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 associated with clinical outcomes and are used to categorize ALL/LBL (table 1). 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].
Clinical features — Age, white blood cell (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) [8-10]. Age and WBC count are important prognostic features for B cell ALL/LBL but are less predictive for T cell ALL/LBL [11,12].
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 [13,14]. 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) [15-17].
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 [8-10].
Age at presentation is associated with certain cytogenetic/molecular features. As examples, infants are more likely than others to have rearrangements involving KMT2A (MLL) [18,19], 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 [20-23]. (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 [1,24]. Infant ALL/LBL typically presents as B cell precursor blasts with coexpression 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 [25,26]. Infants with ALL/LBL are typically treated with more aggressive chemotherapy because they have poor responses to conventional therapy [25,27-29]. Compared with pediatric ALL/LBL with nonrearranged KMT2A, infant ALL/LBL is associated with high rates of early treatment failure and poor outcomes [21,22,24,25,30,31]. As an example, in a 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 five-year EFS for others [31].
White blood cell count — WBC count >50,000/microL at presentation has long been associated with inferior outcomes in ALL/LBL [5,11]. All cooperative groups use hyperleukocytosis as a criterion for a higher-risk category (table 2).
Central nervous system 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 an inferior outcome [8-10]. After adjusting for other prognostic factors, the presence of CSF blasts at diagnosis is associated with inferior outcomes, even for patients with low levels of CNS involvement [32].
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 [33-36]. 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) [37-41], since younger patients with the T cell immunophenotype who do not have high WBC counts or bulky disease have done well using either T cell-specific regimens or protocols for higher-risk ALL/LBL [40,42,43]. 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) [44-46], 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 [10]. 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 [47-49]. 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 [50-52]. Deletion of the tumor suppressors, CDKN2A/CDKN2B, CDKN1B, RB1, or CCND3 can alter cell cycle control [48,53]. 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 [10]. (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. ETP blasts lack expression of CD1a and CD8, have weak or negative CD5 expression, and express one or more myeloid or stem cell markers; the same immunophenotype, but with stronger CD5 expression, has been called near-ETP [54].
ETP ALL/LBL often manifests slow treatment response; in some, but not all, studies ETP ALL/LBL has been associated with inferior outcomes. The Children’s Oncology Group (COG) AALL0434 trial of 1256 children, adolescents, and young adults with T cell ALL/LBL reported that patients with ETP and near-ETP subtypes had higher rates of induction failure than patients with non-ETP disease T cell ALL/LBL (6 versus 1 percent), but the three groups had similar five-year OS (87 to 90 percent) [55]. Another cooperative group study that included 35 cases of ETP ALL/LBL reported no difference in EFS compared with non-ETP T cell ALL/LBL [56]. A single-institution study of 38 children with ETP ALL/LBL reported inferior outcomes in this subtype of T cell ALL/LBL [57].
Cytogenetics — Cytogenetic features are important for classification of ALL/LBL in the WHO scheme (table 1) [1,58], 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 [59].
High hyperdiploidy — The presence of ≥50 chromosomes is a favorable prognostic feature [13,60-63]. 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 [64]. As a result, patients with trisomies of these chromosomes do not require intensification of therapy.
Although rare cases with near-triploidy (68 to 80 chromosomes) or near-tetraploidy (>80 chromosomes) have been associated with poor outcomes [65], a large series reported favorable outcomes in B-lineage ALL/LBL [66]. Care must be used to assure that near-triploidy or near-tetraploidy are not near-haploid or diploid, which have a very poor prognosis [67].
Hypodiploidy — The presence of <44 chromosomes is an adverse prognostic indicator, and the likelihood of a poor outcome increases with decreasing numbers of chromosomes.
Definitions for categories of hypodiploidy vary, but cases lacking only a single chromosome have a prognosis similar to that of diploid cases, whereas cases with fewer chromosomes are associated with inferior outcomes [60,68,69]. In one study, 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) [70]; 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 do not require treatment intensification. While late relapses are more common with this finding, these patients have an excellent response rate to chemotherapy following relapse [71,72]. Patients with ETV::RUNX1 mutations in association with a complex karyotype have a standard risk assessment and treatment varies according to the specific protocol [73]. (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 [74]. 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 [75]. (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 [76,77].
Ph-like ALL/LBL is three- to fourfold more common than Ph+ ALL/LBL and has worse outcomes than other high-risk ALL/LBL [78]. 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 [79]. 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 [80]. Other cases have abnormalities of ABL1, EPOR (erythropoietin receptor), or other kinases [79]. (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 [59,81,82]. 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) [81]. (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' above.)
11q23 abnormalities are associated with rearrangements of KMT2A and poor prognosis [83]. The leukemic cells are pro-lymphocytes that lack CD10 expression and are often drug resistant (eg, to steroids and asparaginase) [84]. Relapse is common and often involves a lineage switch to acute myeloid leukemia (AML) [85]. (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. 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 [33].
●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 [86,87]. Nevertheless, there is a high correlation in results from molecular and immunophenotypic studies [88-91].
MRD is assessed at EOI; if MRD is positive at EOI, it is again assessed at EOC [92-96]. 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 [97-105]. In general, patients with favorable genetic subtypes clear MRD faster than those with high-risk genetics and T cell ALL/LBL [106], but the relapse risk at a given level of MRD differs between genetic subtypes [94,95].
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 [92,97,98,107-112] and at later time points [96,98,99,113,114].
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 [13]. 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 [107,115-119].
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'.)
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) [3,5,120].
●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, some 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) [121]. 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 'Central nervous system 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.
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