparaginase in acute lymphoblastic leukemia.
117 : Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor.
118 : Pharmacogenetics of outcome in children with acute lymphoblastic leukemia.
119 : The gene expression signature of relapse in paediatric acute lymphoblastic leukaemia: implications for mechanisms of therapy failure.
120 : Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy.
121 : Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2.
122 : Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase.
123 : Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone.
124 : Genetic alterations determine chemotherapy resistance in childhood T-ALL: modelling in stage-specific cell lines and correlation with diagnostic patient samples.
125 : Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia.
126 : Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia.
127 : Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.
128 : Ancestry and pharmacogenetics of antileukemic drug toxicity.
129 : Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia.
130 : Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial.
131 : No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study Group L95-14 protocol.
