Your activity: 14 p.v.
< Back

Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents

Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents
Author:
Terzah M Horton, MD, PhD
Section Editors:
Julie R Park, MD
Peter Newburger, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Jun 10, 2022.

INTRODUCTION — Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) is the most common malignancy in children, accounting for one-third of all childhood cancers. The term ALL/LBL is used because the current system for diagnosis and classification does not distinguish between clinical presentations as leukemia or lymphoma [1]; by convention, the term lymphoma is used when it is confined to a mass lesion with little or no blood and marrow involvement.

Outcomes for pediatric ALL/LBL have improved dramatically since the 1980s, with approximately 90 percent five-year overall survival [2-4]. Improved outcomes and reduced toxicity are related to widespread adoption of standardized research protocols, improved prevention/treatment of leukemic meningitis, and risk-based stratification of treatment.

This topic discusses prognostic features and risk stratification for ALL/LBL in children, adolescents, and young adults.

Clinical presentation, classification, treatment, and outcomes of childhood ALL/LBL are discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

PROGNOSTIC FACTORS — In pediatric ALL/LBL, the immunophenotype and cytogenetic/molecular findings of leukemic blasts are used to categorize ALL/LBL (table 1) and are associated with outcomes. Response to therapy and certain clinical features are also associated with prognosis. Cooperative groups use different clinical, biologic, and disease-response criteria to allocate patients to as many as five prognostic categories [5-7].

Immunophenotype — B cell ALL/LBL accounts for a large majority of pediatric ALL/LBL. T cell ALL/LBL is less common and is associated with inferior prognosis.

Burkitt lymphoma/leukemia, which is a malignancy with a mature B cell phenotype that is associated with t(8;14) translocation, is not considered a category of ALL/LBL in the current World Health Organization (WHO) classification scheme [1]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

T cell — T cell immunophenotype accounts for up to 15 percent of newly diagnosed pediatric ALL/LBL and has distinctive clinical and biological features. For pediatric T cell ALL/LBL, the response to initial treatment is a more important prognostic determinant than clinical and laboratory features. (See 'T cell ALL/LBL' below.)

Historically, T cell ALL/LBL was considered an adverse prognostic feature, but use of more intensive treatments has been associated with outcomes that approach those with B cell ALL/LBL. It is uncertain if inferior outcomes are intrinsic to the T cell immunophenotype, or if they relate to its association with other adverse clinical features (eg, increased age, leukocytosis) [8-12], since younger patients with the T cell immunophenotype who do not have high white blood cell (WBC) counts or bulky disease have done well using either T cell-specific regimens or protocols for higher-risk ALL/LBL [11,13,14]. Gene expression profiling may be useful for identifying patients with T cell ALL/LBL at higher risk for induction failure, relapse, and/or inferior overall survival (OS) [15-17], but this requires validation in larger studies.

Most cases of T cell ALL/LBL are associated with one of three pathophysiologic mechanisms: abnormal T lineage transcription factors, aberrant NOTCH1/MYC signaling, or altered cell-cycle control [18]. Prognosis is not associated with the specific molecular features of T cell ALL/LBL. Examples of abnormalities of T lineage transcription factors include rearrangement with T cell receptor (TCR) enhancers, structural variants, or enhancer mutations of TAL1, TAL2, TLX1, TLX, HOXA, LMO1/LMO2, LMO2/LYL1, or NKX2-1 [19-21]. Aberrant activation of NOTCH1 (a critical transcription factor for T cell development) promotes uncontrolled cell growth, partly through increased MYC expression; this is associated with activating NOTCH1 mutations in three-quarters of cases and with loss-of-function mutations of FBXW7 in others [22-24]. Deletion of the tumor suppressors, CDKN2A/CDKN2B, CDKN1B, RB1, or CCND3 can alter cell cycle control [20,25]. Less often, T cell ALL/LBL is associated with abnormal signaling (eg, activated PI3K-AKT through loss of PTEN) or derangement of MYB, LEF1, or BCL11B; ribosomal function; ubiquitination; RNA processing; epigenetic modifiers, and other mechanisms [18]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'T-ALL/LBL'.)

Early T cell precursor — Early T cell precursor (ETP) ALL/LBL is a subcategory (12 to 15 percent) of T cell ALL/LBL that is characterized by a distinct immunophenotype and may be associated with inferior outcomes [26,27]. ETP blasts lack expression of CD1a and CD8, have weak CD5 expression, and express one or more myeloid or stem cell markers [17]. The ETP phenotype was associated with inferior outcomes in a single-institution study of 38 children [27], but a cooperative group study that included 35 cases of ETP ALL/LBL reported no difference in event-free survival (EFS) compared with non-ETP T-ALL/LBL [28].

Cytogenetics — Cytogenetic features are important for classification of ALL/LBL in the WHO scheme (table 1) [1,29], as discussed separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

Prognosis is associated with abnormal structural features of chromosomes (eg, translocations) and with aneuploidy (eg, hypodiploidy or hyperdiploidy). In a study of 1725 children with B cell ALL/LBL, favorable outcomes were associated with high hyperdiploidy (>50 chromosomes), while iAMP21, t(9;22), 11q23 translocation, abnormal 17p, and loss of 13q were associated with increased risk for relapse [30].

High hyperdiploidy — The presence of ≥50 chromosomes is a favorable prognostic feature [31-35]. Among patients with high hyperdiploidy, the best outcomes are associated with double trisomies of chromosomes 4 and 10, or triple trisomies of chromosomes 4, 10, and 17 [36]; as a result, patients with trisomies of these chromosomes are often treated with lower intensity therapy.

Although rare cases with near-triploidy (68 to 80 chromosomes) or near-tetraploidy (>80 chromosomes) have been associated with poor outcomes [37], a large series reported favorable outcomes in B-lineage ALL/LBL [38]. Care must be used to assure that near-triploidy or near-tetraploidy are not near-haploid or diploid, which have a very poor prognosis [39].

Hypodiploidy — The presence of <44 chromosomes is an adverse prognostic indicator, and the likelihood of a poor outcome increases with decreasing numbers of chromosomes. Hypodiploid cases lacking only a single chromosome have a prognosis similar to that of diploid cases, whereas near-haploid (24 to 28 chromosomes) leukemic cells are associated with inferior outcomes [32,40,41]. Low hypodiploid (32-39 chromosomes) cases are associated with tumor and germline TP53 mutations (91 percent), tumor IKAROS mutations (53 percent), and tumor RB1 abnormalities (41 percent) [42]; near haploid (<31 chromosomes) cases are also associated with TP53 and RAS mutations (70 percent). Both groups are chemotherapy resistant and require more aggressive chemotherapy.

Structural abnormalities — Structural chromosomal abnormalities include translocations, deletions, insertions, and inversions.

t(12;21)/ETV6::RUNX1 — The t(12;21) translocation is the most common translocation in pediatric ALL/LBL (25 percent of cases) and in many cases it is associated with a favorable prognosis. The t(12;21) translocation creates the ETV6::RUNX1 fusion gene (formerly known as TEL::AML1). Patients with this finding are assigned to low intensity treatment; while late relapses are more common in this group, these patients have an excellent response rate to chemotherapy following relapse [43,44]. Patients with ETV::RUNX1 mutations in association with a complex karyotype have a standard risk assessment and treatment varies according to the specific protocol [45]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 't(12;21)(p13.2;q22.1); ETV6::RUNX1'.)

t(9;22)/BCR::ABL1 — The t(9;22) translocation (the so-called Philadelphia chromosome [Ph]) is found in 4 percent of ALL/LBL cases; it can found in either B cell or T cell ALL/LBL and is associated with poor prognosis [46]. The t(9;22) translocation creates the BCR::ABL1 fusion gene, which encodes a constitutively active tyrosine kinase. Patients with Ph+ ALL/LBL receive higher intensity treatments, including the use of a tyrosine kinase inhibitor (TKI; eg, imatinib or dasatinib), which has improved outcomes [47]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 't(9;22); BCR::ABL1'.)

Ph-like (BCR::ABL1-like ) — This category of ALL/LBL exhibits gene expression profiles and outcomes that resemble those with BCR::ABL1, but the leukemic cells do not express the BCR::ABL1 protein; it is also referred to as BCR::ABL1-like B cell ALL/LBL. This finding is three- to fourfold more common than Ph+ ALL/LBL and has worse outcomes than other high-risk ALL/LBL [48]. Ph-like ALL/LBL often has activated cytokine receptor genes and/or altered kinase signaling pathways and may be amenable to treatment with a TKI [49]. Half of these patients overexpress CRLF2, of which half have a JAK mutation, which may respond to JAK or STAT inhibitors, but treatment with ruxolitinib or other JAK inhibitors is not yet considered to be standard of care in pediatric ALL/LBL [50]. Other cases have abnormalities of ABL1, EPOR (erythropoietin receptor), or other kinases [49]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'BCR::ABL1-like B cell ALL'.)

iAMP21 — Intrachromosomal amplification of chromosome 21 (iAMP21) is found in approximately 2 percent of children with B cell ALL/LBL and is associated with a high risk of relapse when treated with less aggressive chemotherapy [30,51,52]. In a retrospective analysis, treatment intensification was associated with improved outcomes; compared with standard treatment, use of more intensive therapy for children with iAMP21 was associated with superior five-year OS (89 versus 67 percent), EFS (78 versus 29 percent), and fewer relapses (16 versus 70 percent) [51]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 'iAMP21'.)

11q23/KMT2A — Rearrangements of 11q23 are found in approximately 10 percent of children with ALL/LBL overall but >70 percent in infants. (See 'Infant ALL/LBL' below.)

11q23 abnormalities are associated with rearrangements of KMT2A and poor prognosis [53]. The leukemic cells are pro-lymphocytes that lack CD10 expression and are often drug resistant (eg, to steroids and asparaginase) [54]. Relapse is common and often involves a lineage switch to acute myeloid leukemia (AML) [55]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 't(v;11q23.3)'.)

Response to treatment/MRD — Early response to chemotherapy is the most important prognostic factor for pediatric ALL/LBL. The standard method for evaluating response to treatment is assessment of measurable residual disease (MRD) by flow cytometry or molecular techniques [56]. Serial, quantitative assessment of MRD indicates the disappearance and reappearance of marrow blasts, which can predict relapse and is incorporated in contemporary pediatric ALL/LBL treatment protocols.

Most bone marrow aspirates performed at the end-of-induction (EOI) therapy reveal a histologic complete remission (CR; ie, <5 percent lymphoblasts with evidence of hematopoietic recovery). A proportion of children will later relapse, indicating that small numbers of leukemic lymphoblasts persisted in marrow despite the histologic CR. Assessment of MRD enables identification of patients with residual leukemic blasts who may benefit from more intensive chemotherapy. In T cell ALL/LBL, MRD is assessed at both EOI and at the end of consolidation (EOC); the presence of EOC MRD is used for risk stratification and treatment determination [57].

●MRD methods – MRD can be measured by flow cytometry (for leukemia-specific aberrant immunophenotypes) or by polymerase chain reaction (PCR) and/or next-generation sequencing (NGS) to detect unique immunoglobulin (Ig) and T cell receptor (TCR) genes or leukemia-specific transcripts (eg, BCR::ABL1). Molecular methods routinely detect one ALL cell among 10⁴ to 10⁵ cells; by comparison, flow cytometry is about 1 log less sensitive for detecting MRD [58,59]. Nevertheless, there is a high correlation in results from molecular and immunophenotypic studies [60-63].

MRD may be assessed at EOI, EOC, and at the end of maintenance therapy [64-67]. The preferred technique for detecting MRD and its timing vary with the immunologic and molecular features of the individual case and according to the dictates of the cooperative group or clinical protocol. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

●Prognostic impact of MRD – MRD is the most powerful prognostic factor for pediatric ALL/LBL in all age groups, including patients in low-risk categories [68-76]. In general, patients with favorable genetic subtypes clear MRD faster than those with high-risk genetics and T cell ALL/LBL [77], but the relapse risk at a given level of MRD differs between genetic subtypes [66,67].

Large studies of pediatric ALL/LBL that incorporated prospective MRD monitoring confirmed that long-term relapse-free survival is directly related to the level of residual disease, both early in the course of treatment [64,68,69,78-83] and at later time points [69,70,84,85].

In addition to the prognostic value of MRD status, the rate of disappearance of blasts is associated with outcomes. In one trial, 2090 children with ALL/LBL were randomly assigned to receive either standard or intensified therapy, independent of risk factors [31]. In multivariate analysis, after controlling for age, sex, and WBC count, the only significant predictors of outcome were bone marrow blast percentage on day 8 of induction therapy, remission status at EOI, and blast karyotype; the effects of these risk factors were similar in both treatment groups. Other studies support early response to therapy (eg, day 8 MRD in peripheral blood) as an independent prognostic factor [78,86-90].

Roles for MRD in management of ALL/LBL are discussed separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia" and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Response assessment'.)  

Clinical features — Age, WBC count, and involvement of the central nervous system (CNS) or testes at diagnosis are standard criteria used by cooperative groups for risk assignment in pediatric ALL/LBL (table 2) [18,91,92]. Age and WBC are important prognostic features for B cell ALL/LBL but are less predictive for T cell ALL/LBL [93,94].

As treatment has improved, clinical features that were formerly used to categorize patients are no longer independently associated with treatment outcomes. Examples of factors that are no longer used to stratify treatment include sex; race/ethnicity; presence of a mediastinal mass, organomegaly, or lymphadenopathy; and hemoglobin, platelet count, and serum immunoglobulin levels [31,95]. Adverse outcomes associated with race (Black) and ethnicity (Hispanic) have, instead, been linked to socioeconomic factors and/or genomic variations (eg, Hispanic children are more likely to have somatic CRLF2 rearrangements) [96-98].

Use of clinical features for risk stratification in pediatric ALL/LBL is described below. (See 'Risk stratification' below.)

Age — Patients ≥10 years or ≤1 year have less favorable outcomes and are assigned to higher risk groups [18,91,92].  

Age at presentation is associated with certain cytogenetic/molecular features. As examples, infants are more likely than others to have rearrangements involving KMT2A (MLL) [99,100], while adolescents are more likely to have certain adverse molecular findings (eg, BCR::ABL1 rearrangement, Ph-like ALL/LBL) and less likely to have low-risk subtypes (hyperdiploidy, ETV6::RUNX1 rearrangement).

Infant ALL/LBL — ALL/LBL in infants has distinct biological characteristics and prognosis. Approximately three-quarters of infants with ALL/LBL have translocations involving 11q23 at the KMT2A gene locus [101-104]. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 't(v;11q23.3)'.)

Translocations of 11q23 involve rearrangements of KMT2A with one of numerous partner genes; the resultant fusion products drive distinct patterns of gene expression [1,105]. Infant ALL/LBL typically presents as B cell precursor blasts with co-expression of myeloid markers; as a result, KMT2A was previously called mixed-lineage leukemia (MLL).

Diagnosis of ALL/LBL in the first three months of life is associated with particularly poor prognosis [106,107]. Infants with ALL/LBL are typically treated with more aggressive chemotherapy because they have poor responses to conventional therapy [106,108-110]. Compared with pediatric ALL/LBL with non-rearranged KMT2A, infant ALL/LBL is associated with high rates of early treatment failure and poor outcomes [102,103,105,106,111,112]. As an example, in a series of 147 infants, the estimated five-year EFS rate in infants with ALL/LBL and a KMT2A rearrangement was 19 percent, compared with 46 percent five-year EFS for others [112].

White blood cell count — WBC count >50,000/microL at presentation has long been associated with inferior outcomes in ALL/LBL [5,93]. All cooperative groups use hyperleukocytosis as a criterion for a higher risk category (table 2).

CNS or testicular involvement — Involvement of the CNS or testes at diagnosis is an adverse prognostic feature (table 2).

All children who present with ALL/LBL should undergo an initial diagnostic lumbar puncture (LP). In addition, boys should have a pretreatment testicular examination for a mass or swelling. Pretreatment evaluation of ALL/LBL and interpretation of findings from the initial LP are discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Pretreatment evaluation' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Lumbar puncture'.)

Detection of blasts in the cerebrospinal fluid (CSF) with the initial LP is associated with inferior outcome [18,91,92]. After adjusting for other prognostic factors, presence of CSF blasts at diagnosis is associated with inferior outcomes, even for patients with low levels of CNS involvement [113].

RISK STRATIFICATION — Risk-stratified therapy enables reduced treatment intensity and less toxicity in low-risk patients, while supporting more aggressive therapy for those with a high risk of relapse. Risk-based treatment, along with routine use of clinical trials and introduction of preventive central nervous system (CNS) therapy have contributed to improved survival rates for children with ALL/LBL.

Clinical features (eg, initial white blood cell [WBC] count, age, CNS or testicular involvement), cytogenetic/molecular findings, immunologic subtype, and rapidity and degree of cytoreduction are used to stratify treatment of ALL/LBL (table 2) because of their association with prognosis. (See 'Prognostic factors' above.)

Details of risk-stratified treatment for pediatric ALL/LBL are presented separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Risk stratification'.)

B cell ALL/LBL — B cell lineage is the most common category of ALL/LBL. In this lineage, the following four risk groups with different outcomes have been identified based upon initial clinical and biological risk factors and validated in a retrospective analysis of more than 6000 children with ALL/LBL [5]:

●Low risk – Children with favorable age (ie, 1 to 10 years); low WBC count (<50,000/microL); favorable cytogenetic changes (eg, hyperdiploidy, ETV6::RUNX1 rearrangement); and rapid response to treatment are in the low-risk category and have the best prognosis, with approximately 95 percent five-year event-free survival (EFS) [3,5,114].

●Standard risk – Children age 1 to 10 years with low WBC count and favorable response to treatment, but without favorable cytogenetics, are considered to have standard-risk ALL/LBL with EFS of approximately 90 percent.

●High risk – Patients >10 years, those with unfavorable cytogenetic changes, or measurable residual disease (MRD) >0.01 percent at end-of induction (EOI) have high-risk ALL/LBL. Such patients who then have an inadequate response to initial therapy (persistent MRD at EOI) are considered very high-risk (see below).

●Very high risk – Children with extreme hypodiploidy (≤44 chromosomes), t(9;22) (Philadelphia chromosome)/BCR::ABL1 rearrangement, t(4;11)/KMT2A rearrangement, iAMP21, and/or failure to achieve complete remission (CR) at EOI are considered very high risk; in the United States, children >13 years are also included in this category. Five-year EFS was ≤45 percent [5]. Despite the adverse prognosis, subsets of these patients can be successfully treated with aggressive chemotherapy, often in combination with hematopoietic stem cell transplantation.

Treatment of B cell ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

T cell ALL/LBL — The key prognostic determinant in T cell ALL/LBL is MRD response at EOI and at the end of consolidation (EOC) [56]. Age and presenting WBC count are not independently prognostic in T-ALL/LBL.

Treatment of T cell ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'T cell 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

●Description – Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) is the most common cancer in children. Overall, >90 percent of children with ALL/LBL are cured, but some survivors experience long-term treatment-related toxicity (eg, effects on growth and development, endocrine conditions, and secondary cancers).

Outcomes are related to certain clinical and laboratory features at the time of diagnosis and to an early response to treatment. Stratification of treatment of ALL/LBL according to prognosis enables preservation of excellent outcomes for children with favorable prognostic features, while limiting treatment-related toxicity; conversely, treatment is intensified for children with certain adverse prognostic features.

●Prognostic factors – Validated adverse prognostic features include:

•Immunologic subtype – T cell immunophenotype is less common than B cell lineage and it is associated with adverse prognosis. (See 'Immunophenotype' above.)

•Cytogenetic/molecular features – Chromosome changes (ie, numerical or structural abnormalities) and certain molecular abnormalities are associated with either favorable or adverse outcomes. (See 'Cytogenetics' above.)

Examples of such features and their prognostic influence include:

-High hyperdiploidy – Favorable (see 'High hyperdiploidy' above)

-Hypodiploidy – Adverse (see 'Hypodiploidy' above)

-t(12;21)/ETV6::RUNX1 – Favorable or neutral (see 't(12;21)/ETV6::RUNX1' above)

-t(9;22)/BCR::ABL1 (Philadelphia chromosome [Ph]-positive) – Adverse (see 't(9;22)/BCR::ABL1' above)

-Ph-like (BCR::ABL1-like) ALL/LBL – Adverse (see 'Ph-like (BCR::ABL1-like )' above)

-iAMP21 (intrachromosomal amplification of chromosome 21) – Adverse (see 'iAMP21' above)

-11q23/KMT2A rearrangements – Adverse (see '11q23/KMT2A' above)

•Treatment response – Measurable residual disease (MRD) response at specified time points in treatment. (See 'Response to treatment/MRD' above.)

•Clinical

-Age ≤1 year or ≥10 years at diagnosis – Adverse (see 'Age' above)

-White blood cell (WBC) count >50,000/microL – Adverse (see 'White blood cell count' above)

-Central nervous system (CNS) or testicular involvement at diagnosis – Adverse (see 'CNS or testicular involvement' above)

●Risk stratification – Risk stratification for treatment of pediatric ALL/LBL varies according to clinical and laboratory features, cytogenetic/molecular findings, and immunophenotype, and response to therapy (table 2). (See 'Risk stratification' above.)

●Treatment – Treatment of pediatric ALL/LBL according to risk stratification is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges C Philip Steuber, MD, who contributed to an earlier version of this topic review.

  1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017.
  2. Teachey DT, Pui CH. Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia. Lancet Oncol 2019; 20:e142.
  3. Hunger SP, Loh ML, Whitlock JA, et al. Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer 2013; 60:957.
  4. Kato M, Manabe A. Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr Int 2018; 60:4.
  5. 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 2007; 109:926.
  6. Inaba H, Azzato EM, Mullighan CG. Integration of Next-Generation Sequencing to Treat Acute Lymphoblastic Leukemia with Targetable Lesions: The St. Jude Children's Research Hospital Approach. Front Pediatr 2017; 5:258.
  7. Vrooman LM, Blonquist TM, Harris MH, et al. Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001. Blood Adv 2018; 2:1449.
  8. Greaves MF, Janossy G, Peto J, Kay H. Immunologically defined subclasses of acute lymphoblastic leukaemia in children: their relationship to presentation features and prognosis. Br J Haematol 1981; 48:179.
  9. Kalwinsky DK, Roberson P, Dahl G, et al. Clinical relevance of lymphoblast biological features in children with acute lymphoblastic leukemia. J Clin Oncol 1985; 3:477.
  10. Reiter A, Schrappe M, Ludwig WD, et al. Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 2000; 95:416.
  11. Shuster JJ, Falletta JM, Pullen DJ, et al. Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 1990; 75:166.
  12. 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 2003; 21:3616.
  13. Steinherz PG, Gaynon PS, Breneman JC, et al. 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. Cancer 1998; 82:600.
  14. van den Berg H, Zsiros J, Veneberg A, et al. Favorable outcome after 1-year treatment of childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia. Med Pediatr Oncol 1998; 30:46.
  15. Gottardo NG, Hoffmann K, Beesley AH, et al. Identification of novel molecular prognostic markers for paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol 2007; 137:319.
  16. Winter SS, Jiang Z, Khawaja HM, et al. Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2007; 110:1429.
  17. 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 2009; 10:147.
  18. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica 2020; 105:2524.
  19. Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 2002; 1:75.
  20. Liu Y, Easton J, Shao Y, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 2017; 49:1211.
  21. Gianni F, Belver L, Ferrando A. The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia. Cold Spring Harb Perspect Med 2020; 10.
  22. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306:269.
  23. Palomero T, Lim WK, Odom DT, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 2006; 103:18261.
  24. Herranz D, Ambesi-Impiombato A, Palomero T, et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med 2014; 20:1130.
  25. Hebert J, Cayuela JM, Berkeley J, Sigaux F. Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. Blood 1994; 84:4038.
  26. Haydu JE, Ferrando AA. Early T-cell precursor acute lymphoblastic leukaemia. Curr Opin Hematol 2013; 20:369.
  27. Allen A, Sireci A, Colovai A, et al. Early T-cell precursor leukemia/lymphoma in adults and children. Leuk Res 2013; 37:1027.
  28. 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 2014; 166:421.
  29. Harrison CJ. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol 2009; 144:147.
  30. Moorman AV, Ensor HM, Richards SM, et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; 11:429.
  31. Hann I, Vora A, Harrison G, et al. Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol. Br J Haematol 2001; 113:103.
  32. Heerema NA, Sather HN, Sensel MG, et al. Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes). J Clin Oncol 2000; 18:1876.
  33. Chauvenet AR, Martin PL, Devidas M, et al. Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201. Blood 2007; 110:1105.
  34. Rubnitz JE, Wichlan D, Devidas M, et al. Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. J Clin Oncol 2008; 26:2186.
  35. 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 2013; 121:2415.
  36. Sutcliffe MJ, Shuster JJ, Sather HN, et al. 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. Leukemia 2005; 19:734.
  37. Pui CH, Carroll AJ, Head D, et al. Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood. Blood 1990; 76:590.
  38. Raimondi SC, Zhou Y, Shurtleff SA, et al. 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. Cancer Genet Cytogenet 2006; 169:50.
  39. Carroll AJ, Heerema NA, Gastier-Foster JM, et al. 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]. Blood 2009; 114:1580.
  40. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood 2007; 110:1112.
  41. Safavi S, Paulsson K. Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis. Blood 2017; 129:420.
  42. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013; 45:242.
  43. Shurtleff SA, Buijs A, Behm FG, et al. 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. Leukemia 1995; 9:1985.
  44. Sun C, Chang L, Zhu X. Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 2017; 8:35445.
  45. Becker M, Liu K, Tirado CA. The t(12;21)(p13;q22) in Pediatric B-Acute Lymphoblastic Leukemia: An Update. J Assoc Genet Technol 2017; 43:99.
  46. Jones LK, Saha V. Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 2005; 130:489.
  47. Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia 2014; 28:1467.
  48. Loh ML, Zhang J, Harvey RC, et al. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project. Blood 2013; 121:485.
  49. Tran TH, Loh ML. Ph-like acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2016; 2016:561.
  50. Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res 2016; 111:784.
  51. Moorman AV, Robinson H, Schwab C, et al. 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. J Clin Oncol 2013; 31:3389.
  52. Heerema NA, Carroll AJ, Devidas M, et al. 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. J Clin Oncol 2013; 31:3397.
  53. Pui CH, Gaynon PS, Boyett JM, et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002; 359:1909.
  54. Ramakers-van Woerden NL, Beverloo HB, Veerman AJ, et al. In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. Leukemia 2004; 18:521.
  55. Winters AC, Bernt KM. MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches. Front Pediatr 2017; 5:4.
  56. Raetz EA, Teachey DT. T-cell acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2016; 2016:580.
  57. Teachey DT, Devidas M, Wood BL, et al. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol 2022; 40:2106.
  58. Brüggemann M, Kotrova M. Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Hematology Am Soc Hematol Educ Program 2017; 2017:13.
  59. Wood B, Wu D, Crossley B, et al. Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood 2018; 131:1350.
  60. Gaipa G, Cazzaniga G, Valsecchi MG, et al. Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal residual disease detection in childhood acute lymphoblastic leukemia. Haematologica 2012; 97:1582.
  61. Irving J, Jesson J, Virgo P, et al. Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting. Haematologica 2009; 94:870.
  62. Malec M, van der Velden VH, Björklund E, et al. Analysis of minimal residual disease in childhood acute lymphoblastic leukemia: comparison between RQ-PCR analysis of Ig/TcR gene rearrangements and multicolor flow cytometric immunophenotyping. Leukemia 2004; 18:1630.
  63. Ryan J, Quinn F, Meunier A, et al. Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches. Br J Haematol 2009; 144:107.
  64. 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 2015; 126:964.
  65. 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 2011; 118:2077.
  66. Pui CH, Pei D, Raimondi SC, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia 2017; 31:333.
  67. 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 2018; 36:34.
  68. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352:1731.
  69. Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339:591.
  70. 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 2008; 111:5477.
  71. Berry DA, Zhou S, Higley H, et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol 2017; 3:e170580.
  72. 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 2013; 14:199.
  73. Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006; 107:1116.
  74. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009; 113:4153.
  75. Patel B, Rai L, Buck G, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol 2010; 148:80.
  76. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 1998; 351:550.
  77. Willemse MJ, Seriu T, Hettinger K, et al. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 2002; 99:4386.
  78. Laughton SJ, Ashton LJ, Kwan E, et al. Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia. J Clin Oncol 2005; 23:2264.
  79. Brisco MJ, Condon J, Hughes E, et al. Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. Lancet 1994; 343:196.
  80. Nyvold C, Madsen HO, Ryder LP, et al. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood 2002; 99:1253.
  81. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 2002; 100:52.
  82. Conter V, Valsecchi MG, Parasole R, et al. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood 2014; 123:1470.
  83. Mullighan CG, Jeha S, Pei D, et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood 2015; 126:2896.
  84. Goulden N, Bader P, Van Der Velden V, et al. Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia. Br J Haematol 2003; 122:24.
  85. 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 2015; 16:465.
  86. Ribera JM, Ortega JJ, Oriol A, et al. Prognostic value of karyotypic analysis in children and adults with high-risk acute lymphoblastic leukemia included in the PETHEMA ALL-93 trial. Haematologica 2002; 87:154.
  87. Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia 2000; 14:2205.
  88. Visser JH, Wessels G, Hesseling PB, et al. Prognostic value of day 14 blast percentage and the absolute blast index in bone marrow of children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2001; 18:187.
  89. Roy A, Bradburn M, Moorman AV, et al. 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. Br J Haematol 2005; 129:35.
  90. 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 2009; 27:5168.
  91. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet 2020; 395:1146.
  92. Brown P, Inaba H, Annesley C, et al. Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2020; 18:81.
  93. 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 1996; 14:18.
  94. Maloney KW, Shuster JJ, Murphy S, et al. Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994. Leukemia 2000; 14:2276.
  95. Rabin KR, Gramatges MM, Margolin JF, et al. Acute lymphoblastic leukemia. In: Principles and Practice of Pediatric Oncology, Seventh edition, Pizzo PA, Poplack DG (Eds), Wolters Kluwer, Philadelphia 2016.
  96. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 2010; 115:5312.
  97. Yang JJ, Cheng C, Devidas M, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet 2011; 43:237.
  98. 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 2012; 30:751.
  99. Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 2010; 116:4874.
  100. Clappier E, Auclerc MF, Rapion J, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia 2014; 28:70.
  101. Chen CS, Sorensen PH, Domer PH, et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 1993; 81:2386.
  102. Rubnitz JE, Link MP, Shuster JJ, et al. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 1994; 84:570.
  103. Hilden JM, Frestedt JL, Moore RO, et al. Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4; 11)(q21; q23). Blood 1995; 86:3876.
  104. Cimino G, Lo Coco F, Biondi A, et al. ALL-1 gene at chromosome 11q23 is consistently altered in acute leukemia of early infancy. Blood 1993; 82:544.
  105. Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002; 30:41.
  106. 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 2006; 108:441.
  107. 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 2012; 119:1872.
  108. Stam RW, den Boer ML, Meijerink JP, et al. Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. Blood 2003; 101:1270.
  109. Stam RW, den Boer ML, Pieters R. Towards targeted therapy for infant acute lymphoblastic leukaemia. Br J Haematol 2006; 132:539.
  110. 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 2006; 107:4663.
  111. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58:71.
  112. Dreyer ZE, Hilden JM, Jones TL, et al. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer 2015; 62:419.
  113. 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 2017; 35:2527.
  114. Moorman AV, Richards SM, Martineau M, et al. Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia. Blood 2003; 102:2756.
Topic 6248 Version 34.0

References

1 : WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017.

2 : Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia.

3 : Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia.

4 : Treatment and biology of pediatric acute lymphoblastic leukemia.

5 : 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).

6 : Integration of Next-Generation Sequencing to Treat Acute Lymphoblastic Leukemia with Targetable Lesions: The St. Jude Children's Research Hospital Approach.

7 : Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001.

8 : Immunologically defined subclasses of acute lymphoblastic leukaemia in children: their relationship to presentation features and prognosis.

9 : Clinical relevance of lymphoblast biological features in children with acute lymphoblastic leukemia.

10 : Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report.

11 : Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

12 : Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.

13 : 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.

14 : Favorable outcome after 1-year treatment of childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia.

15 : Identification of novel molecular prognostic markers for paediatric T-cell acute lymphoblastic leukaemia.

16 : Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group.

17 : Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.

18 : Pediatric acute lymphoblastic leukemia.

19 : Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.

20 : The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.

21 : The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia.

22 : Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.

23 : NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.

24 : A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.

25 : Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias.

26 : Early T-cell precursor acute lymphoblastic leukaemia.

27 : Early T-cell precursor leukemia/lymphoma in adults and children.

28 : Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003.

29 : Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia.

30 : Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.

31 : Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol.

32 : Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (>50 chromosomes).

33 : Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201.

34 : Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study.

35 : Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results.

36 : 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.

37 : Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood.

38 : 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.

39 : 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]

40 : Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia.

41 : Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis.

42 : The genomic landscape of hypodiploid acute lymphoblastic leukemia.

43 : 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.

44 : Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse.

45 : The t(12;21)(p13;q22) in Pediatric B-Acute Lymphoblastic Leukemia: An Update.

46 : Philadelphia positive acute lymphoblastic leukaemia of childhood.

47 : Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031.

48 : Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project.

49 : Ph-like acute lymphoblastic leukemia.

50 : Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases.

51 : 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.

52 : 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.

53 : Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.

54 : In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype.

55 : MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches.

56 : T-cell acute lymphoblastic leukemia.

57 : Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.

58 : Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation.

59 : Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL.

60 : Time point-dependent concordance of flow cytometry and real-time quantitative polymerase chain reaction for minimal residual disease detection in childhood acute lymphoblastic leukemia.

61 : Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting.

62 : Analysis of minimal residual disease in childhood acute lymphoblastic leukemia: comparison between RQ-PCR analysis of Ig/TcR gene rearrangements and multicolor flow cytometric immunophenotyping.

63 : Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches.

64 : Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.

65 : Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study.

66 : Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy.

67 : Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia.

68 : Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood.

69 : Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group.

70 : Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study.

71 : Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis.

72 : Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

73 : Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.

74 : Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).

75 : Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993.

76 : Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia.

77 : Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL.

78 : Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia.

79 : Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction.

80 : Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome.

81 : Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.

82 : Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study.

83 : Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels.

84 : Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia.

85 : Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.

86 : Prognostic value of karyotypic analysis in children and adults with high-risk acute lymphoblastic leukemia included in the PETHEMA ALL-93 trial.

87 : Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster.

88 : Prognostic value of day 14 blast percentage and the absolute blast index in bone marrow of children with acute lymphoblastic leukemia.

89 : 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.

90 : Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow.

91 : Acute lymphoblastic leukaemia.

92 : Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

93 : Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

94 : Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994.

95 : Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994.

96 : Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.

97 : Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia.

98 : ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia.

99 : Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome.

100 : An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions.

101 : Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome.

102 : Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study.

103 : Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4; 11)(q21; q23).

104 : ALL-1 gene at chromosome 11q23 is consistently altered in acute leukemia of early infancy.

105 : MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.

106 : Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group.

107 : Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study.

108 : Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia.

109 : Towards targeted therapy for infant acute lymphoblastic leukaemia.

110 : 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.

111 : Cancer statistics, 2008.

112 : Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3).

113 : 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.

114 : Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia.