Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 2/5 —Health Professional Version - National Cancer Institute

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

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

Risk-Based Treatment Assignment

In This Section

• Introduction to Risk-Based Treatment
• Prognostic Factors Affecting Risk-Based Treatment
  • Patient and clinical disease characteristics
  • Leukemic characteristics
  • Response to initial treatment
• Prognostic (Risk) Groups
  • Children’s Oncology Group (COG) risk groups
  • Berlin-Frankfurt-Münster (BFM) risk groups
  • Prognostic (risk) groups under clinical evaluation
• Current Clinical Trials

Introduction to Risk-Based Treatment

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

Certain ALL study groups, such as the Children’s Oncology Group (COG), use a more- or less-intensive induction regimen based on a subset of pretreatment factors, while other groups give a similar induction regimen to all patients. Factors used by the COG to determine the intensity of induction include immunophenotype, the presence or absence of extramedullary disease, steroid pretreatment, the presence or absence of Down syndrome, and the National Cancer Institute (NCI) risk group classification. The NCI risk group classification for B-cell ALL stratifies risk according to age and white blood cell (WBC) count:[3]

• Standard risk—WBC count less than 50,000/μL and age 1 to younger than 10 years.
• High risk—WBC count 50,000/μL or greater and/or age 10 years or older.

All study groups modify the intensity of postinduction therapy based on a variety of prognostic factors, including NCI risk group, immunophenotype, early response determinations, and cytogenetics and genomic alterations.[4] Detection of the Philadelphia chromosome leads to immediate changes in induction therapy.[5]

Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of factors have demonstrated prognostic value, some of which are described below.[6] Factors affecting prognosis are grouped into the following three categories:

• Patient and clinical disease characteristics.
• Leukemic characteristics.
• 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. Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors.

A subset of the prognostic and clinical factors discussed below is used for the initial stratification of children with ALL for treatment assignment. (Refer to the Prognostic (risk) groups under clinical evaluation section of this summary for brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.)

(Refer to the Prognostic Factors After First Relapse of Childhood ALL section of this summary for information about important prognostic factors at relapse.)

Prognostic Factors Affecting Risk-Based Treatment

Patient and clinical disease characteristics

Patient and clinical disease characteristics affecting prognosis include the following:

1. Age at diagnosis.
2. WBC count at diagnosis.
3. Central nervous system (CNS) involvement at diagnosis.
4. Testicular involvement at diagnosis.
5. Down syndrome (trisomy 21).
6. Sex.
7. Race and ethnicity.
8. Weight at diagnosis and during treatment.

Age at diagnosis

Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7]

1. Infants (younger than 1 year)
   Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in the following groups:
   • Infants younger than 6 months (with an even poorer prognosis for those aged ≤90 days).[8-12]
   • Infants with extremely high presenting leukocyte counts (>200,000–300,000 × 109/L).[9]
   • Infants with a poor response to a prednisone prophase.[9]
   • Infants with an MLL (KMT2A) gene rearrangement.[8-11]
   Up to 80% of infants with ALL have a translocation of 11q23 with numerous chromosome partners generating an MLL (KMT2A) gene rearrangement.[9,11,13,14] The most common rearrangement is MLL (KMT2A)-AFF1 (t(4;11)(q21;q23)), but MLLrearrangements with many other translocation partners are observed.
   The rate of MLL (KMT2A) gene rearrangements is extremely high in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL rearrangements decreases but remains higher than that observed in older children.[9,15] Black infants with ALL are significantly less likely to have MLL rearrangements than are white infants.[15]
   Infants with leukemia and MLL (KMT2A) rearrangements typically have very high WBC counts and an increased incidence of CNS involvement. Event-free survival (EFS) and overall survival (OS) are poor, with 5-year EFS and OS rates of only 35% to 40% for infants with MLL-rearranged ALL.[9-11] A comparison of the landscape of somatic mutations in infants and children with MLL-rearranged ALL revealed significant differences between the two groups, suggesting distinctive age-related biological behaviors for MLL-rearranged ALL that may relate to the significantly poorer outcome for infants.[16,17]
   Blasts from infants with MLL (KMT2A) rearrangements are often CD10 negative and express high levels of FLT3.[9,10,14,18] Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10-positive precursor-B immunophenotype. These infants have a significantly better outcome than do infants with ALL characterized by MLL rearrangements.[9,10,14,19]
   (Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)
2. Young children (aged 1 to <10 years)
   Young children (aged 1 to <10 years) have a better disease-free survival than older children, adolescents, and infants.[3,7,20-22] The improved prognosis in young children is at least partly explained by the more frequent occurrence of favorable cytogenetic features in the leukemic blasts, including hyperdiploidy with 51 to 65 chromosomes and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21)(p13;q22), also known as the TEL-AML1 translocation).[7,23,24]
3. Adolescents and young adults (aged ≥10 years)
   In general, the outcome of patients aged 10 years and older is inferior to that of patients aged 1 to younger than 10 years. However, the outcome for older children, especially adolescents, has improved significantly over time.[25-27] Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).[28-30]
   Multiple retrospective studies have established that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[31-33] (Refer to the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about adolescents with ALL.)

WBC count at diagnosis

A WBC count of 50,000/µL is generally used as an operational cut point between better and poorer prognosis,[3] although the relationship between WBC count and prognosis is a continuous rather than a step function. Patients with precursor B-cell ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts.[34]

The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for precursor B-cell ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[34-41]

CNS involvement at diagnosis

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

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

Children with ALL who present with CNS disease (CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically) than are patients who are classified as CNS1 or CNS2.[42,43] Some studies have reported increased risk of CNS relapse and/or inferior EFS in CNS2 patients, compared with CNS1 patients,[44,45] while others have not.[42,46-48]

A traumatic lumbar puncture (≥10 erythrocytes/µL) that includes blasts at diagnosis has also been associated with increased risk of CNS relapse and overall poorer outcome in some studies,[42,47,49] but not others.[45,46,50] Patients with CNS2, CNS3, or traumatic lumbar puncture have a higher frequency of unfavorable prognostic characteristics than do those with CNS1, including significantly higher WBC counts at diagnosis, older age at diagnosis, an increased frequency of the T-cell ALL phenotype, and MLL (KMT2A) gene rearrangements.[42,46,47]

Most clinical trial groups have approached CNS2 and traumatic lumbar puncture by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.[42,51,52]; [46][Level of evidence: 2A]

To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.[53]

Testicular involvement at diagnosis

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males, most commonly in T-cell ALL.

In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.[54,55] For example, the European Organization for Research and Treatment of Cancer (EORTC [EORTC-58881]) reported no adverse prognostic significance for overt testicular involvement at diagnosis.[55]

The role of radiation therapy for testicular involvement is unclear. A study from St. Jude Children's Research Hospital (SJCRH) suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[54] The COG has also adopted this strategy for boys with testicular involvement that resolves completely by the end of induction therapy. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.

Down syndrome (trisomy 21)

Outcome in children with Down syndrome and ALL has generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome.[56-61] In some studies, the lower EFS and OS of children with Down syndrome appear to be related to increased frequency of treatment-related mortality, as well as higher rates of induction failure and relapse in Down syndrome patients.[56-59,62,63] The inferior anti-leukemic outcome may be due, in part, to favorable biological features such as ETV6-RUNX1or hyperdiploidy (51–65 chromosomes) with trisomies of chromosomes 4 and 10 in Down syndrome ALL patients.[62,63]

• In a large retrospective study that included 653 patients with Down syndrome and ALL, Down syndrome patients had a lower CR rate (97% vs. 99%, P < .001), higher cumulative incidence of relapse (26% vs. 15%, P < .001) and higher treatment-related mortality (7% vs. < 1%, P < .001) compared with non-Down syndrome patients.[63] Amongst the Down syndrome patients, age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6-RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS.
• In a report from the COG, among precursor B-cell ALL patients who lacked MLL (KMT2A) rearrangements, BCR-ABL1, ETV6-RUNX1, and hyperdiploidy with trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome.[62]
• Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAKmutations are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[64-68] Studies of Down syndrome children with ALL suggest that the presence of IKZF1 deletions (but not CRLF2 aberrations or JAKmutations) is associated with an inferior prognosis.[63,68,69]

Sex

In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[70-72] One reason for the better prognosis for girls is the occurrence of testicular relapses among boys, but boys also appear to be at increased risk of bone marrow and CNS relapse for reasons that are not well understood.[70-72] While some reports describe outcomes for boys as closely approaching those of girls,[22,51,73] larger clinical trial experiences and national data continue to show somewhat lower survival rates for boys.[21,28,29,74]

Race and ethnicity

Over the last several decades in the United States, survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[75-78]

The following factors associated with race and ethnicity influence survival:

• ALL subtype. The reason for better outcomes in white and Asian children than in black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, black children have a higher relative incidence of T-cell ALL and lower rates of favorable genetic subtypes of precursor B-cell ALL.
• Treatment adherence. Differences in outcome may also be related to treatment adherence, as illustrated by two studies of adherence to oral mercaptopurine (6-MP) in maintenance therapy. In the first study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even when adjusting for other known variables. However, at adherence rates of 90% or more, Hispanic children continued to demonstrate increased rates of relapse.[79] In the second study, adherence rates were significantly lower in Asian American and African American patients than in non-Hispanic white patients. A greater percentage of patients in these ethnic groups had adherence rates of less than 90%, which was associated with a 3.9-fold increased risk of relapse.[80]
• Ancestry-related genomic variations. Ancestry-related genomic variations may also contribute to racial and ethnic disparities in both the incidence and outcome of ALL.[81] For example, the differential presence of specific host polymorphisms in different racial and ethnic groups may contribute to outcome disparities, as illustrated by the occurrence of single nucleotide polymorphisms in the ARID5B gene that occur more frequently among Hispanics and are linked to both ALL susceptibility and to relapse hazard.[82]

Weight at diagnosis and during treatment

Studies of the impact of obesity on the outcome of ALL have had variable results. In most of these studies, obesity is defined as weight above the 95th percentile for age and height.

• Three studies have not demonstrated an independent effect of obesity on EFS.[83][Level of evidence: 2Dii]; [84,85][Level of evidence: 3iiDi]
• Two studies have shown obesity to be an independent prognostic factor only in patients older than 10 years or in patients with intermediate-risk or high-risk disease.[86,87][Level of evidence: 3iiDi]
• The COG reported on the impact of obesity on outcome in 2,008 children, 14% of whom were obese, who were enrolled on a high-risk ALL trial (CCG-1961 [NCT00002812]).[88][Level of evidence: 2Di] Obesity was found to be an independent variable for inferior outcome compared with nonobese patients (5-year EFS, 64% vs. 74%; P = .002.) However, obese patients at diagnosis who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.
• In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease (MRD) at the end of induction and an inferior EFS.[89][Level of evidence: 3iiDi]
• In a different retrospective study of 373 patients treated at a single institution, body mass index (BMI) at diagnosis was not associated with MRD at days 19 and 46, cumulative incidence of relapse, or EFS. OS was lower in patients with a high BMI, primarily resulting from treatment-related mortality and inferior salvage after relapse.[90][Level of evidence: 3iiA]

In a study of 762 pediatric patients with ALL (aged 2–17 years), the Dutch Childhood Oncology Group found that those who were underweight at diagnosis (8% of the population) had an almost twofold higher risk of relapse compared with patients who were not underweight (after adjusting for risk group and age), although this did not result in a difference in EFS or OS. Patients with loss of BMI during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.[91]

Leukemic characteristics

Leukemic cell characteristics affecting prognosis include the following:

1. Morphology.
2. Immunophenotype.
3. Cytogenetics/genomic alterations.

Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[92] However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used.

Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a MYC gene translocation identical to those seen in Burkitt lymphoma (i.e., t(8;14)(q24;q32), t(2;8)) that join MYC to one of the immunoglobulin genes. 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 about the treatment of B-cell ALL and Burkitt lymphoma.)

Immunophenotype

The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics.[93,94] (Refer to the Diagnosis section of this summary for more information.)

Either B- or T-lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.

1. Precursor B-cell ALL (WHO B-lymphoblastic leukemia)
   Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.
   Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with MLL (KMT2A) rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[9,95] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[96]
   The major immunophenotypic subtypes of precursor B-cell ALL are as follows:
   • Common precursor B-cell ALL (CD10 positive and no surface or cytoplasmic Ig)
     Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.
   • Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig)
     Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with MLL (KMT2A) gene rearrangements.
   • Pre-B ALL (presence of cytoplasmic Ig)
     The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19)(q21;p13) translocation with TCF3-PBX1 (previously known as E2A-PBX1) fusion (see below).[97,98]
     Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[99]
     Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and an 8q24 translocation involving MYC), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with MYC gene translocations should also be treated as mature B-cell leukemia.[99] (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with B-cell ALL and Burkitt lymphoma.)
2. T-cell ALL
   T-cell ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-cell ALL is frequently associated with a constellation of clinical features, including the following:[20,36,73]
   • Male sex.
   • Older age.
   • Leukocytosis.
   • Mediastinal mass.
   With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that of children with B-lineage ALL.[20,36,39,40,73,100]
   There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[35-41,101] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[102]
   Early T-cell precursor ALL
   Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[103] The subset of T-cell ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers).
   Initial reports describing early T-cell precursor ALL suggested that this subset has a poorer prognosis than other cases of T-cell ALL.[103-105] However, another study indicated that the early T-cell precursor ALL subgroup had nonsignificantly inferior 5-year EFS compared with non–early T-cell precursor cases (76% vs. 84%).[106] Similarly, the COG AALL0434 trial observed similar 5-year EFS rates for early T-cell precursor cases and non-early T-cell precursor cases, with both at approximately 87%.[107] Further study in additional patient cohorts is needed to firmly establish the prognostic significance of early T-cell precursor ALL, but most ALL treatment groups do not change patient treatment based on early T-cell precursor status.
3. 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 (KMT2A) rearrangements and those with the ETV6-RUNX1 gene rearrangement.[108,109] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[108,109]
   (Refer to the 2016 WHO Classification of Acute Leukemias of Ambiguous Lineagesection of this summary for information about leukemia of ambiguous lineage.)

Cytogenetics/genomic alterations

(Refer to the Cytogenetics/Genomics of Childhood ALL section of this summary for information about B-cell ALL and T-cell ALL cytogenetics/genomics and gene polymorphisms in drug metabolic pathways.)

Response to initial treatment

The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual disease at the end of induction are associated with long-term outcome. Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[110] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:

1. MRD determination.
2. Day 7 and day 14 bone marrow responses.
3. Peripheral blood response to steroid prophase.
4. Peripheral blood response to multiagent induction therapy.
5. Peripheral blood MRD before end of induction (day 8, day 15).
6. Marrow morphology at the end of induction (induction failure).

MRD determination

Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive. Traditionally, a cutoff of 5% blasts in the bone marrow (detected by light microscopy) has been used to determine remission status. This corresponds to a level of 1 in 20 malignant cells. If one wishes to detect lower levels of leukemic cells in either blood or marrow, specialized techniques such as PCR assays, which determine unique Ig/T-cell receptor gene rearrangements, fusion transcripts produced by chromosome translocations, or flow cytometric assays, which detect leukemia-specific immunophenotypes, are required. With these techniques, detection of as few as 1 leukemia cell in 100,000 normal cells is possible, and MRD at the level of 1 in 10,000 cells can be detected routinely.[111] Newer techniques involving high-throughput sequencing of Ig/T-cell receptor gene rearrangements can increase sensitivity of MRD detection to 1 in 1 million cells (10-6).[112]

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[113-115] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[116] In general, patients with higher levels of end-induction MRD have a poorer prognosis than do those with lower or undetectable levels.[111,113-115] However, the absolute risk of relapse associated with specific MRD levels varies by genetic subtype. For example, at any given level of detectable end-induction MRD, patients with favorable cytogenetics, such as ETV6-RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients.[117] This observation may have important implications when MRD is used to develop risk classification plans.

End-induction MRD is used by almost all groups as a factor determining the intensity of postinduction treatment, with patients found to have higher levels (typically >10-3 to 10-4) allocated to more intensive therapies.[111,114,118]; [119][Level of evidence: 2A]

A study of 619 children with ALL compared the prognostic utility of MRD by flow cytometry with the more sensitive high-throughput sequencing assay. Using an end-induction MRD cutpoint level of 10-4, high-throughput sequencing identified approximately 30% more cases as positive (i.e., >10-4). Patients identified as positive by high-throughput sequencing, but negative by flow cytometry, had an intermediate prognosis compared with patients categorized as either positive or negative by both methods. Patients meeting the criteria for standard-risk ALL with undetectable MRD by high-throughput sequencing had an especially good prognosis (5-year EFS, 98.1%).[112]

MRD levels obtained 10 to 12 weeks after the start of treatment (end-consolidation) have also been shown to be prognostically important; patients with high levels of MRD at this time point have a significantly inferior EFS compared with other patients.[115,116]

• B-cell ALL: For patients with B-cell ALL, evaluating MRD at two time points (end-induction and end-consolidation) can identify the following three prognostically distinct patient subsets:[116]
  1. Low or undetectable end-induction MRD—best prognosis.
  2. Detectable or high MRD at end-induction but low or negative end-consolidation MRD—intermediate prognosis.
  3. Detectable or high MRD at end-consolidation (week 12 of therapy)—worst prognosis.
• T-cell ALL: There are fewer studies documenting the prognostic significance of MRD in patients with T-cell ALL. The UK-ALL group reported that T-cell ALL patients with nondetectable end-induction MRD had excellent outcomes, while those with very high MRD levels (>5%) at the end of induction had a poor prognosis; however, for all other T-cell ALL patients, an association between end-induction MRD level and relapse risk was not found.[117] Another study also indicated that MRD at a later time point may be more prognostically significant in T-cell ALL.[120] In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-cell ALL.[120] Patients with detectable MRD at end-induction who had negative MRD by day 78 generally had a favorable prognosis similar to that of patients who achieved MRD-negativity at the earlier end-induction time point.[120]

MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse. The COG reported a very favorable prognosis (5-year EFS of 97% ± 1%) for patients with precursor B-cell phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).[114] The excellent outcomes in patients with low MRD at the end of induction is sustained for more than 10 years from diagnosis.[121]

Modifying therapy based on MRD determination has been shown to improve outcome.

• The UKALL2003 (NCT00222612) study demonstrated that reduction of therapy (i.e., one rather than two courses of delayed intensification) did not adversely impact outcome in non-high–risk patients with favorable end-induction MRD.[21][Level of evidence: 1iiDii] In a randomized controlled trial, the UKALL2003 study also demonstrated improved EFS for standard-risk and intermediate-risk patients who received augmented therapy if end-induction MRD was greater than 0.01% (5-year EFS, 89.6% for augmented therapy vs. 82.8% for standard therapy).[122]
• The Dutch AAL10 trial stratified patients into the following three risk groups on the basis of MRD after the first month of treatment and after the second cycle of chemotherapy:[123][Level of evidence: 2A]
  • Standard risk (low MRD after the first month of treatment).
  • Moderate risk (high MRD after the first month of treatment, low MRD after the second cycle of chemotherapy).
  • High risk (high MRD after the second cycle of chemotherapy).
  Compared with previous trials conducted by the same group, therapy was deintensified for standard-risk patients but more intensive for moderate-risk and high-risk patients. The overall 5-year EFS (87%) and OS (92%) were superior to the previous Dutch studies.

Day 7 and day 14 bone marrow responses

Patients who have a rapid reduction in leukemia cells to less than 5% in their bone marrow within 7 or 14 days after the initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[124] MRD assessments at the end of induction therapy have generally replaced day 7 and day 14 morphological assessments as response to therapy prognostic indicators because the latter lose their prognostic significance in multivariate analysis once MRD is included in the analyses.[114,125]

Peripheral blood response to steroid prophase

Patients with a reduction in peripheral blast count to less than 1,000/µL after a 7-day induction prophase with prednisone and one dose of intrathecal methotrexate (a good prednisone response) have a more favorable prognosis than do patients whose peripheral blast counts remain above 1,000/µL (a poor prednisone response).[20] Poor prednisone response is observed in fewer than 10% of patients.[20,126] Treatment stratification for protocols of the Berlin-Frankfurt-Münster (BFM) clinical trials group is partially based on early response to the 7-day prednisone prophase (administered immediately before the initiation of multiagent remission induction).

Peripheral blood response to multiagent induction therapy

Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation.[127] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[127]

Peripheral blood MRD before end of induction (day 8, day 15)

MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy has also been evaluated as an early response-to-therapy prognostic factor.

• In a COG study involving nearly 2,000 children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with adverse prognosis, with increasing MRD levels being associated with a progressively poorer outcome.[114]
• In multivariate analysis, end of induction therapy MRD was the most powerful prognostic factor, but day 8 peripheral blood MRD maintained its prognostic significance, as did NCI risk group and the presence of favorable trisomies. A smaller study assessed the prognostic significance of peripheral blood MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy.[128] This study also observed multivariate significance for peripheral blood MRD levels after 1 week of multiagent induction therapy.

Both studies identified a group of patients who achieved low MRD levels after 1 week of multiagent induction therapy who had a low rate of subsequent treatment failure.

Marrow morphology at the end of induction (induction failure)

The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. The presence of greater than 5% lymphoblasts at the end of the induction phase is observed in 1% to 2% of children with ALL.[21,22,129,130]

Patients at highest risk of induction failure have one or more of the following features:[131,132]

• T-cell phenotype (especially without a mediastinal mass).
• Precursor B-cell ALL with very high presenting leukocyte counts.
• MLL (KMT2A) gene rearrangement.
• Older age.
• Philadelphia chromosome (before the use of tyrosine kinase inhibitors).

In a large retrospective study, the OS of patients with induction failure was only 32%.[129] However, there was significant clinical and biological heterogeneity. A relatively favorable outcome was observed in patients with precursor B-cell ALL between the ages of 1 and 5 years without adverse cytogenetics (MLL [KMT2A] rearrangement or BCR-ABL1). This group had a 10-year survival exceeding 50%, and HSCT in first remission was not associated with a survival advantage compared with chemotherapy alone for this subset. Patients with the poorest outcomes (<20% 10-year survival) included those who were aged 14 to 18 years, or who had the Philadelphia chromosome or MLL rearrangement. B-cell ALL patients younger than 6 years and T-cell ALL patients (regardless of age) appeared to have better outcomes if treated with allogeneic HSCT after achieving CR than those who received further treatment with chemotherapy alone.

Some investigators have suggested that the definition of induction failure should be expanded to include end-of-induction MRD of more than 5%, regardless of morphologic findings. In the UKALL2003 (NCT00222612) study, 59 of 3,113 patients (1.9%) had morphologic induction failure; the 5-year EFS was 51%, and the OS was 58%. However, 2.3% of patients had a morphologic remission, with MRD of 5% or more measured by real-time quantitative IgH-T-cell receptor (TCR) PCR; this group had a 5-year EFS of 47%, similar to those with morphologic induction failure. The authors suggest that using both morphologic and MRD criteria to define induction failure more precisely identifies patients with poor outcomes.[133]

Prognostic (Risk) Groups

For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens based on their estimated risk of treatment failure. Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response (e.g., at day 8 or day 15) and with other groups utilizing response of circulating leukemia cells to single agent prednisone. Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate cytogenetics and genomic lesions of leukemia cells at diagnosis (e.g., favorable and unfavorable translocations) and response to therapy based on detection of MRD at end of induction (and in some cases at later time points).[120] The risk classification systems of the COG and the BFM groups are briefly described below.

Children’s Oncology Group (COG) risk groups

In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) based on a subset of prognostic factors, including the following:

• Age.
• WBC count at diagnosis.
• Immunophenotype.
• Cytogenetics/genomic alterations.
• Presence of extramedullary disease.
• Down syndrome.
• Steroid pretreatment.

EFS rates exceed 85% in children meeting good-risk criteria (aged 1 to <10 years, WBC count <50,000/μL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 75%.[4,51,126,134,135] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage for patients with Down syndrome and MRD levels in peripheral blood on day 8 and in bone marrow samples at the end of induction), considered in conjunction with presenting age, WBC count, immunophenotype, the presence of extramedullary disease, and steroid pretreatment can identify patient groups for postinduction therapy with expected EFS rates ranging from less than 40% to more than 95%.[4,114]

Patients who are at very high risk of treatment failure include the following: [136-139]

• Infants with MLL (KMT2A) rearrangements.
• Patients with hypodiploidy (<44 chromosomes).
• Patients with initial induction failure.

Berlin-Frankfurt-Münster (BFM) risk groups

Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two time points, end induction (week 5) and end consolidation (week 12).

The BFM risk groups include the following:[116]

• Standard risk: Patients who are MRD-negative (i.e., <10-4) at both time points are classified as standard risk.
• Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<10-3) at week 12 are considered intermediate risk.
• High risk: Patients with high MRD (≥10-3) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD.

Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22)(q34;q11.2) or the t(4;11)(q21;q23) are considered high risk, regardless of early response measures.

Prognostic (risk) groups under clinical evaluation

COG AALL08B1 (Classification of Newly Diagnosed ALL): COG protocol AALL08B1 stratifies four risk groups for patients with precursor B-cell ALL (low risk, average risk, high risk, and very high risk) based on the following criteria:[1]

• Age and presenting leukocyte count (using NCI risk-group criteria).[3]
• Extramedullary disease (presence or absence of CNS and/or testicular leukemia).
• Genomic alterations in leukemia cells.
• Day 8 peripheral blood MRD.
• Day 29 bone marrow morphologic response and MRD.
• Down syndrome.
• Steroid pretreatment.

Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification. Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way.

For patients with precursor B-cell ALL:

• Favorable genetics are defined as the presence of either hyperdiploidy with trisomies of chromosomes 4 and 10 (double trisomy) or the ETV6-RUNX1 fusion.
• Unfavorable characteristics are defined as CNS3 status at diagnosis, induction failure (M3 marrow at day 29), age 13 years and older, and the following unfavorable genomic alterations: hypodiploidy (<44 chromosomes or DNA index <0.81), MLL (KMT2A) rearrangement, t(17;19), and iAMP21. The presence of any of these unfavorable characteristics is sufficient to classify a patient as very high risk, regardless of other presenting features. Infants and children with BCR-ABL1 (Ph+ ALL) are treated on a separate clinical trial.
• MRD levels at day 8 from peripheral blood and at day 29 from bone marrow are used in risk classification.

The four risk groups for precursor B-cell ALL are defined in Table 3.[1]

Table 3. Risk Groups for Precursor B-cell Acute Lymphoblastic Leukemia

ENLARGE

	Low Risk	Average Risk		High Risk			Very High Risk
EFS = event-free survival; HR = age and WBC count risk group is high risk; MRD = minimal residual disease; NCI = National Cancer Institute; PB = peripheral blood; SR = age/WBC count risk group is standard risk; WBC = white blood cell.
NCI Risk (Age/WBC)	SR	SR	SR	SR	SR	HR (age <13 y)	SR	HR	HR (age ≥13 y)	SR or HR
Favorable Genetics	Yes	Yes	No	Yes	No	Any	No	Any	Any	Any
Unfavorable Characteristics	None	None	None	None	None	None	None	None	None	Yes
Day 8 PB MRD	<0.01%	≥0.01%	<1%	Any Level	≥1%	Any Level	Any Level	Any Level	Any Level	Any Level
Day 29 Marrow MRD	<0.01%	<0.01%	<0.01%	≥0.01%	<0.01%	<0.01%	≥0.01%	≥0.01%	<0.01%	Any Level
% of Patients (Estimated)	15%	36%		25%			24%
Anticipated 5-year EFS	>95%	90%–95%		88%–90%			<80%

NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II-IV T-Cell Lymphoblastic Lymphoma): For patients with T-cell ALL, COG uses the following criteria to assign risk category:

Standard risk

• M1 marrow with MRD <0.01% on day 29.
• CNS1 status and no testicular disease at diagnosis.
• No steroid therapy pretreatment.

Intermediate risk

• M1 or M2 marrow at day 29 with MRD ≥0.01%.
• MRD <0.1% at end of consolidation.
• Any CNS status at diagnosis.

Very high risk

• M3 marrow at day 29 or MRD ≥0.1% at end of consolidation.
• Any CNS status.

SJCRH (Total XVI): Patients are classified into one of three categories (low, standard, or high risk) based on the presenting age, leukocyte count, presence or absence of CNS3 status or testicular leukemia, immunophenotype, cytogenetics and molecular genetics, DNA index, and early response to therapy. Hence, definitive risk assignment (for provisional low-risk or standard-risk cases based on presenting features) will be made after completion of remission induction therapy. The criteria and the estimated proportion of patients in each category (based on data from the Total XV study) are provided below.

Criteria for low-risk ALL (approximately 48% of patients)

• Precursor B-cell ALL with DNA index ≥1.16, ETV6-RUNX1 fusion, or age 1 to 9.9 years and presenting WBC <50 × 109/L.
• Must not have:
  • CNS3 status (≥5 WBC/µl of CSF with morphologically identifiable blasts or cranial nerve palsy).
  • Overt testicular leukemia (evidenced by ultrasonogram).
  • Adverse genetic features—t(9;22)(q34;q11.2) or BCR-ABL1 fusion; t(1;19) with E2A-PBX1 fusion; rearranged MLL (KMT2A) (as measured by FISH and/or PCR); or hypodiploidy (<44 chromosomes).
  • Poor early response (≥1% lymphoblasts on day 15 of remission induction, ≥0.01% lymphoblasts by immunologic or molecular methods on remission date).

Criteria for standard-risk ALL (approximately 44% of patients)

• All cases of T-cell ALL and those of precursor B-cell ALL that do not meet the criteria for low-risk or high-risk ALL.

Criteria for high-risk ALL (approximately 8% of patients)

• t(9;22)(q34;q11.2) or BCR-ABL1 fusion.
• Infants with t(4;11)(q21;q23) or MLL (KMT2A) fusion.
• Induction failure or >1% leukemia lymphoblasts in the bone marrow on remission date.
• >0.1% leukemic lymphoblasts in the bone marrow in week 7 of continuation treatment (i.e., before reinduction 1, about 14 weeks postremission induction).
• Re-emergence of leukemic lymphoblasts by MRD (at any level) in patients previously MRD negative.
• Persistently detectable MRD at lower levels.
• Early T-cell precursor ALL, defined by low expression of T-cell markers together with aberrant expression of myeloid markers.[103] The following features characterize early T-cell precursor ALL:
  • Levels of CD5 expression at least tenfold lower than that of normal peripheral blood T-lymphocytes. In the study that identified this subset of T-cell ALL, CD5 expression was tenfold to more than 200-fold lower than that of normal lymphocytes and median percentage of leukemic cells expressing CD5 in the 17 atypical cases was 45%; in contrast to more than 98% for the 122 cases in the typical group.
  • Absence (<10%) of CD1a and CD8 expression.
  • Expression of cytoplasmic CD3 together with the expression of one or more markers associated with myeloid leukemia such as HLA-Dr, CD34, CD13, CD33, or CD11b, while myeloperoxidase is less than 3% by cytochemistry and/or flow cytometry.

DFCI ALL 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL): Patients are assigned an initial risk group by day 10 of therapy on the basis of presenting features and leukemia biology:

• Initial low risk: All of the following criteria are met: B-cell ALL, age 1 to younger than 15 years, WBC count less than 50 x 109/L, CNS1 or CNS2, no intrachromosomal amplification of chromosome 21 (iAMP21), no very high-risk features.
• Initial high risk: Any of the following criteria are met: Aged 15 years or older, WBC count greater than 50 x 109/L, T-cell ALL, CNS3, presence of iAMP21. Very high-risk features must be absent.
• Initial very high risk: Any of the following criteria are met: IKZF1 deletion, MLL gene-rearrangement, low hypodiploidy (<40 chromosomes).

Patients with BCR-ABL1 are removed from protocol therapy at day 15. The final risk group is based on the initial risk group and MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 of therapy (second time point):

• Final low risk: Initial low risk and MRD less than104 at the first time point.
• Final high risk: Initial low risk with MRD greater than 104 at the first time point and less than 103 at the second time point or initial high risk with MRD less than 103 at the second time point.
• Final very high risk: Initial very high-risk patients or any patient with MRD greater than 103 at the second time point.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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