Topic Contents
- General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
- Cellular Classification and Prognostic Variables
- Treatment Option Overview
- Remission Induction for Newly Diagnosed ALL
- Postinduction Treatment of ALL
- Postinduction Treatment for Specific ALL Subgroups
- Treatment of Recurrent ALL
- Changes to this Summary (05 / 18 / 2012)
- About This PDQ Summary
- Get More Information From NCI
Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Childhood Acute Lymphoblastic Leukemia Treatment
General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] Because treatment of children with acute lymphoblastic leukemia (ALL) entails many potential complications and requires intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), this treatment is best coordinated by pediatric oncologists and performed in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. It is important that the clinical centers and the specialists directing the patient's care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.
Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For ALL, the 5-year survival rate has increased over the same time from 60% to 89% for children younger than 15 years and from 28% to 50% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Incidence and Epidemiology
ALL is the most common cancer diagnosed in children and represents 23% of cancer diagnoses among children younger than 15 years. ALL occurs at an annual rate of approximately 30 to 40 per million.[3,4] There are approximately 2,900 children and adolescents younger than 20 years diagnosed with ALL each year in the United States,[4,5] and there has been a gradual increase in the incidence of ALL in the past 25 years.[6] A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>80 per million per year), with rates decreasing to 20 per million for ages 8 to 10 years. The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is nearly tenfold greater than that for adolescents aged 16 to 21 years.
For unexplained reasons, the incidence of ALL is substantially higher in white children than in black children, with a nearly threefold higher incidence from age 2 to 3 years in white children compared with black children.[3,4] The incidence of ALL appears to be highest in Hispanic children (43 per million).[3,4]
Risk Factors for Developing ALL
Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:
- Prenatal exposure to x-rays.
- Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
- Down syndrome and other genetic conditions.
- Inherited genetic polymorphisms.
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[7,8] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[7,8] Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL. Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21) and hyperdiploidy) and unfavorable (t(9;22), t(4;11), and hypodiploidy) cytogenetic findings and a lower incidence of T-cell phenotype.[9,10,11,12] Approximately 50% of children with Down syndrome and ALL have a recurring interstitial deletion of the pseudoautosomal region (PAR) of chromosomes X and Y that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. The resulting P2RY8-CRLF2 fusion gene is observed at a much lower frequency (<10%) in non-Down children with B-precursor ALL.[13,14] Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[15,16,17] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL.[18] Almost all Down syndrome ALL cases with JAK2 mutations also have the PAR deletion and express the P2RY8-CRLF2 fusion gene.[13] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL.[16]
While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[9] ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[10,11] Increased occurrence of ALL is also associated with other genetic conditions, including neurofibromatosis,[19] Shwachman syndrome,[20,21] Bloom syndrome,[22] and ataxia telangiectasia.[23]
Genome-wide association studies show that germline (inherited) genetic polymorphisms are associated with the development of childhood ALL.[24] For example, the risk alleles of ARID5B, a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation, are strongly associated with the development of hyperdiploid B-precursor ALL.[25,26]
Some cases of ALL have a prenatal origin. Evidence in support of this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient's leukemia cells can be detected in blood samples obtained at birth.[27,28] Similarly, in ALL characterized by specific chromosomal abnormalities, data exist to support that patients had blood cells carrying the abnormalities at the time of birth with additional cooperative genetic changes acquired postnatally.[27,28,29] In one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the TEL-AML1 translocation, far exceeding the number of cases of TEL-AML ALL in children.[30] Other reports confirm [31] and do not confirm [32] this finding; nonetheless, this may support the hypothesis that additional genetic changes are needed for the development of this type of ALL. Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[33]
Overall Outcome for ALL
Among children with ALL, more than 95% attain remission and 75% to 90% survive free of leukemia recurrence at least 5 years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system preventive therapy (e.g., intrathecal chemotherapy with or without cranial radiation).[34,35,36,37,38,39]
Despite the treatment advances noted in childhood ALL, numerous important biologic and therapeutic questions remain to be answered to achieve the goal of curing every child with ALL with the least associated toxicity. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials, in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery, and tested in carefully randomized, controlled clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
References:
Cellular Classification and Prognostic Variables
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.[1,2,3] Certain ALL study groups 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. All groups modify the intensity of postinduction therapy based on a variety of prognostic factors.
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.[4] The factors described are grouped into the following categories:
- Patient characteristics at diagnosis.
- Leukemic cell characteristics at diagnosis.
- 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.[5,6] 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. At the end of this section are brief descriptions of the prognostic groupings currently applied in ongoing clinical trials in the United States.
Patient Characteristics at Diagnosis
| 1. |
Age at diagnosis
Age at diagnosis has strong prognostic significance, reflecting the different underlying biology of ALL in different age groups.[7] Young children (aged 1–9 years) have a better disease-free survival (DFS) than older children, adolescents, or infants.[1,7,8] 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 and/or favorable chromosome trisomies, or the ETV6-RUNX1 (t(12;21), also known as the TEL-AML1 translocation).[7,9] The outcome for adolescents has improved significantly over time.[10,11,12] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.[13,14,15] (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 6 months and in those with extremely high presenting leukocyte counts and/or a poor response to a prednisone prophase.[16,17,18,19] Infants with ALL can be divided into two subgroups on the basis of the presence or absence of translocations that involve the MLL gene located at chromosome 11q23.[18,19,20] Approximately 80% of infants with ALL have an MLL gene rearrangement.[18,20,21] The rate of MLL gene translocations is extremely high in infants younger than 6 months; from 6 months to 1 year the incidence of MLL translocations decreases but remains higher than that observed in older children.[18] Infants with leukemia and MLL translocations have very high white blood cell (WBC) counts, increased incidence of central nervous system (CNS) involvement, and a poor outcome.[18,19] Blasts from infants with MLL translocations are typically CD10 negative and express high levels of FLT3.[18,19,20,22] 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 infants with ALL characterized by MLL translocations.[18,19,20] Infants diagnosed within the first month of life have higher WBC counts, higher incidence of MLL translocations, significantly higher relapse rate, and poorer overall survival compared with infants older than 1 month at diagnosis.[23] |
|---|---|
| 2. |
WBC count at diagnosis
Patients with B-precursor ALL and high WBC counts at diagnosis have an increased risk of treatment failure compared with patients with low initial WBC counts. 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. The median WBC count at diagnosis is much higher for T-cell ALL (>50,000/µL) than for B-precursor ALL (<10,000/µL), and there is no consistent effect of WBC count at diagnosis on prognosis for T-cell ALL.[6,24,25,26,27,28,29,30] One factor that might explain the lack of prognostic effect for WBC count at diagnosis may be the very poor outcome observed for T-cell ALL with the early T-cell precursor phenotype, as patients with this subtype appear to have lower WBC count at diagnosis (median <50,000/µL) compared with other T-cell ALL patients.[31] |
| 3. |
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:
Compared with patients classified as CNS1 or CNS2, children with ALL who present with CNS disease (i.e., CNS3) at diagnosis are at a higher risk of treatment failure (both within the CNS and systemically).[32] The adverse prognostic significance associated with CNS2 status, if any, may be overcome by the application of more intensive intrathecal therapy, especially during the induction phase.[32,33]; [34][Level of evidence: 2A] 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.[32,35] To determine whether a patient with a traumatic lumbar puncture (with blasts) should be treated as CNS3, the Children's Oncology Group (COG) uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.[36] |
| 4. |
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.[37,38] 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.[38] 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.[37] The COG has also adopted this strategy for boys with testicular leukemia that resolves completely by the end of induction therapy. 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. |
| 5. |
Down syndrome (trisomy 21)
Outcome in Down syndrome children with ALL has generally been reported as somewhat inferior to outcomes observed in non-Down syndrome children.[39,40,41,42] 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 and the absence of favorable biological features.[39,40,41,42,43] Patients with Down syndrome and ALL have a significantly lower incidence of favorable cytogenetic abnormalities such as ETV6-RUNX1 or trisomies of chromosomes 4 and 10.[43] In a report from the COG, among B-precursor ALL patients who lacked MLL translocations, BCR-ABL1, ETV6-RUNX1, or trisomies of chromosomes 4 and 10, the EFS and OS were similar in children with and without Down syndrome.[43] |
| 6. |
Gender
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL.[44,45,46] 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.[44,45,46] However, in clinical trials with high 5-year EFS rates (>80%), outcomes for boys are closely approaching those of girls.[33,47] |
| 7. |
Race
Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.[48,49] This difference may be therapy-dependent; a report from SJCRH found no difference in outcome by racial groups.[50] Asian children with ALL fare slightly better than white children.[49] The reason for better outcome in white and Asian children compared with black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes. For example, blacks have a higher incidence of T-cell ALL and lower rates of favorable genetic subtypes of ALL. However, these differences do not completely explain the observed racial differences in outcome.[49] |
Leukemic Cell Characteristics at Diagnosis
| 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.[51] 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 C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., 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
The World Health Organization (WHO) classifies ALL as either B lymphoblastic leukemia or T lymphoblastic leukemia. B lymphoblastic leukemia is subdivided by the presence or absence of specific recurrent genetic abnormalities (t(9;22)), MLL rearrangement, t(12;21), hyperdiploidy, hypodiploidy, t(5;14), and t(1;19).[52] Prior to 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, now termed Burkitt leukemia, which requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.
|
| 3. |
Cytogenetics
A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion, are associated with more favorable outcomes, while others, including the Philadelphia chromosome (t(9;22)), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21), are associated with a poorer prognosis.[86] Prognostically significant chromosomal abnormalities in childhood ALL include the following:
|
Response to Initial Treatment
The rapidity with which leukemia cells are eliminated following onset of treatment is associated with long-term 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,[134] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:
| 1. |
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 following initiation of multiagent chemotherapy have a more favorable prognosis than do patients who have slower clearance of leukemia cells from the bone marrow.[135] |
|---|---|
| 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).[8] Poor prednisone response is observed in fewer than 10% of patients.[8,136] Treatment stratification for protocols of the German Berlin-Frankfurt-Muenster (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 with no circulating blasts on day 7 have a better outcome than those patients whose circulating blast level is between 1 and 999/µL.[137,138] |
| 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.[139] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL.[139] |
| 4. |
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 up to 5% of children with ALL. Patients at highest risk of induction failure include those with T-cell phenotype (especially without a mediastinal mass) and patients with B-precursor ALL with very high presenting leukocyte counts and/or the Philadelphia chromosome.[140,141] Induction failure portends a very poor outcome.[140] In the French FRALLE 93 study, the 5-year OS rate for patients with initial induction failure was 30%.[141] |
| 5. |
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/TCR 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.[142] Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.[102,143,144,145] MRD response discriminates outcome in subsets of patients defined by age, leukocyte count, and cytogenetic abnormalities.[146] Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels.[102,142,143,144,147] 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 allocated to more intensive therapies. MRD levels at earlier (e.g., day 8 and day 15 of induction) and later time points (e.g., week 12 of therapy) also predict outcome.[102,142,144,146,147,148,149,150,151] 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 B-precursor phenotype, NCI standard risk age/leukocyte count, CNS1 status, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the ETV6-RUNX1 fusion) who had less than 0.01% MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow).[102] There are fewer studies documenting the prognostic significance of MRD in T-cell ALL. In the AIEOP-BFM ALL 2000 trial, MRD status at day 78 (week 12) was the most important predictor for relapse in patients with T-cell ALL. Patients with detectable MRD at end-induction who had negative MRD by day 78 did just as well as patients who achieved MRD-negativity at the earlier end-induction time point. Thus, unlike in B-cell precursor ALL, end-induction MRD levels were irrelevant in those patients whose MRD was negative at day 78. A high MRD level at day 78 was associated with a significantly higher risk of relapse.[151] Although MRD is the most important prognostic factor in determining outcome, there are no data to conclusively show that modifying therapy based on MRD determination significantly improves outcome in newly diagnosed ALL.[146] |
Prognostic Groups
This subsection does not discuss infants as a prognostic group. For information about infants with acute lymphoblastic leukemia, refer to the Postinduction Treatment for Specific ALL 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 early response to therapy with slow early responders being treated as high-risk patients.
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 ETV6-RUNX1 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.[102] 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).[94]
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). Patients who are MRD negative at both time points are classified as standard risk, those who have positive MRD at week 5 and low MRD (<10-3) at week 12 are considered intermediate 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, 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.
Prognostic groups under clinical evaluation
COG AALL08B1(Classification of Newly Diagnosed ALL): COG protocol AALL08B1 defines four risk groups for patients with B-precursor ALL (low risk, average risk, high risk and very high risk) based on age and presenting leukocyte count (using NCI risk-group criteria),[1] initial CNS status, genetic abnormalities, day 8 peripheral blood MRD, and day 29 bone marrow morphologic response and MRD. 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 B-precursor ALL:
- Favorable genetics are defined as the presence of either hyperdiploidy with trisomies of chromosomes 4 and 10 (double trisomy) or the the ETV6-RUNX1 fusion.
- Unfavorable characteristics are defined as CNS3 status at diagnosis, induction failure (M3 marrow at day 29), older than 13 years, and the following unfavorable genetic abnormalities: low hypodiploidy (<44 chromosomes), MLL rearrangement, 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. Patients with BCR-ABL (Philadelphia chromosome–positive [Ph+] ALL) are treated on a separate clinical trial.
- MRD is assessed by flow cytometry. At day 29, a level of less than 0.01% is considered low risk.
The four risk groups for B-precursor ALL are defined in Table 1.
Table 1. Risk Groups for B-Precursor Acute Lymphoblastic Leukemia
| Low Risk | Average Risk | High Risk | Very High Risk | |||||||
| EFS = event-free survival; HR = age/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 | Yes or No | No | Yes or No | Yes or No | Yes or No |
| 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 | Low | Low | Low | High | Low | Low | High | High | <0.01% | Any Level |
| % of Patients (Estimated) | 15% | 36% | 25% | 24% | ||||||
| Anticipated 5-year EFS | >95% | 90%–95% | 88%–90% | <80% | ||||||
On the current clinical trial conducted by the Dana-Farber Cancer Institute ALL Consortium (protocol 11-001), patients with B-precursor ALL are initially classified as either standard risk or high risk based on age, presenting leukocyte count, and the presence or absence of CNS disease (CNS3). At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined via PCR assay. Patients with high MRD (≥0.001) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.001) 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 (<44 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Ph+ patients are removed from study mid-induction and are eligible to enroll on the COG protocol for patients with Ph+ ALL.
At SJCRH, 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% – <1%), and high risk (≥1%). Patients with early T-cell precursor ALL are also considered to be high risk.[31]
References:
Treatment Option Overview
Treatment of childhood acute lymphoblastic leukemia (ALL) typically involves chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are anticipated consequences of both leukemia and chemotherapy treatment, patients must be closely monitored at diagnosis and during treatment. Adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications.[1,2] Children with ALL should be cared for at a center with specialized expertise in pediatric cancer.[3]
Nationwide clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the therapeutic innovations that produced increased survival rates in children with ALL have been established through nationwide clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial. Treatment planning by a multidisciplinary team of pediatric cancer specialists with experience and expertise in treating leukemias of childhood is required to determine and implement optimum treatment.
Treatment for children with ALL is typically divided as follows:
- Remission induction (at the time of diagnosis).
- Postinduction therapy (after achieving complete remission).
- Consolidation/intensification therapy.
- Maintenance or continuation therapy.
Risk-Based Treatment Assignment
Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with modest therapy and to be spared more intensive and toxic treatment, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. As discussed in the Cellular Classification and Prognostic Variables section of this summary, a number of clinical and laboratory features have demonstrated prognostic value. The intensity of induction (some, but not all groups) is determined by National Cancer Institute (NCI) risk group and immunophenotype and postinduction therapy (all groups) is determined by prognostic factors such as early response determinations and cytogenetics.[4] With this treatment approach, approximately 80% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors.[5,6,7,8,9,10]
In COG protocols, a subset of the known prognostic factors (e.g., age, white blood cell [WBC] count at diagnosis, immunophenotype, and presence of extramedullary disease) are used for the initial stratification of children with ALL into treatment groups with varying degrees of risk of treatment failure. Event-free survival (EFS) rates exceed 85% in children meeting good-risk criteria (aged 1–9 years, WBC count <50,000/μL, and precursor B-cell immunophenotype); in children meeting high-risk criteria, EFS rates are approximately 70%.[5,6,7,8,11] Additional factors, including cytogenetic abnormalities and measures of early response to therapy (e.g., day 7 and/or day 14 marrow blast percentage and minimal residual disease [MRD] levels at the end of induction), considered in conjunction with presenting age, WBC count, and immunophenotype, can identify patient groups with expected EFS rates ranging from less than 40% to greater than 95%.[11,12]
Subgroups of patients who have a poor prognosis with current risk-adapted, multiagent chemotherapy regimens may require different therapeutic approaches. For example, infants with ALL are at much higher risk for treatment failure than older children.[13,14] Infants with ALL are generally treated on separate protocols using more intensified regimens, although the likelihood of long-term EFS appears to be no better than 50% for infants with MLL translocations even with a more intensive therapeutic approach.[13,14,15,16] Infants with MLL translocations and other subsets of patients who have a less than 50% chance of long-term remission with current therapies (such as patients with hypodiploidy or with initial induction failure) are sometimes considered candidates for allogeneic stem cell transplantation in first remission.[15,17,18,19] However, because of small numbers, possible patient selection bias, and center preference, studies to definitively show whether CR1 transplantation is superior to intensive chemotherapy for these very high-risk patients have not been feasible.
Allogeneic bone marrow transplantation was once considered to be the treatment of choice for children with t(9;22) Philadelphia chromosome–positive (Ph+) ALL, especially those with high-risk clinical features (age >10 years or high initial leukocyte count) or poor early treatment response.[20,21] However, a COG study demonstrated a 3-year EFS rate of 80.5% in Ph+ patients treated with concurrent intensive chemotherapy and a tyrosine kinase inhibitor (imatinib) given daily during premaintenance therapy.[22] While longer follow-up is necessary to determine if this treatment regimen indeed improves cure rates or merely prolongs the duration of disease-free survival, these results suggest that the presence of the Philadelphia chromosome should no longer be considered an absolute indication for transplantation in first remission.
Treatment of Sanctuary Sites (Central Nervous System, Testes)
Successful treatment of children with ALL requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes), as well as the prevention or treatment of extramedullary disease, particularly in the central nervous system (CNS). Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid specimen with ≥5 WBC/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis. Therapies that may be used for CNS prophylaxis include intrathecal chemotherapy and cranial radiation. CNS-penetrant systemic chemotherapy (such as intravenous methotrexate and high-dose cytarabine) and other drugs, including dexamethasone and asparaginase, may contribute to CNS prophylaxis as well. At present, most newly diagnosed children with ALL are treated without cranial radiation; many groups administer cranial radiation only to those patients considered to be at highest risk for subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/μL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count.[23] Ongoing trials seek to determine if radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[7,8]
CNS-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols provide ongoing intrathecal chemotherapy during maintenance (COG, St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute), while others do not (Berlin-Frankfurt-Muenster).
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.[24,25] The role of radiation therapy for testicular involvement is also unclear. A study from SJCRH suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[24] The COG has also adopted this strategy for boys with testicular leukemia that resolves completely during induction chemotherapy.
References:
Remission Induction for Newly Diagnosed ALL
Induction Chemotherapy
Three-drug induction therapy using vincristine, corticosteroid (prednisone or dexamethasone), and L-asparaginase in conjunction with intrathecal (IT) therapy, results in complete remission (CR) rates of greater than 95%.[1] For patients presenting with high-risk features, a more intensive induction regimen (four or five agents) may result in improved event-free survival (EFS).[2,3] Such patients generally receive induction therapy that includes an anthracycline (e.g., daunorubicin) in addition to vincristine, prednisone/dexamethasone, plus L-asparaginase. For patients who are at standard risk or low risk of treatment failure, four or more drug induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[2,4,5] The Children's Oncology Group (COG) protocols risk stratify at diagnosis and do not administer anthracycline during induction to patients with National Cancer Institute (NCI) standard-risk precursor B-cell acute lymphoblastic leukemia (ALL). While other groups, such as the Berlin-Frankfurt-Muenster (BFM) Group in Europe, St. Jude Children's Research Hospital (SJCRH), and the Dana-Farber Cancer Institute (DFCI) ALL Consortium, utilize either a four- or five-drug induction for all patients, regardless of presenting features.[6,7,8]
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy. The Children's Cancer Group (CCG) conducted a randomized trial comparing dexamethasone and prednisone in standard-risk ALL patients, and reported that dexamethasone was associated with a superior EFS.[9] Results from another randomized trial conducted by the United Kingdom Medical Research Council (MRC) demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.[10] In the MRC trial, patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than patients who received prednisolone.[10] However, other randomized trials did not confirm an EFS advantage with dexamethasone.[11] It appears that the ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio is 1:5 to 1:7 have shown a better result for dexamethasone, while studies using a 1:10 ratio have shown similar outcomes.[12]
While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may also be more toxic, especially in the context of more intensive induction regimens and in adolescents.[13] Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens.[14,15] The increased risk of infection with dexamethasone during the induction phase has not been noted with three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase).[10] Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone,[16] and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.[17]
Several forms of L-asparaginase are available for use in the treatment of children with ALL in the United States. PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients. PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion following a single injection.[18] A single intramuscular (IM) dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).[19] Studies have shown that a single dose of PEG-L-asparaginase given either IM or intravenously (IV) as part of multiagent induction results in serum enzyme activity (>100 IU/mL) in nearly all patients for at least 2 to 3 weeks.[19,20,21] The toxicity of PEG-L-asparaginase seems to be similar to that observed with native E. coli asparaginase. In a randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase in which each agent was to be given for a 30-week period following achievement of remission, similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.[22] In another randomized trial in which patients with standard-risk ALL were randomly assigned to receive PEG-L-asparaginase versus native E. coli asparaginase in induction and each of two delayed intensification courses, the use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.[19] It is safe to give IV PEG-L-asparaginase in pediatric patients.[20,21] Pharmacokinetics and toxicity profiles are similar for IV and IM PEG-L-asparaginase administration.[21]
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase. The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days).[18] If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose to achieve adequate asparagine depletion. In two studies, newly diagnosed patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E. coli L-asparaginase had a significantly worse EFS.[23,24] However, when administered more frequently (twice weekly), the use of Erwinia asparaginase did not adversely impact EFS in patients experiencing an allergic reaction to E. coli L-asparaginase.[25]
More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of the 2% to 4% of patients who fail to achieve CR within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[24,26,27]; [28][Level of evidence: 3iA] Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic stem cell transplant once CR is achieved.[29,30,31]
For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, as discussed in the Cellular Classification and Prognostic Variables section of this summary. Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher relapse risk,[32] and has been used by the COG to risk-stratify patients. Similarly, end-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[33,34,35,36] Intensification of postinduction therapy for patients with high levels of end-induction MRD is under investigation by many groups. MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance.[35,37,38]
Central Nervous System (CNS) Therapy
Historically, survival rates for children with ALL did not improve until CNS-directed therapy was instituted. The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in all patients. Options for CNS-directed therapy include IT chemotherapy, CNS-penetrant systemic chemotherapy, and cranial radiation. The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurotoxicity and other late effects. The proportion of patients receiving cranial radiation has decreased significantly over time. In patients still receiving cranial radiation, the dose has been significantly reduced.
All therapeutic regimens for childhood ALL include IT chemotherapy. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (four to eight doses of IT given every 2–3 weeks), and, in certain protocols, continued throughout the maintenance phase. IT chemotherapy typically consists of either methotrexate alone or methotrexate with cytarabine and hydrocortisone.[39] Unlike IT cytarabine, IT methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.[40]
In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. Systemically administered drugs, such as dexamethasone, L-asparaginase, and high-dose methotrexate with leucovorin rescue, provide some degree of CNS prophylaxis. For example, in a randomized CCG study of standard-risk patients who all received the same dose and schedule of IT methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.[9] In a recent standard-risk ALL trial (COG-1991), lower-dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared to oral methotrexate given during each of two interim maintenance phases.[41] In a randomized clinical trial conducted by the Pediatric Oncology Group, T-cell ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate compared with those who did not receive high-dose methotrexate.[42]
CNS therapy for standard-risk patients
Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[4,26,43,44,45,46] The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[24,47]
The CCG-1952 study for NCI standard-risk patients compared the relative efficacy and toxicity of triple IT chemotherapy (methotrexate, prednisone, and cytarabine) with methotrexate as the sole IT agent in nonirradiated patients.[48] There was no significant difference in either CNS or non-CNS toxicities. Triple IT chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% ± 1.0% compared with 5.9% ± 1.2% for IT methotrexate; P = .004). This effect was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in cerebrospinal fluid [CSF] cytospin, but with <5 WBC/hpf on CSF cell count); the isolated CNS relapse rate was 7.7% ± 5.3% for CNS2 patients who received triple IT chemotherapy compared with 23.0% ± 9.5% for those who received IT methotrexate alone (P = .04). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) (90.3% ± 1.5%) compared with the IT methotrexate group (94.4% ± 1.1%; P = .01). When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single IT therapy in terms of rates of CNS relapse rate, OS, or EFS.[48] In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[49][Level of evidence: 1iiC]
Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) are at increased risk of CNS relapse,[50] although this risk appears to be nearly fully abrogated if they receive more intensive IT chemotherapy, especially during the induction phase.[51] Data also suggest that patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis have an increased risk of CNS relapse, and these patients receive more intensive CNS-directed therapy on some treatment protocols.[51,52]
CNS therapy for high-risk patients
Controversy exists as to which, if any, high-risk patients should be treated with cranial radiation. Depending on the protocol, up to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis. Patients receiving cranial radiation on many treatment regimens include those with T-cell phenotype and high initial WBC count and certain patients with high-risk precursor B-cell ALL (e.g., those with extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities).[53]
Both the proportion of patients receiving radiation and the dose of radiation administered has decreased over the last 2 decades. For example, in a trial conducted between 1990 and1995, the BFM group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients.[27] In the follow-up trial conducted by that group between 1995 and 2000 (BFM-95), cranial radiation was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities.[45] While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historic (irradiated) cohorts, their overall EFS rate was not significantly different.[45]
Several groups, including the SJCRH, the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[4,46,54] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of IT chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy,[4,46] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 patients.[54] The 5-year cumulative incidence of isolated CNS relapse on those trials was between 2% and 4%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, or the presence of blasts in the CSF at diagnosis.[46] The long-term EFS for CNS3 patients on these trials ranged from 43% (SJCRH) to 68% (EORTC). The overall EFS for the SJCRH study was 85.6% and 81% for the DCOG study, both in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation, but was lower on the EORTC trial (8-year EFS, 69.6%).[54] Of note, on the SJCRH study 33 of 498 (6.6%) patients in first remission with high-risk features (including 26 with high MRD, six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic stem cell transplant, which included total-body irradiation.[46]
Therapy for ALL patients with clinically evident CNS disease (>5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes IT chemotherapy and cranial radiation (usual dose is 18 Gy).[24,45] Spinal radiation is no longer used. On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ± 23%).[46] On that study, CNS-leukemia at diagnosis (defined as CNS3 status or traumatic LP with blasts) was an independent predictor of inferior EFS. The 5-year EFS of CNS3 patients (N = 21) treated without cranial radiation on the DCOG-9 trial was 67% ± 10%.[4] Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Toxicity of CNS-directed therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
- Acute/subacute toxicities include seizures, stroke, somnolence syndrome, and ascending paralysis.
- Late developing toxicities include meningiomas and other second neoplasms, leukoencephalopathy and a range of neurocognitive, behavioral, and neuroendocrine disturbances.[55,56,57]
The most common acute side effect associated with IT chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of IT chemotherapy will have at least one seizure during therapy.[46] Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to IT chemotherapy.[58] Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.[59] Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.[59]
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[60,61,62,63,64] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[65,66,67] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[66,67,68] Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24 Gy–28 Gy) on clinical trials conducted in the 1970s and 1980s.[69] In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; in fact, cognitive function for both groups was not significantly impaired.[70]; [71][Level of evidence: 1iiC] On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose (12 Gy). Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae.
In general, patients who receive IT chemotherapy without cranial radiation appear to have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[71,72,73,74] This modest decline is primarily seen in young children and girls.[75] A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple IT therapy showed no clinically meaningful difference.[49][Level of evidence: 3iiiC] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances,[76] although long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.[77]
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas.[57,78,79] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered.[80] In general, systemic methotrexate doses greater than 1 g/m2 should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
Presymptomatic CNS therapy options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-AALL0434(Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): In the COG-AALL0434 protocol for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-risk features and a rapid response to induction therapy) are treated without cranial radiation, and intermediate-risk T-cell patients receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients continue to receive 18 Gy cranial radiation. All patients are randomly assigned to receive either high-dose methotrexate (5 g/m2 over 24 hours) with leucovorin rescue or escalating-dose methotrexate without leucovorin rescue during the initial interim maintenance phase of therapy.
- COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of IT triple chemotherapy (methotrexate, cytarabine, and hydrocortisone) with IT methotrexate, with the objective of determining whether IT triple chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy). Patients with induction failure or low hypodiploidy are eligible for allogeneic stem cell transplantation in first remission.
- SJCRH Total XVI (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features, including those with a t(1;19) translocation, receive intensified intrathecal therapy.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References:
Postinduction Treatment of ALL
Consolidation/Intensification Therapy
Once remission has been achieved, systemic treatment in conjunction with central nervous system (CNS) sanctuary therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification following achievement of remission and before beginning maintenance therapy. Intensification may involve use of the following:
- Intermediate-dose or high-dose methotrexate (1–5 g/m2) with leucovorin rescue or escalating-dose methotrexate without rescue.[1,2,3,4]
- Drugs similar to those used to achieve remission (reinduction or delayed intensification).[1,5]
- Different drug combinations with little known cross-resistance to the induction therapy drug combination including cyclophosphamide, cytarabine, and a thiopurine.[6]
- L-asparaginase for an extended period of time.[4,7]
- Combinations of the above.[1,8,9]
Standard-risk ALL
In children with standard-risk acute lymphoblastic leukemia (ALL), there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[10,11,12] For example, regimens utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase) have been used with good results for children with standard-risk ALL.[2,3,11] Similarly favorable results for standard-risk patients have been achieved with regimens utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without any postinduction exposure to alkylating agents or anthracyclines.[7,13]
Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of delayed intensification improved outcome for children with standard-risk ALL treated with regimens using a German Berlin-Frankfurt-Muenster (BFM) backbone.[14,15,16] The delayed intensification phase on such regimens, including those of the Children's Oncology Group, consists of a 3-week reinduction (including anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after remission is achieved.[1,14,17] In a Children's Cancer Group (CCG-1991/COG-1991) study for standard-risk ALL, which utilized dexamethasone for induction, a second delayed intensification phase provided no benefit in patients who were rapid early responders.[18][Level of evidence: 1iiDi] This study also compared escalating intravenous (IV) methotrexate in conjunction with vincristine versus a standard maintenance combination including oral methotrexate given during two interim maintenance phases. IV methotrexate produced a significant improvement in event-free survival (EFS), which was primarily a result of a decreased incidence of CNS relapse.[18]
High-risk ALL
In high-risk patients, a number of different approaches have been used with comparable efficacy.[7,19]; [17][Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients, and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short- and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens. In a Dana-Farber Cancer Institute (DFCI) ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2 /dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy. Study results demonstrated that the use of the cardioprotectant dexrazoxane prior to doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk compared with the use of doxorubicin alone 5 years posttreatment. In addition, a greater long-term protective effect was noted in girls compared to boys.[20,21]
The former CCG developed an augmented BFM treatment regimen featuring repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine/L-asparaginase pulses during initial consolidation and delayed intensification. Augmented therapy also included a second interim maintenance and delayed intensification phase. In the CCG-1882 trial, National Cancer Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy. The augmented therapy regimen produced a significantly better EFS compared with standard CCG modified BFM therapy.[22] In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[23]
The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies as well as therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among rapid early responders. Augmented therapy was associated with an improvement in EFS; there was no benefit associated with the administration of the second interim maintenance and delayed intensification phases.[24][Level of evidence: 1iiA] Of note, there was a significant incidence of osteonecrosis of bone in teenaged patients who received the augmented-BFM regimen.[25]
Very high-risk ALL
Approximately 10% to 20% of patients with ALL are classified as very high risk, including infants, those with adverse cytogenetic abnormalities (e.g., t(9;22), t(4;11), or low hypodiploidy [<44 chromosomes]) and poor response to initial therapy (e.g., high end-induction minimal residual disease [MRD] or high absolute blast count after a 7-day steroid prophase).[17,26] Patients who fail induction therapy are also at very high risk of subsequent relapse even if they achieve complete remission. Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase, often including agents not typically used in frontline ALL regimens for standard- and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[17] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,27]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic stem cell transplantation (SCT) in first remission, [27,28,29] although it is not clear if outcomes are better with transplantation. In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22), t(4;11), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting WBC >100,000/μL) were assigned to receive either an allogeneic SCT in first remission (based on the availability of a human lymphocyte antigen [HLA]-matched related donor) or intensive chemotherapy.[27] Using an intent-to-treat analysis, patients assigned to allogeneic SCT (on the basis of donor availability) had a superior 5-year disease-free survival (DFS) compared with those assigned to intensive chemotherapy (57% ± 7% for transplant versus 41% ± 3% for chemotherapy, P = .02); however, there was no significant difference in overall survival (OS) (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = .12) . For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic SCT.[28] In another study of very high-risk patients, which included children with extremely high presenting leukocyte counts in addition to those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow), allogeneic SCT in first remission was not associated with either a DFS or OS advantage.[29]
Maintenance Therapy
Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally call for giving oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS.[30] On many protocols, intrathecal (IT) chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[31]
Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[32,33] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[32,33] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than patients who are homozygous for the normal allele.[32]
The use of continuous 6-thioguanine (6-TG) instead of 6-mercaptopurine (6-MP) during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[34,35,36,37,38] In a meta-analysis of randomized trials comparing thiopurines, 6-TG did not improve the overall EFS, although particular subgroups may have benefitted from its use. However, because of increased toxicity of 6-TG, 6-MP remains the standard drug of choice.[39]
The Brazilian Childhood Cooperative group reported a variation in approach to maintenance therapy.[40][Level of evidence: 1A] In a cohort that was comprised of mostly lower-risk children, standard oral versus intermittent IV dosing of methotrexate (weekly vs. every three weeks) and 6-mercaptopurine (daily vs. 10 days on and 11 days off) was compared. Intermittently dosed medications were given at higher doses overall compared with standard dosing. In addition, boys on the protocol received only 2 years of therapy. A significant survival advantage was noted in boys receiving intermittent dosing, while the outcome with girls was equivalent. Because of differences in risk classification and OS rates slightly lower than reported by other groups, it is difficult to know whether the benefits this approach offered to boys would apply in other settings.
Treatment protocols from the St. Jude Children's Research Hospital previously included an intensified maintenance phase that consisted of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins, along with more standard maintenance agents.[6] A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.[41] The intensified maintenance with rotating pairs of agents has also been associated with more episodes of febrile neutropenia [41] and a higher risk of secondary acute myelogenous leukemia,[42] and is no longer used in upfront therapy.[41]
Vincristine/corticosteroid pulses
Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains controversial.
A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses,[43] and a meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[44,45] However, a systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy.[45]
In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[46] However, a small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In that study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[47][Level of evidence: 1iiA]
When steroid pulses are used during the maintenance phase, dexamethasone is preferred over prednisone for younger patients based on data from a CCG study, in which dexamethasone was compared with prednisone for children aged 1 to 9 years with lower-risk ALL.[14,48] On that trial, patients randomized to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.[14,48] In a Medical Research Council trial comparing dexamethasone versus prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients, the EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.[49] The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.[25,50]
Duration of maintenance therapy
Maintenance chemotherapy generally continues until 2 to 3 years of continuous complete remission. On some studies, boys are treated longer than girls;[14] on others, there is no difference in the duration of treatment based on gender.[7,17] It is not clear that longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[17][Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.[44]
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk for treatment failure. The Cellular Classification and Prognostic Variables section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.
COG studies for B-precursor ALL
Standard-risk ALL
COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL): This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/WBC, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, BCR-ABL).
All patients will receive a three-drug induction (dexamethasone, vincristine, and intravenous [IV] PEG-L-asparaginase) with IT chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive either a regimen based on POG-9404, including six courses of intermediate-dose methotrexate (1 g/m2) but without any alkylating agents or anthracyclines, or a modified BFM-backbone including two interim maintenance phases with IV methotrexate and one delayed intensification phase. The objective is not to prove superiority of either regimen, but rather to determine if excellent outcomes (at least 95% 5-year DFS) can be achieved.
All average-risk patients will receive a modified BFM-backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.
High-risk ALL
COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): This protocol is open to patients aged 30 years or younger. Patients treated on this trial are classified as either high risk or very high risk. The presence of any of the following is sufficient to classify a patient as very high risk: age younger than 13 years, CNS3 at diagnosis, M3 marrow at day 29, unfavorable genetics (e.g., iAMP21, low hypodiploidy, MLL gene rearrangements), and high marrow MRD (>0.01% by flow cytometry) at day 29 (with the exception of NCI standard-risk patients with favorable genetics). The high-risk group includes patients aged 10 to 12 years and/or those with WBC count greater than 50,000 who lack very high risk features, and two groups of NCI standard-risk patients who otherwise lack very high risk features: (1) those without favorable genetics (no ETV6-RUNX1 or double trisomies 4 and 10), and with day 8 peripheral blood MRD >1%; and (2) those with favorable cytogenetics and with high marrow MRD at day 29. Patients with BCR-ABL (Philadelphia chromosome–positive) are treated on a separate clinical trial.
Patients on this trial will receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV PEG-L-asparaginase) with IT chemotherapy. Patients younger than 10 years receive dexamethasone during induction and those older than 10 years receive prednisone. Postinduction therapy consists of a modified BFM-backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase. Very high-risk patients receive a second interim maintenance phase prior to beginning more standard maintenance. Only patients with CNS3 status at diagnosis receive cranial radiation. Those with M3 marrow at day 29 or low hypodiploidy are eligible for allogeneic stem cell transplant in first remission.
For high-risk patients, the study will compare, in a randomized fashion, triple IT chemotherapy (methotrexate, cytarabine, and hydrocortisone) with IT methotrexate to determine whether triple IT chemotherapy reduces CNS relapse rates and improves EFS.
For very high-risk patients, the study will test, in a randomized fashion, whether intensified consolidation phases (including either cyclophosphamide/etoposide or clofarabine/cyclophosphamide/etoposide) improves 4-year DFS compared with the standard consolidation phase.
Other studies
- Total XVI study (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): A study at St. Jude Children's Research Hospital is randomly assigning patients to receive either standard-dose (2,500 u/m2) or high-dose (3,500 u/m2) PEG-L-asparaginase during postremission therapy.
- DFCI-11-001 (NCT01574274)(SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): A DFCI Consortium protocol is comparing the pharmacokinetics and toxicity of two forms of IV PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calapargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase. This protocol is also testing: (1) whether an intensified consolidation including high-dose cytarabine and etoposide improves the outcome for very high-risk patients (patients with high MRD at the end of remission induction, MLL translocations, or hypodiploidy [<44 chromosomes]); and (2) whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References:
Postinduction Treatment for Specific ALL Subgroups
T-cell ALL
Historically, patients with T-cell ALL have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 5-year event-free survival (EFS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) Consortium ALL protocols was 75% compared with 84% for children with precursor B-cell ALL.[1]
Treatment options
Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL differently from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy regimen for this protocol was based on the DFCI-87001 regimen.[2] Results of the POG study indicated that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen resulted in significantly improved EFS in patients with T-cell ALL (10-year EFS, 78% for those randomly assigned to high-dose methotrexate versus 68% for those randomly assigned to therapy without high-dose methotrexate, P = .05). High-dose methotrexate was associated with a lower incidence of relapses involving the central nervous system (CNS).[3] This POG study was the first clinical trial to provide evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase, doxorubicin, and prophylactic cranial irradiation were also important components of this regimen.[1,4]
Protocols of the former Children's Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria. Results from CCG-1961 showed that an augmented Berlin-Frankfurt-Muenster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy (estimated 5-year EFS 83%).[5] Almost 60% of events in this group, however, were isolated CNS relapses. Overall results from POG-9404 and CCG-1961 were similar, though POG-9404 used cranial radiation for every patient while CCG-1961 used cranial radiation only for patients with slow morphologic response.[6,4] Among children with NCI standard-risk T-cell ALL, the EFS for children treated on CCG-1952 and COG-1991 studies was inferior to the EFS for children treated on the POG-9404 study.[7]
In the Children's Oncology Group (COG), children with T-cell ALL are no longer treated on the same protocols as children with precursor B-cell ALL. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [8,9] in the context of a BFM regimen for patients with newly diagnosed T-cell ALL; efficacy is being evaluated in the current trial.[10]
The role of prophylactic cranial radiation in the treatment of T-cell ALL is controversial. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation in first-line treatment of ALL, while other groups, such as DFCI, COG, and BFM, use radiation for the majority of patients with T-cell ALL.
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-AALL0434(Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): COG-AALL0434 is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial are (1) to determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients, (2) to determine the relative safety and efficacy of high-dose (5 g/m2) versus Capizzi escalating lower dose methotrexate without rescue during interim maintenance, and (3) to test the efficacy of treating NCI standard-risk T-cell ALL patients who are rapid responders (about 15% of patients) without cranial radiation.
- DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): Patients with T-cell ALL are eligible to enroll on a DFCI Consortium protocol that is comparing the pharmacokinetics and toxicity of two forms of intravenous (IV) PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calapargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase. This protocol is also testing whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase. All T-cell patients are treated on the high-risk arm of this trial, regardless of other presenting characteristics.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Infants With ALL
Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[11] Because of their distinctive biological characteristics and their high risk for leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.[12,13,14] Despite intensification of therapy, long-term EFS rates remain below 50%, and for those infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[12,13,15,16,17][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include a very young age (<6 months), extremely high presenting leukocyte count (≥200,000–300,000/μL), and high levels of MRD at the end of induction and consolidation phases of treatment.[13]; [18][Level of evidence: 3iDii] Infants with congenital leukemia (diagnosed within 1 month of birth) have a particularly poor outcome (17% overall survival).[17][Level of evidence: 2A]
Treatment options
Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients. The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations.[13] The COG tested intensification of therapy with a regimen including multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide, with a 5-year EFS of 34%.[12]
The role of allogeneic stem cell transplant during first remission in infants with MLL gene translocations remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective.[19,20,21]; [22][Level of evidence: 3iA] On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL-rearrangement were intended to proceed to allogeneic stem cell transplant (SCT) from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis. The 3-year EFS for all enrolled infants was 44%. This result was due, in part, to the high frequency of early relapses, even with intensive chemotherapy; of the 41 infants with MLL-rearrangment on that study who achieved CR, 11 infants (27%) relapsed prior to proceeding to transplant.[22] In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who received stem cell transplant (SCT) in first complete remission (CR) and those who received chemotherapy alone.[23] The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone response) with MLL translocations treated on the Interfant-99 trial with either allogeneic SCT in first CR or chemotherapy alone.[13] However, in a subset analysis from the same trial, allogeneic SCT in first remission was associated with a significantly better DFS for infants with MLL translocations who were younger than 6 months at diagnosis and had either a poor response to steroids at day 8 or leukocytes ≥300 g/L.[24] In this subset, SCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.
The optimal treatment for infants without MLL translocations also remains unclear. On the Interfant-99 trial, such patients achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%).[13] A favorable outcome for this subset of patients was obtained in a Japanese study using therapy comparable to that used to treat older children with ALL;[15] however, that study was limited by small numbers.
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- Interfant-06 Study Group trial (DCOG-INTERFANT-06) (Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia): The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC >300,000 /µL) or poor peripheral blood response to steroid prophase. Infants with MLL-rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic SCT in first remission regardless of other presenting features.
- COG-AALL0631(Combination Chemotherapy With or Without Lestaurtinib in Treating Infants With Newly Diagnosed ALL): In this COG study of infant ALL, an FLT3 inhibitor, lestaurtinib, is being studied in infants with MLL rearrangement. Infants with MLL rearrangement are known to have a high level of FLT3 mRNA expression and lestaurtinib has been shown to selectively kill MLL-rearranged ALL cells in vitro and in vivo.[25] This study combines lestaurtinib with intensive chemotherapy previously utilized in POG-P9407. There is an initial safety/activity phase followed by an efficacy phase in which children will be randomly assigned to chemotherapy with or without lestaurtinib. Infants with germline MLL will be nonrandomly assigned to less-intensive chemotherapy without lestaurtinib.
Adolescent and Young Adult Patients with ALL
Treatment options
Older children and adolescents (>10 years) with ALL more frequently present with adverse prognostic factors at diagnosis, including T-cell immunophenotype and Philadelphia chromosome–positivity, and have a lower incidence of favorable cytogenetic abnormalities.[26,27] These patients have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed.[28] A study from France of patients aged 15 to 20 years and diagnosed between 1993 and 1999, demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).[29]
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (see Table 2).[27,30,31,32]; [33][Level of evidence: 2A] For instance, the DFCI ALL Consortium reported a 5-year EFS of 78% in adolescents aged 15 to 18 years in a pediatric trial.[27] In the COG high-risk study (CCG-1961), the 5-year EFS rate for patients aged 16 to 21 years was 71.5%.[34][Level of evidence: 1iiDi] For rapid responders randomized to early intensive postinduction therapy on the augmented intensity arms of this study, the 5-year EFS rate was 82%. In a SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% ± 5%.[35] Also, in a Spanish study, adolescents (aged 15–18 years) and young adults (aged 19–30 years) with standard risk ALL were treated with a pediatric-based regimen.[33][Level of evidence: 2A] The complete remission rate was 98%, EFS rate was 61%, and overall survival rate was 69%, with no differences in outcome between adolescents and young adults. Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for pediatric ALL, there is no role for the routine use of allogeneic SCT in first remission for adolescents and young adults with ALL.[34]
The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and the components of protocol therapy.[30] Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[27,36,37,38] High body mass index is also a risk factor for osteonecrosis,[39] and may be associated with a higher relapse rate in older patients.[40]
Table 2. Outcomes for Published or Ongoing Prospective, Pediatric-Based Studies of Adolescents and Young Adults with Acute Lymphoblastic Leukemiaa
| Protocol | Country | Age Range in Years (Number of Patients) | Survival (%) |
| DFCI = Dana-Farber Cancer Institute; GRAALL = Group for Research on Adult Acute Lymphoblastic Leukemia; PETHEMA = Programa Español de Tratamientos en Hematología. | |||
| a Adapted from Ribera and Oriol.[41] | |||
| b Event-free survival. | |||
| c Relapse-free survival. | |||
| d Estimated at 2 years. | |||
| DFCI 91-01, 95-01[27] | United States | 15–18 (51) | 78b |
| PETHEMA ALL-96[33] | Spain | 15–18 (35) | 60b |
| PETHEMA ALL-96[33] | Spain | 19–30 (46) | 63b |
| GRAALL-2003[42] | France | 15–45 (172) | 58b |
| Modified DFCI[43] | Canada | 18–35 (42) | 77c |
| DFCI[44] | United States | 18–50 (74) | 72.5d |
Treatment options under clinical evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-AALL0434 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): This is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and MRD level at day 29. The objectives of the trial are (1) to determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients, (2) to determine the relative safety and efficacy of high-dose versus Capizzi methotrexate during interim maintenance, and (3) to test the efficacy of treating low-risk T-cell ALL patients without cranial radiation.
- CALGB-10403 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed ALL): This is a phase II trial for adolescent and young adults aged 15 to 40 years with newly diagnosed ALL (B-cell or T-cell) treated with a regimen that is nearly identical to the Capizzi methotrexate arm of the COG-AALL0232 trial and treated by adult hematologists/oncologists at multiple sites.
- OSU-08066 (Combination Chemotherapy in Treating Adult Patients With Newly Diagnosed ALL): DFCI protocol 06-254 (OSU-08066) is a phase II trial conducted by the DFCI ALL Consortium for patients aged 18 to 50 years with newly diagnosed ALL. The treatment regimen is similar to the very high-risk arm on the pediatric DFCI protocol, DFCI-05001, and includes 30 weeks of postinduction consolidation with IV PEG-asparaginase (given every 3 weeks). Older adolescents (aged 15–18 years) are treated on pediatric protocol DFCI-11-001 (NCT01574274) as high-risk patients.
Philadelphia Chromosome–Positive ALL
Treatment options
Prior to use of imatinib mesylate (see below), hematopoietic stem cell transplantation (HSCT) from a matched sibling donor was the treatment of choice for patients with Philadelphia chromosome–positive (Ph+) ALL.[45,46,47] Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome compared with standard (pre-imatinib) chemotherapy.[48] In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib era), transplantation with matched-related or matched-unrelated donors were equivalent. Disease-free survival at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and overall survival was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.[49]
Factors significantly associated with favorable prognosis in the pre-imatinib era included younger age and lower leukocyte count at diagnosis.[49] Early response measures were also shown to be prognostically significant in patients with Ph+ ALL in the pre-imatinib era.[49,50,51] Patients with Ph+ ALL who showed a rapid morphologic response or peripheral blood response to induction therapy had an improved outcome compared with patients who showed a slow response.[49,50] Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may also be useful to help predict outcome for Ph+ patients.[52,53,54]
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[55,56] Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[57,58,59] Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[60,61,62,63]
The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic SCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases. The 3-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib is 87.7% ± 10.9%. These patients fared better than historic controls treated with chemotherapy alone (without imatinib), and at least as well as the other patients on the trial who underwent allogeneic transplantation.[59] Longer follow-up is necessary to determine if this novel treatment improves cure rate or merely prolongs DFS.
As opposed to imatinib, dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial treatment of Ph+ ALL. Of note, dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.[64]
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-AALL1122 (NCT01460160) (Pediatric Ph+ ALL): In this international collaborative study, patients receive a second-generation tyrosine kinase inhibitor, dasatinib, with increased affinity for BCR/ABL1, in conjunction with a chemotherapy backbone based on the European EsPhALL regimen. Allogeneic stem cell transplant in first remission is reserved for those patients with suboptimal early response to therapy, as measured by morphology and MRD techniques. The goals of this study are to determine the safety and feasibility of administering dasatinib with this chemotherapy regimen, to determine the 3-year EFS of patients treated in this manner, and to compare outcomes with patients treated on prior trials using similar chemotherapy with imatinib.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References:
Treatment of Recurrent ALL
Prognostic Factors in Recurrent ALL
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the time from diagnosis to relapse and site of relapse, as well as cytogenetics and immunophenotype.[1,2,3,4,5,6,7,8,9,10,11,12,13]; [14][Level of evidence: 3iiDi] For patients with relapsed B-precursor ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For instance, survival rates after marrow relapse range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to 40% to 50% for those whose relapses occur more than 36 months from diagnosis.[5,13] For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early relapse (<18 months from diagnosis) are 40% to 50% and are 75% to 80% for those with late relapses (>18 months from diagnosis).[13,15] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.[16]
Patients who have combined marrow/extramedullary relapses fare better than those with isolated marrow relapses.[5,13] The Berlin-Frankfurt-Muenster (BFM) group has also reported that high peripheral blast counts at the time of relapse (>10,000/μL) were associated with inferior outcomes in patients with late marrow relapses.[10] The Children's Oncology Group (COG) reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.[13] Age older than 10 years has also been reported as an independent predictor of poor outcome.[13]
Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any point during treatment or posttreatment have a very poor prognosis.[5]
Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second remission (CR2).[17][Level of evidence: 2Di]; [18][Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[17,19,20,21]; [22][Level of evidence: 3iiiDi] High levels of MRD at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse. TP53 alterations (mutations and/or copy number alterations) are observed in approximately 11% of patients with ALL at first relapse and have been associated with inferior reinduction failure rate (38.5% vs. 12.5%) and event-free survival (EFS) (9% vs. 49%), of which approximately one-half are newly observed at time of relapse.[23]
Treatment of Bone Marrow Relapse
Reinduction chemotherapy
Initial treatment of relapse consists of induction therapy to achieve a CR2. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a CR2 at the end of the first month of treatment.[5];[24][Level of evidence: 2A]; [17][Level of evidence: 2Di] A United Kingdom-based randomized trial of patients with relapsed ALL compared reinduction with a four-drug combination using idarubicin versus mitoxantrone. A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse was reported.[25][Level of evidence: 1iiA] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation. Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) compared with those with late marrow relapses (approximately 95%).[17,24] Compared with patients with B-precursor phenotype, patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens.[17] Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%.[26] The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.[27]
Other combinations of agents have been reported to induce remissions in patients with multiple-relapsed or refractory ALL. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 44% to 56% of patients with refractory or relapsed disease.[28]; [29][Level of evidence: 2A]
Postreinduction therapy (second complete remission)
Post-CR2 therapy for patients who experience a bone marrow relapse (either isolated or combined) while on therapy or within 6 months of discontinuing therapy generally includes hematopoietic stem cell transplantation (HSCT).[30,31] For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in longer leukemia-free survival when compared with a chemotherapy approach.[7,22,32,33,34,35,36,37,38] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%.
For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[9,39,40,41]; [42][Level of evidence: 3iiA] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no SCT) in CR2. In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in CR2, the 2-year cumulative incidence of relapse was 49% for the 12 patients who were MRD-positive at the end of reinduction and 0% for the 11 patients who were MRD-negative.[20] Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction treatment requires further study.
For patients with T-cell ALL and marrow relapse, outcomes with chemotherapy alone have generally been poor,[5] and these patients are usually treated with allogeneic SCT in CR2, regardless of time to relapse.
For patients proceeding to allogeneic SCT, total-body irradiation (TBI) appears to be an important component of the conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant conditioning regimens that include TBI produce higher cure rates than chemotherapy-only preparative regimens.[32,43,44] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent,[45] although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary.[46] The potential neurotoxic effects of TBI should be considered, particularly for very young patients.
In addition to the conditioning regimen, disease status at the time of transplantation also appears to be an important predictor of outcome. Several studies have demonstrated that the level of MRD at the time of transplant is an important predictor of survival in patients in CR2.[21,47,48]
Outcomes following matched unrelated donor and umbilical cord blood transplants have improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants.[36,49,50,51,52]; [53][Level of evidence: 2A]; [54][Level of evidence: 3iiiA] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain higher with unrelated than with matched sibling transplants.[37,49,55] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and Center for International Blood and Marrow Transplant Research (CIBMTR) analyses have demonstrated that rates of GVHD, TRM, and OS have improved over time.[56]; [57,58][Level of evidence: 3iiA] Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor.[59] In certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered.[60] For T cell-depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells may have a better outcome than those who receive paternal stem cells.[61][Level of evidence: 3iiA] There are a number of new options under study for preventing subsequent relapse after transplantation, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.[62]
For patients relapsing after an allogeneic HSCT for relapsed ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure due to failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.[63] Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term EFS.[63,64,65] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with complete remission at the time of the second HSCT.[64,65] Reduced intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a complete remission confirmed by flow cytometry.[66][Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.[67]; [68][Level of evidence: 3iiiA] Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is unknown, and a small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[69][Level of evidence: 3iA]
Treatment of Extramedullary Relapse
With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5% and testicular relapse is less than 1% to 2%.[70,71,72] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse.[73] In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques,[74] and successful treatment strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis compared with patients with either no MRD or MRD less than 0.01%.[74]
CNS relapse
While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal (IT) therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.[15,75,76,77] In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or greater had a 4-year EFS rate of approximately 80% compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.[77] In a follow-up POG study, children who had not previously received radiation therapy and with initial remission of 18 months or more were treated with intensive systemic and IT chemotherapy for 1 year followed by 18 Gy of cranial radiation only.[15] The 4-year EFS was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS of 52%.
A number of case series describing SCT in the treatment of isolated CNS relapse have been published.[78,79] In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiotherapy as in the POG studies above, 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[80][Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses. Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis treated with chemoradiation therapy alone (>75%), transplantation is generally not recommended for this group. However, use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study. The use of post-HSCT IT chemotherapy has been controversial, although the most current data would suggest no benefit.[81,82]
Testicular relapse
The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.[83] The standard approach for treating isolated testicular relapse in North America is to administer chemotherapy plus radiation therapy. In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control (surgical removal or radiation) is to be performed. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes is being tested in clinical trials. Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation. All five boys were long-term survivors.[84] A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.[85] In a small series of boys who had an isolated testicular relapse after a SCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second SCT.[69][Level of evidence: 3iA]
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
COG trials for ALL in first relapse
The COG has divided patients with first relapse into three risk categories as outlined in Table 3. Clinical trials in some risk categories are available.
Table 3. Children's Oncology Group ALL Relapse Risk Stratification for B-Precursor ALLa
| Isolated CNS or Testicular Relapse | Bone Marrow or Combined Relapse | |
| ALL = acute lymphoblastic leukemia; CNS = central nervous system. | ||
| a All relapsed T-cell ALL is considered high risk. | ||
| <18 months from diagnosis | Intermediate risk | High risk |
| 18–36 months from diagnosis | Low risk | High risk |
| >36 months from diagnosis | Low risk | Intermediate risk |
- COG-AALL0433 (Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell ALL [high-dose vincristine arm closed to accrual as of September 2010]): Patients with intermediate-risk relapse are eligible for this study. Patients will receive a chemotherapy regimen similar to POG studies, POG-9061 and POG-9412, which have been shown to be efficacious in the isolated relapse setting and well tolerated. Intensification of vincristine is being studied in a randomized fashion. For patients with a matched sibling, the choice of bone marrow transplant or chemotherapy is left to the discretion of the treating physician and/or family. The vincristine randomization has been closed for patients younger than 10 years at diagnosis due to increased toxicity in the higher-dose vincristine arm.
- COG-AALL07P1 (Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed ALL or Lymphoblastic Lymphoma): Patients with marrow relapse of T-cell ALL and early marrow relapse (<36 months) of B-precursor ALL are eligible for this study. This is a phase II pilot study to determine the feasibility and safety of adding bortezomib to intensive reinduction chemotherapy. Bortezomib is a proteasome inhibitor that has been shown to sensitize leukemic cells to apoptosis induced by chemotherapy.
Other trials for ALL in first relapse
- TACL 2008-002 (NCT00981799) (Trial of Nelarabine, Etoposide, and Cyclophosphamide in Relapsed T-cell ALL and T-cell Lymphoblastic Lymphoma): This trial, conducted by the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) clinical trials group, is testing the feasibility of administering nelarabine in combination with cyclophosphamide and etoposide as reinduction for patients with T-cell ALL in first relapse (as well as those who failed primary induction therapy). Doses of nelarabine and cyclophosphamide will be escalated in successive cohorts of patients to determine the maximum tolerated doses of these drugs when given in combination.
- DFCI-11-237 (NCT01523977) (Everolimus With Multiagent Reinduction Chemotherapy in Pediatric Patients With ALL): Patients in first relapse are eligible to enroll on a Dana-Farber Cancer Institute Consortium trial testing the feasibility of administering everolimus, an oral mTOR inhibitor, in combination with multiagent reinduction (vincristine, prednisone, doxorubicin, intravenous PEG-L-asparaginase, and IT chemotherapy).
- COG-ADVL1114 (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed ALL or Non-Hodgkin Lymphoma [NHL]): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALL R3 induction regimen for patients with relapsed ALL and NHL.
Trials for ALL in second or subsequent relapse
Multiple clinical trials investigating new agents and new combinations of agents are available for children with multiply relapsed or refractory ALL and should be considered. These trials are testing targeted treatments specific for ALL, including monoclonal antibody–based therapies and drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
References:
Changes to this Summary (05 / 18 / 2012)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Childhood Acute Lymphoblastic Leukemia (ALL)
Added Dores et al. as reference 5.
Revised text to state that among children with ALL, more than 95% attain remission and 75% to 90% survive free of leukemia recurrence at least 5 years from diagnosis with current treatments that incorporate systemic therapy and specific central nervous system preventive therapy (cited Hunger et al. as reference 39).
Cellular Classification and Prognostic Variables
Added text about the molecular and genetic characterization and transcriptional profile of early T-cell precursor ALL (cited Zhang et al. as reference 59).
Postinduction Treatment for Specific ALL Subgroups
Added text about the results of a Pediatric Oncology Group study that indicated that the addition of high-dose methotrexate to the Dana-Farber Cancer Institute-based chemotherapy regimen resulted in significantly improved event-free survival (EFS) in patients with T-cell ALL, and high-dose methotrexate was associated with a lower incidence of relapses involving the central nervous system (cited Asselin et al. as reference 3).
Added text about a Japanese clinical trial conducted between 1998 and 2002, where all MLL-rearranged infants were intended to proceed to allogeneic stem cell transplant from the best available donor 3 to 5 months after diagnosis. The 3-year EFS for all enrolled infants was 44%; this result was due, in part, to the high frequency of early relapses, even with intensive chemotherapy.
The Adolescent and Young Adult Patients with ALL subsection was renamed from Adolescent Patients with ALL.
Added Table 2 about the outcomes for published or ongoing prospective, pediatric-based studies of adolescents and young adults with ALL (cited Ribera et al. as reference 41, Huguet et al. as reference 42, Storring et al. as reference 43, and DeAngelo et al. as reference 44).
Revised text to state that preliminary outcome of results for Philadelphia chromosome–positive ALL demonstrated a better outcome after hematopoietic stem cell transplantation if imatinib was given before or after transplant (cited Rives et al. as reference 63).
Treatment of Recurrent ALL
Revised text to state that high levels of minimal residual disease at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse. TP53 alterations (mutations and/or copy number alterations) are observed in approximately 11% of patients with ALL at first relapse and have been associated with inferior reinduction failure rate and EFS, of which approximately one-half are newly observed at time of relapse.
Revised text to state that the combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 44% to 56% of patients with refractory or relapsed disease (cited Hijiya et al. as reference 29 and level of evidence 2A).
Added text about the COG-ADVL1114 trial as a treatment option under clinical evaluation.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:
- Robert J. Arceci, MD, PhD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
- Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Michael A. Pulsipher, MD (Primary Children's Medical Center)
- Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
- Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Malcolm Smith, MD, PhD (National Cancer Institute)
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Levels of Evidence
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National Cancer Institute: PDQ® Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childALL/HealthProfessional. Accessed <MM/DD/YYYY>.
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