Clinical and Laboratory Features at Diagnosis
Leukemic Cell Characteristics
Response to Treatment
Prognostic Groups
        Prognostic groups under clinical evaluation

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that those children who have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, thus more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival.[1,2]

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of clinical and laboratory features have demonstrated prognostic value, some of which are described below. The factors described are grouped into the following categories: clinical and laboratory features at diagnosis; leukemic cell characteristics at diagnosis; and response to initial treatment. As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables.[3,4] Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors. For example, a report from the Children’s Cancer Group (CCG) showed that the adverse prognostic significance of slow early response disappears when these patients receive intensified postinduction chemotherapy.[5]

Outcome in Down syndrome children with ALL has generally been reported as poorer than that of non–Down syndrome children.[6-8] The lower event-free survival (EFS) and overall survival (OS) of children with Down syndrome appear to be related to higher rates of treatment-related mortality, especially during induction therapy,[7,8] and to the absence of favorable biological features.[6,8]

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[9] The European Organization for Research and Treatment of Cancer (EORTC) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[10] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[9] The Children's Oncology Group (COG) has also adopted this strategy.

A subset of the prognostic factors discussed below is used for the initial stratification of children with ALL for treatment assignment, and at the end of this section there are brief descriptions of the prognostic groupings currently applied to clinical trials in the United States.

1. Age at diagnosis

   Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[11] Young children (aged 1–9 years) have a better disease-free survival than older children, adolescents, or infants.[1,12,13] The improved prognosis in younger children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts including hyperdiploidy with 51 or more chromosomes, or the t(12;21) (TEL-AML1 translocation).[11,14] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[15-18] (For more information about adolescents with ALL, see the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.)

   Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in infants younger than 3 months and in those with a poor response to a prednisone prophase.[19-26] Infants with ALL can be divided into two subgroups on the basis of the presence or absence of MLL gene rearrangements.[27] Approximately 80% of infants with ALL have an MLL gene rearrangement.[22,27,28] An MLL gene rearrangement is most common in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL rearrangements decreases.[29] Infants with leukemia and MLL gene rearrangements have very high white blood cell (WBC) counts, increased incidence of central nervous system (CNS) involvement, and a poor outcome.[29] Blasts from infants with MLL gene rearrangements are typically CD10/cALLa negative and express high levels of FLT3.[30] Conversely, infants whose leukemia has a germline (nonrearranged) MLL gene frequently present with CD10/cALLa-positive precursor B-cell immunophenotype. These infants have a significantly better outcome than infants with ALL and MLL gene rearrangements.[22,31,32]




2. WBC count at diagnosis

   Higher WBC counts at diagnosis represent an increased risk of treatment failure in patients with precursor B-cell ALL. A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[1] although the relationship between WBC count and prognosis is a continuous rather than a step function.[13,33] Elevated WBC count is often associated with other high-risk prognostic factors, including unfavorable chromosomal translocations such as t(4;11) and t(9;22) (see below).




3. CNS status at diagnosis

   CNS status at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence/absence of blasts on cytospin:

   • CNS1: Cerebrospinal fluid (CSF) that is cytospin negative for blasts regardless of WBC count.
   • CNS2: CSF with fewer than 5 WBC/µL and cytospin positive for blasts.
   • CNS3 (CNS disease): CSF with 5 or more WBC/µL and cytospin positive for blasts.

   Children with ALL who present with CNS disease at diagnosis (i.e., CNS3) are at a higher risk of treatment failure (both within the CNS and systemically) compared with patients not meeting the criteria for CNS disease at diagnosis. Patients with CNS2 status at diagnosis may be at increased risk of CNS relapse,[34] though this observation may not apply for all treatment regimens.[35] Any increased risk associated with CNS2 status on overall outcome may be overcome by more intensive intrathecal therapy.[36,37] A traumatic lumbar puncture (≥10 erythrocytes/µl) that includes blasts at diagnosis appears to be associated with increased risk of CNS relapse and indicates an overall poorer outcome.[37,38] High leukemia cell expression of the gene for interleukin-15 (IL-15) is associated with an increased likelihood of CNS3 status at diagnosis and also may predict for a higher rate of CNS relapse in patients who present with CNS1 status at diagnosis.[39]




4. Gender

   In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[40-42] One reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.[40-42] However, in clinical trials with high 5-year EFS rates (>80%), male gender is not an adverse risk factor.[43,44]




5. Race

   Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[45] This difference may be therapy-dependent; a report from St. Jude Children's Research Hospital found no difference in outcome by racial groups.[46] Asian children with ALL fare slightly better than white children.[47] The reason for better outcome in white and Asian children compared with black and Hispanic children is not known, but it cannot be completely explained based on known prognostic factors.[47]

1. Morphology

   In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[48] Because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used in the United States. Most cases of ALL that show L3 morphology express surface immunoglobulin and have a C-MYC gene translocation identical to the findings for Burkitt lymphoma (e.g., t[8;14]). Patients with this specific, rare form of leukemia (mature B-cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information on the treatment of B-cell ALL and Burkitt lymphoma.)




2. Immunophenotype
   • Precursor B-cell ALL: Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B-cell–associated antigens, represents 80% to 85% of childhood ALL. Approximately 80% of precursor B-cell ALL expresses CD10 (cALLa). Absence of CD10 is associated with MLL gene rearrangements, particularly t(4;11), and a poor outcome.[19,49] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of MLL gene rearrangements.[49,50]
   
   
   
   • Immunologic subtypes of precursor B-cell ALL: There are three major subtypes of precursor B-cell ALL:
     • Pro-B ALL-CD10 negative and no surface or cytoplasmic immunoglobulin.
     • Common precursor B-cell ALL-CD10 positive and no surface or cytoplasmic immunoglobulin.
     • Pre-B ALL-presence of cytoplasmic immunoglobulin.

     Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in young infants and is often associated with a t(4;11) translocation. The leukemic cells of patients with pre-B ALL contain cytoplasmic immunoglobulin (cIg), an intermediate stage of B-cell differentiation, and 25% of patients with pre-B ALL have the t(1;19) translocation (see below).[51]

     Approximately 3% of patients have transitional pre-B ALL with expression of surface immunoglobulin heavy chain without light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[52]

     Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and C-MYC gene translocation), also called Burkitt leukemia. This leukemia is a systemic manifestation of Burkitt and Burkitt-like non-Hodgkin lymphoma and its treatment is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as Burkitt leukemia.[53] (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma Treatment for more information on the treatment of children with B-cell ALL and Burkitt lymphoma.)

   
   
   

   • Precursor T-cell ALL: T-cell ALL is defined by the leukemic cell expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) and is frequently associated with a constellation of clinical features, including male gender, older age, leukocytosis, and mediastinal mass.[51,54,55] With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that of children with B-lineage ALL.[51,54,56] Neither the presence of a mediastinal mass at diagnosis nor the rate of resolution when receiving treatment have prognostic significance.[56,57]

     Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[58] Multiple other chromosomal translocations have been identified in T-cell ALL, with many involving transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) and resulting in aberrant expression of these transcription factors in leukemia cells.[59] These translocations are often not apparent by karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).[59] High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases,[60-62] and is associated with more favorable outcome in both adults and children with T-cell ALL.[60,62-65] Overexpression of TLX3/HOX11L2 resulting from the t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases [61,62,66] and appears to be associated with increased risk of treatment failure,[60,61,63,66] though not in all studies.[62] NOTCH1 mutations occur in approximately 50% of T-cell ALL cases, but the prognostic significance is unclear.[67,68] In the context of ALL Berlin-Frankfurt-Munster (BFM) 2000 therapy, NOTCH1 mutations appear to be associated with a favorable prognosis.[68] Another report, however, observed an unfavorable prognosis for the presence of NOTCH1 mutations in a cohort of children and adults with T-cell ALL, with the negative prognostic effect being most pronounced in adults.[69]

   
   
   
   • Myeloid antigen expression: Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL gene rearrangements and those with the TEL-AML1 gene rearrangement.[70] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[70,71]
   
   
   



3. Cytogenetics
   • Chromosome number
     • Hyperdiploidy: Hyperdiploidy (>50 chromosomes per cell or a DNA index >1.16) is the presence of additional copies of whole chromosomes and occurs in 20% to 25% of cases of precursor B-cell ALL but very rarely in cases of T-cell ALL. Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases either with a normal karyotype or in which cytogenetic analysis was unevaluable.[72] Hyperdiploidy generally occurs in cases with favorable prognostic factors (patients aged 1–9 years with a low WBC count) and is itself associated with favorable prognosis.[12,73-75][Level of evidence: 3iiA] Outcome of children with hyperdiploidy, however, is heterogeneous and depends on age, sex, and specific trisomies.[11,76] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis [77] and accumulate methotrexate and high levels of its active polyglutamate metabolites,[78] which may explain the favorable outcome commonly observed for these cases. Certain patients with hyperdiploid ALL and more than 64 chromosomes may have a hypodiploid clone that has doubled. These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome.[79]
     
     
     
     • Trisomies: In the treatment approaches utilized by both the former Pediatric Oncology Group (POG) and the former CCG, extra copies of certain chromosomes appear to be specifically associated with favorable prognosis among hyperdiploid ALL cases. Patients with triple trisomies (4, 10, and 17) have been shown to have an improved outcome as demonstrated by both POG and CCG analyses of National Cancer Institute (NCI) standard-risk but not high-risk ALL.[76,80-83] A United Kingdom Medical Research Council study showed that trisomies 4 and 18 were independent favorable prognostic indicators among hyperdiploid ALL cases.[76]
     
     
     
     • Hypodiploidy: A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome.[84,85]
     
     
     
   
   
   
   • Chromosomal translocations

     Recurring chromosomal translocations can be detected in a substantial number of cases of childhood ALL, and some of these translocations, as described below, have prognostic significance.

     TEL-AML1 (t[12;21] cryptic translocation): Fusion of the TEL (ETV6) gene on chromosome 12 to the AML1 (CBFA2) gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL.[86] Children with the t(12;21) cryptic translocation resulting in the TEL-AML1 fusion are generally aged 2 to 9 years and have an excellent outcome.[87][Level of evidence: 2Di][11,88-90] Hispanic children with ALL have a lower incidence of t(12;21) compared with white children.[91] Reports indicate favorable EFS and OS in children with the TEL-AML1 fusion, however, this favorable prognosis may be modified by factors such as slow response to treatment, NCI risk category, and treatment regimen.[86,92-95] In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not TEL-AML1, to be independent prognostic factors.[86] Patients with TEL-AML1 fusion seem to have a better outcome after relapse than do other patients; however, because of small numbers, the difference is not statistically significant.[96] Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the TEL-AML1 translocation).[97]

     The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and confers an unfavorable prognosis, especially when it is associated with either a high WBC count or slow early response to initial therapy.[74,98-102] Philadelphia-positive ALL is more common in older patients with precursor B-cell ALL and high WBC count.

     Rearrangements involving the MLL (11q23) gene occur in approximately 8% of childhood ALL cases and are generally associated with an increased risk of treatment failure.[77] The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.[103] Patients with t(4;11) are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy.[104] While both infants and adults with the t(4;11) are at high risk of treatment failure, children with the t(4;11) appear to have a better outcome than either infants or adults.[74,104,105] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.[25,29] Of interest, the t(11;19) occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL.[106] Outcome for infants with t(11;19) is poor, but outcome appears relatively favorable in children with T-cell ALL and the t(11;19) translocation.[25,106]

     The t(1;19) translocation occurs in 5% to 6% of childhood ALL, and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1.[107,108] The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL (cytoplasmic immunoglobulin positive). Black children are more likely than white children to have pre-B ALL with the t(1;19).[46] Its presence was initially associated with inferior outcome in the context of antimetabolite-based therapy.[107] Studies have shown that the poorer prognosis associated with t(1;19) can be largely overcome by more intensive therapy.[109,110] Some studies suggested that cases with a balanced translocation t(1;19) had a worse outcome than did those with an unbalanced translocation der(19)t(1;19),[108] but this finding has not been observed consistently.[111]

   
   
   
   • Other chromosomal abnormalities

     Intrachromosomal amplification of the chromosome 21 (iAMP21) with multiple extra copies of the RUNX1 (AML1) gene occurs in fewer than 5% of precursor B-cell ALL cases and has been associated with poor outcome.[72,112,113]

   
   
   

The rapidity with which leukemia cells are eliminated following onset of treatment is associated with outcome, as is level of residual disease at the end of induction. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[114] this measure has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including:

1. Day 7 and day 14 bone marrow responses:

   Patients who have a rapid reduction in the leukemia cells to less than 5% in their bone marrow within 7 or 14 days following initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[74,115,116] Morphologic response to treatment continues to be used in new COG ALL trials to stratify patients into prognostic categories for treatment assignment.




2. Peripheral blood response to steroid prophase:

   Patients with a reduction in peripheral blast count to less than 1,000/µL after a 7-day induction prophase with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response).[21,99,117] Treatment stratification for protocols of the German BFM clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately prior to the initiation of multiagent remission induction). Patients whose blast counts are less than 1,000/µL at diagnosis have a slightly better outcome compared with other patients with a good prednisone response.[118]




3. Peripheral blood response to multiagent induction therapy:

   Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation.[119,120] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[121]




4. Induction failure

   The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. Persistent leukemia at the end of that initial induction phase is observed in up to 5% of children with ALL. Induction failure portends a very poor outcome. In the French FRALLE 93 study, there was a 3.8% induction failure rate.[122][Level of evidence: 3iA] The 5-year overall survival rate of this group was 30%. Patients at highest risk of induction failure were those with Philadelphia chromosome-positive B-precursor ALL or T-cell phenotype, especially without mediastinal mass.




5. Minimal residual disease after induction therapy:

   Patients in clinical remission after induction therapy may have minimal residual disease (MRD), (i.e., leukemia cells in the blood or bone marrow) [123] that can only be detected by highly sensitive techniques such as PCR or specialized flow cytometry. Numerous groups have reported that patients with higher levels of MRD have a poorer prognosis than those who have lower levels of MRD.[124-134][Level of evidence: 3iiDi] Even for patients with the TEL-AML1 translocation or high hyperdiploidy and unfavorable trisomies, a population with generally favorable outcomes, higher levels of MRD at the end of induction therapy appear to be associated with higher risk of subsequent relapse.[94,95] Measuring MRD in the peripheral blood of patients with T-cell ALL has been studied and demonstrates a high concordance with MRD measurements using bone marrow.[123]

   No study to date has shown that decreasing therapeutic intensity for patients with early low-level MRD or without MRD can maintain efficacy while decreasing morbidity. Likewise, no study to date has shown that increasing therapeutic intensity in patients with early high-level MRD improves outcome. Clinical trials of three major United States pediatric ALL groups (Dana-Farber Cancer Institute [DFCI], St. Jude Children's Research Hospital, and COG) use MRD measurements to determine post-induction treatment. Therapeutic adjustments based on MRD determinations in ALL should only be utilized in clinical trials.

 [Note: This subsection does not discuss infants as a prognostic group. For information about infants with acute lymphoblastic leukemia, refer to the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.]

Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk based on the NCI consensus age and WBC criteria, regardless of phenotype.[1] The standard-risk category included patients aged 1 to 9 years who had a WBC count at diagnosis less than 50,000/µL. The remaining patients were classified as high risk. Final treatment assignment for CCG protocols was based on the early response to therapy (day 7 or day 14 bone marrow response) with slow early responders in either risk group receiving augmented post-induction therapy.

Former POG studies defined the low-risk group based on the NCI consensus age and WBC criteria and required the absence of adverse translocations, absence of CNS disease and testicular disease, and the presence of either the TEL-AML1 translocation or trisomy of chromosomes 4 and 10. The high-risk group required the absence of favorable translocations and the presence of CNS or testicular leukemia, or the presence of MLL gene rearrangement, or unfavorable age and WBC count.[135] The standard-risk category included patients not meeting the criteria for inclusion in any of the other risk group categories. In POG studies, patients with T-cell ALL were treated on different protocols than patients with precursor B-cell ALL.

The very high-risk category for CCG and POG was defined by one of the following factors taking precedence over all other considerations: presence of the t(9;22), M3 marrow on day 29 or M2 or M3 marrow on day 43, or hypodiploidy (DNA index <0.95).[136]

Historically, the BFM group in Germany categorized risk groups differently than POG or CCG. Age and initial WBC count were not considered when assigning risk groups. Patients with an absolute blast count of 1,000/μL or greater at the end of a 7-day prednisone prophase (prednisone poor responders) were considered to be high risk. Prednisone good responders (those with absolute blast count <1,000/μL at the end of the prophase) were classified as either standard risk or moderate risk depending on whether their estimated leukemic cell mass estimate was relatively low (standard risk) or high (moderate risk). All patients with T-cell phenotype, mediastinal mass, or CNS involvement were considered moderate risk, and all patients with the t(9;22) were considered high risk.[13]

Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two timepoints: 5 weeks and 12 weeks after initiation of therapy. Patients who are MRD negative at both timepoints are classified as standard risk, those who have low MRD (<10^-3) at week 12 are considered moderate risk, and those with high MRD (≥10^-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD. Phenotype, leukemic cell mass estimate, also known as BFM risk factor (BFM-RF), and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures.

A large, retrospective analysis of CCG and POG data led to the development of a new classification system for the COG.[137] Based on this analysis, patients with precursor B-cell ALL are initially assigned to a standard-risk or high-risk group based on age and initial WBC count (aged 1–9.99 years, and <50,000 WBC/µL is considered standard risk). All children with T-cell phenotype are considered high risk regardless of age and initial WBC count. Early treatment response (assessed by day 7 or day 14 marrow morphology and end-induction MRD assessment) and cytogenetics are subsequently used to modify initial risk-group classification. NCI standard-risk patients with rapid morphologic response (day 14 M1 marrow) and MRD less than 0.1% and an M1 marrow on day 29 are assigned to one of two groups based on cytogenetics. Patients with either t(12;21) or trisomies of chromosomes 4, 10, and 17 are considered "standard risk-low" while patients with neither of these two cytogenetics abnormalities are considered "standard risk-average." Standard-risk patients with either slow morphologic response (either day 7 or day 14 M1 marrow) and/or MRD more than 0.1% on day 29 are assigned to a third group (standard risk-high) and receive a more intensive postinduction treatment. High-risk patients with precursor B-cell ALL are divided into rapid-responder (rapid morphologic response and low MRD) or slow-responder groups. Patients are classified as very high risk if they have any of the following features (regardless of initial risk group): t(9;22), hypodiploidy less than 44 chromosomes, MLL translocation with a slow early morphologic response, M3 marrow on day 29 or M2 marrow and/or MRD greater than 1% at days 29 and 43.

The DFCI ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially classified as either standard risk or high risk based upon age, presenting leukocyte count, and the presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥0.1%) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.1%) continue to receive treatment based on their initial risk-group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive an allogeneic stem cell transplant in first remission.

At St. Jude Children's Research Hospital, risk classification is based mainly on MRD level (assessed by flow cytometry) after 6 weeks of remission induction therapy as follows: low risk (<0.01%), standard risk (0.01% to <1%), and high risk (≥1%).

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46. Pui CH, Sandlund JT, Pei D, et al.: Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 290 (15): 2001-7, 2003.  [PUBMED Abstract]
    
    
47. Kadan-Lottick NS, Ness KK, Bhatia S, et al.: Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 290 (15): 2008-14, 2003.  [PUBMED Abstract]
    
    
48. Bennett JM, Catovsky D, Daniel MT, et al.: The morphological classification of acute lymphoblastic leukaemia: concordance among observers and clinical correlations. Br J Haematol 47 (4): 553-61, 1981.  [PUBMED Abstract]
    
    
49. Möricke A, Ratei R, Ludwig WD, et al.: Prognostic factors in CD10 negative precursor b-cell acute lymphoblastic leukemia in children: data from three consecutive trials ALL-BFM 86, 90, and 95. [Abstract] Blood 104 (11): A-1957, 540a, 2004. 
    
    
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53. Navid F, Mosijczuk AD, Head DR, et al.: Acute lymphoblastic leukemia with the (8;14)(q24;q32) translocation and FAB L3 morphology associated with a B-precursor immunophenotype: the Pediatric Oncology Group experience. Leukemia 13 (1): 135-41, 1999.  [PUBMED Abstract]
    
    
54. Uckun FM, Sensel MG, Sun L, et al.: Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 91 (3): 735-46, 1998.  [PUBMED Abstract]
    
    
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60. Bergeron J, Clappier E, Radford I, et al.: Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs. Blood 110 (7): 2324-30, 2007.  [PUBMED Abstract]
    
    
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63. Baak U, Gökbuget N, Orawa H, et al.: Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group. Leukemia 22 (6): 1154-60, 2008.  [PUBMED Abstract]
    
    
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66. Ballerini P, Blaise A, Busson-Le Coniat M, et al.: HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Blood 100 (3): 991-7, 2002.  [PUBMED Abstract]
    
    
67. Weng AP, Ferrando AA, Lee W, et al.: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306 (5694): 269-71, 2004.  [PUBMED Abstract]
    
    
68. Breit S, Stanulla M, Flohr T, et al.: Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 108 (4): 1151-7, 2006.  [PUBMED Abstract]
    
    
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77. Pui CH, Evans WE: Acute lymphoblastic leukemia. N Engl J Med 339 (9): 605-15, 1998.  [PUBMED Abstract]
    
    
78. Synold TW, Relling MV, Boyett JM, et al.: Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94 (5): 1996-2001, 1994.  [PUBMED Abstract]
    
    
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80. Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 79 (12): 3316-24, 1992.  [PUBMED Abstract]
    
    
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86. Loh ML, Goldwasser MA, Silverman LB, et al.: Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 107 (11): 4508-13, 2006.  [PUBMED Abstract]
    
    
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100. Ribeiro RC, Broniscer A, Rivera GK, et al.: Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts. Leukemia 11 (9): 1493-6, 1997.  [PUBMED Abstract]
     
     
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102. Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130 (4): 489-500, 2005.  [PUBMED Abstract]
     
     
103. Rubnitz JE, Look AT: Molecular genetics of childhood leukemias. J Pediatr Hematol Oncol 20 (1): 1-11, 1998 Jan-Feb.  [PUBMED Abstract]
     
     
104. Pui CH, Frankel LS, Carroll AJ, et al.: Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases. Blood 77 (3): 440-7, 1991.  [PUBMED Abstract]
     
     
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114. Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1 (2): 99-108, 2001.  [PUBMED Abstract]
     
     
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120. Rautonen J, Hovi L, Siimes MA: Slow disappearance of peripheral blast cells: an independent risk factor indicating poor prognosis in children with acute lymphoblastic leukemia. Blood 71 (4): 989-91, 1988.  [PUBMED Abstract]
     
     
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125. Dibenedetto SP, Lo Nigro L, Mayer SP, et al.: Detectable molecular residual disease at the beginning of maintenance therapy indicates poor outcome in children with T-cell acute lymphoblastic leukemia. Blood 90 (3): 1226-32, 1997.  [PUBMED Abstract]
     
     
126. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998.  [PUBMED Abstract]
     
     
127. Panzer-Grümayer ER, Schneider M, Panzer S, et al.: Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood 95 (3): 790-4, 2000.  [PUBMED Abstract]
     
     
128. Coustan-Smith E, Sancho J, Hancock ML, et al.: Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 96 (8): 2691-6, 2000.  [PUBMED Abstract]
     
     
129. 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 99 (4): 1253-8, 2002.  [PUBMED Abstract]
     
     
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