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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia (ALL). This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less technical language, and in Spanish.
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.
Cancer in children and adolescents is rare. 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. [1] 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.
In recent decades, dramatic improvements in survival have been achieved in children and adolescents with cancer. 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 Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
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. [2] [3] There are approximately 2,400 children and adolescents younger than 20 years diagnosed with ALL each year in the United States, [3] and there has been a gradual increase in the incidence of ALL in the past 25 years. [4] 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. [2] [3] The incidence of ALL appears to be highest in Hispanic children (43 per million). [2] [3]
Few factors associated with an increased risk of ALL have been identified. The primary accepted nongenetic risk factors for ALL are prenatal exposure to x-rays and postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML), [5] [6] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years. [5] [6] 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. [7] [8] [9] 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. [10] Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations, [11] [12] [13] 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. [14] Almost all Down syndrome ALL cases with JAK2 mutations also have the PAR deletion and express the P2RY8-CRLF2 fusion gene. [10] Preliminary evidence suggests no correlation between JAK2 mutation and 5-year event-free survival. [12]
While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year), [7] 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. [8] [9] Increased occurrence of ALL is also associated with other genetic conditions, including neurofibromatosis, [15] Shwachman syndrome, [16] [17] Bloom syndrome, [18] and ataxia telangiectasia. [19]
Recent genome-wide association studies show that germline (inherited) genetic polymorphisms are associated with the development of childhood ALL. [20] 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 precursor-B ALL. [21] [22]
Many cases of ALL that develop in children 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. [23] [24] 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. [23] [24] Genetic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias. [25]
Among children with ALL, more than 95% attain remission and 75% to 85% 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). [26] [27] [28] [29] [30]
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 potentially better therapy with therapy that is currently accepted as standard. 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.
Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that those children who have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival. [1] [2]
Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. For children with ALL, a number of clinical and laboratory features have demonstrated prognostic value, some of which are described below. [3] The factors described are grouped into the following categories: clinical and laboratory features at diagnosis; leukemic cell characteristics at diagnosis; and response to initial treatment. As in any discussion of prognostic factors, the relative order of significance and the interrelationship of the variables are often treatment dependent and require multivariate analysis to determine which factors operate independently as prognostic variables. [4] [5] Because prognostic factors are treatment dependent, improvements in therapy may diminish or abrogate the significance of any of these presumed prognostic factors. For example, a report from the Children’s Cancer Group (CCG) showed that the adverse prognostic significance of slow early response disappears when these patients receive intensified postinduction chemotherapy. [6]
A subset of the prognostic 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.
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, or the t(12;21) (ETV6-RUNX1, also known as the TEL-AML1 translocation). [7] [9] The outcome for adolescents has improved significantly over time. [10] Multiple retrospective studies have suggested that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols. [11] [12] [13] (For more information about adolescents with ALL, see the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.)
Infants with ALL have a particularly high risk of treatment failure. Treatment failure is most common in infants younger than 3 to 6 months and in those with extremely high presenting leukocyte counts and/or a poor response to a prednisone prophase. [14] [15] [16] [17] Infants with ALL can be divided into two subgroups on the basis of the presence or absence of MLL gene rearrangements. [16] [17] [18] Approximately 80% of infants with ALL have an MLL gene rearrangement. [16] [18] [19] An MLL gene rearrangement is most common in infants younger than 6 months; from 6 months to 1 year, the incidence of MLL rearrangements decreases. [16] Infants with leukemia and MLL gene rearrangements have very high white blood cell (WBC) counts, increased incidence of central nervous system (CNS) involvement, and a poor outcome. [16] [17] Blasts from infants with MLL gene rearrangements are typically CD10/cALLa negative and express high levels of FLT3. [16] [17] [18] [20] Conversely, infants whose leukemic cells show a germline MLL gene configuration frequently present with CD10/cALLa-positive precursor-B immunophenotype. These infants have a significantly better outcome than infants with ALL characterized by MLL gene rearrangements. [16] [17] [18]
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. Elevated WBC count is often associated with other adverse prognostic factors, including T-cell phenotype and unfavorable chromosomal translocations such as t(4;11) and t(9;22) (see below). High WBC count is not an adverse prognostic factor in patients with T-cell ALL when treated with current intensive therapy. [5]
CNS status at diagnosis has prognostic significance. Patients who have a nontraumatic diagnostic lumbar puncture may be placed into one of three categories according to the number of WBC/µL and the presence/absence of blasts on cytospin as follows:
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) compared with patients not meeting the criteria for CNS disease at diagnosis. [7] 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. [7] [21] [22] 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. [21] [23]
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, it does not appear that testicular involvement at diagnosis has prognostic significance. [24] [25] 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. [25] 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. [24] The Children's Oncology Group (COG) has also adopted this strategy.
Outcome in Down syndrome children with ALL has generally been reported as somewhat inferior to outcomes observed in non-Down syndrome children. [26] [27] [28] [29] 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. [26] [27] [28] [29]
In some studies, the prognosis for girls with ALL is slightly better than it is for boys with ALL. [30] [31] [32] 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. [30] [31] [32] However, in clinical trials with high 5-year EFS rates (>80%), male gender is not an adverse risk factor. [22] [33]
Survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL. [34] [35] This difference may be therapy-dependent; a report from SJCRH found no difference in outcome by racial groups. [36] Asian children with ALL fare slightly better than white children. [35] The reason for better outcome in white and Asian children compared with black and Hispanic children is not known, but it cannot be completely explained based on known prognostic factors. [35]
In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology. [37] 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 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.)
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-rearranged, t(12;21), hyperdiploidy, hypodiploidy, t(5;14), and t(1;19). [38]
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, which is treated differently than cases with more immature phenotypic features. The older terminology will continue to be used throughout this summary.
Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in young infants and is often associated with a t(4;11) translocation. The leukemic cells of patients with pre-B ALL contain cytoplasmic immunoglobulin (cIg), and 25% of patients with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1) fusion (see below). [41] [42]
Approximately 3% of patients have transitional pre-B ALL with expression of surface immunoglobulin heavy chain without light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL. [43]
Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and a translocation involving the C-MYC gene), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as mature B-cell leukemia. [43] (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma Treatment for more information on the treatment of children with B cell ALL and Burkitt lymphoma.)
T-cell ALL: T-cell ALL is defined by expression of the T cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts and is frequently associated with a constellation of clinical features, including male gender, older age, leukocytosis, and mediastinal mass. [8] [33] [44] With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that of children with B-lineage ALL. [8] [33] [44]
There are few commonly accepted prognostic factors for patients with T-cell ALL. Unlike B-precursor ALL, high WBC count is not an adverse prognostic factor in patients with T-cell ALL, but patients with high WBC count are generally considered to be in the high-risk group. [5] Patients with T cell ALL whose blasts are CD34+ may have an inferior prognosis compared with patients whose blasts do not express CD34. [45] The presence or absence of a mediastinal mass at diagnosis has not prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance. [46]
Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL. [47] Multiple chromosomal translocations have been identified in T-cell ALL, with many involving transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) and resulting in aberrant expression of these transcription factors in leukemia cells. [47] [48] [49] [50] [51] [52] These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR). [47] High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL. [48] [49] [50] [52] Overexpression of TLX3/HOX11L2 resulting from the t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases [50] and appears to be associated with increased risk of treatment failure, [50] though not in all studies. [50]
NOTCH1 gene mutations occur in approximately 50% of T-cell ALL cases, but their prognostic significance has not been established. [53] [54] [55] [56]
A NUP214–ABL1 fusion has been noted in 4% to 6% of adults with T-cell ALL. The fusion is usually not detectable by standard cytogenetics. Tyrosine kinase inhibitors may have therapeutic benefit in this type of T-cell ALL. [57] [58] [59]
Recently, a distinct subset of childhood T cell ALL, termed early precursor-T cell ALL, was identified by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analyses. [60] This subset, identified in 13% of T cell ALL cases, is characterized by a distinctive immunophenotype (negativity for CD1a and CD8, with weak expression of stem cell or myeloid markers and weak expression of CD5). It has the same gene expression profile of normal early thymic precursor cells, a population of recent immigrants from bone marrow to the thymus which retains multilineage differentiation potential. [60] A retrospective analysis suggested that this subset may have a poorer prognosis than other cases of T cell ALL. [60]
Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study 8% of patients with the Philadelphia chromosome (t[9;22]) also had high hyperdiploidy, [67] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive high hyperdiploid patients.
Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled. These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy. [68]
Near triploidy (68 to 80 chromosomes) and near-tetraploidy (>80 chromosomes) is much less common and appears to be biologically distinct from high hyperdiploidy. [69] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 (TEL-AML1) fusion. [69] [70] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case. [69]
Recurring chromosomal translocations can be detected in a substantial number of cases of childhood ALL, and some of these translocations, as described below, have prognostic significance.
TEL-AML1 (t[12;21] cryptic translocation): Fusion of the TEL (ETV6) gene on chromosome 12 to the AML1 (RUNX1/CBFA2) gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL. [68] The t(12;21) occurs most commonly in children aged 2 to 9 years. [73][ [74] Hispanic children with ALL have a lower incidence of t(12;21) compared with white children. [75] Reports generally indicate favorable EFS and OS in children with the TEL-AML1 fusion, however, the prognostic impact of this genetic feature may be modified by factors such as early response to treatment, NCI risk category, and treatment regimen. [76] [77] [78] In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not TEL-AML1, to be independent prognostic factors. [76] There is a higher frequency of late relapses in patients with TEL/AML1 fusion compared with other B-precursor ALL. [76] [79] Among relapsed cases, patients with TEL-AML1 fusion seem to have a better outcome than do other patients, and in some studies, long-term OS rates exceed 90%. [73] [76] [80] Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the TEL-AML1 translocation). [81]
Philadelphia chromosome (t[9;22] translocation): The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL, and is more common in older patients with precursor B-cell ALL and high WBC count. Historically, it was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic stem cell transplantation in first remission. [67] [82] [83] [84] A study by the COG demonstrated a 3-year EFS rate of 80.5% which was superior to historical controls in the pretyrosine kinase inhibitor (imatinib) era. [85] Longer follow-up is necessary to determine whether the treatment improves the cure rate or merely prolongs DFS.
MLL gene rearrangements: Rearrangements involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases and are generally associated with an increased risk of treatment failure. [39] [86] [87] [88] The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases. [86] Patients with t(4;11) are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease, and to have a poor response to initial therapy. [16] While both infants and adults with the t(4;11) are at high risk of treatment failure, children with the t(4;11) appear to have a better outcome than either infants or adults. [39] [86] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality. [39] [86] Of interest, the t(11;19) occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL. [89] Outcome for infants with t(11;19) is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation. [89]
TCF3-PBX1 (E2A-PBX1; t[1;19] translocation): The t(1;19) translocation occurs in approximately 5% of childhood ALL cases, and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1. [41] [42] The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL (cytoplasmic immunoglobulin positive). Black children are more likely than white children to have pre-B ALL with the t(1;19). [36] The t(1;19) translocation was previously associated with inferior outcome in the context of antimetabolite-based therapy, [90] but with most current treatment protocols, the t(1;19) translocation has no adverse prognostic significance. [42] In a trial conducted by SJCRH on which all patients were treated without cranial radiation, the t(1;19) was associated with a higher risk of CNS relapse. [22]
Intrachromosomal amplification of the chromosome 21 (iAMP21) with multiple extra copies of the RUNX1 (AML1) gene occurs in fewer than 5% of precursor B-cell ALL cases and has been associated with an inferior outcome. [91] [92]
Recent application of microarray-based genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, resequencing and epigenetic approaches, has identified a specific subset of patients with high-risk B-precursor ALL with a very poor prognosis. These patients have a gene-expression signature similar to BCR-ABL-positive ALL, but lack that translocation. IKZF1 deletions were identified in about 30% of high-risk B-precursor ALL and were significantly associated with a very poor outcome. [93] [94] A subset of patients with IKZF1 deletions were found to have JAK kinase mutations (about 10% of all high-risk cases), suggesting a possible future therapeutic target. [95]
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL. [96] [97] [98] For example, patients with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of thioguanines, such as 6-mercaptopurine), appear to have more favorable outcomes, although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression, infection, and liver dysfunction. [99] [100]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction minimal residual disease (MRD) and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols. [101] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations and whether individualized dose modification based upon these findings will improve outcome is unknown.
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, [102] early response has strong prognostic significance. Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:
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. [103] Morphologic response to treatment continues to be used in some ALL trials to stratify patients into prognostic categories for treatment assignment.
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] [104] 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. [105] [106]
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. [107] Rate of clearance of peripheral blasts has been found to be of prognostic significance in both T-cell and B-lineage ALL. [107]
The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment. Persistent leukemia at the end of that initial induction phase is observed in up to 5% of children with ALL. Patients at highest risk of induction failure include those with T-cell phenotype (especially without a mediastinal mass) and B-precursor ALL cases with very high presenting leukocyte counts and/or the Philadelphia chromosome. [108] [109] Induction failure portends a very poor outcome. [108] In the French FRALLE 93 study, the 5-year OS rate for patients with initial induction failure was 30%. [109]
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 one 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 to determine unique immunoglobulin gene rearrangements or flow cytometric assays which detect leukemia-specific immunophenotypes are required. With these techniques, detection of as few as 1 in 100,000 leukemic cells is possible. [110]
Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with ALL. [110] [111] [112] [113] Patients with higher levels of end-induction MRD have a poorer prognosis than those with lower or undetectable levels. [110] [111] [112] [113] MRD at end-induction 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. [110] [112] [113] [114] [115] [116] For example, the BFM group uses both end-induction and week 12 measurements to risk-stratify patients.
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 recently reported a very favorable prognosis (5-year EFS of 97% ± 1%) for patients with B-precursor phenotype, NCI standard risk age/leukocyte count, and favorable cytogenetic abnormalities (either high hyperdiploidy with favorable trisomies or the TEL/AML1 fusion) who had negative MRD levels at both day 8 (from peripheral blood) and end-induction (from bone marrow). [112]
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. Therapeutic adjustments based on MRD determinations in ALL should be utilized only in clinical trials.
This subsection does not discuss infants as a prognostic group. For information about infants with acute lymphoblastic leukemia, refer to the Postinduction Treatment for Childhood Acute Lymphoblastic Leukemia Subgroups section of this summary.
Former CCG studies made an initial risk assignment of patients older than 1 year as standard risk or high risk based on the NCI consensus age and WBC criteria, regardless of phenotype. [1] The standard-risk category included patients aged 1 to 9 years who had a WBC count at diagnosis less than 50,000/µL. The remaining patients were classified as high risk. Final treatment assignment for CCG protocols was based on early response to therapy (day 7 or day 14 bone marrow response) with slow early responders in either risk group receiving augmented postinduction therapy.
Former POG studies defined the low-risk group based on the NCI consensus age and WBC criteria and required the absence of adverse translocations, absence of CNS disease and testicular disease, and the presence of either the TEL-AML1 translocation or trisomy of chromosomes 4 and 10. The high-risk group required the absence of favorable translocations and the presence of CNS or testicular leukemia, or the presence of MLL gene rearrangement, or unfavorable age and WBC count. [112] 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). [68]
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.
A large, retrospective analysis of CCG and POG data led to the development of a new classification system for the COG. [117] Based on this analysis, patients with precursor B-cell ALL are initially assigned to a standard-risk or high-risk group based on age and initial WBC count. Patients aged 1 to 9.99 years with <50,000 WBC/µL are considered standard risk. All children with T cell phenotype are considered high risk regardless of age and initial WBC count. Early treatment response, assessed by day 7 or day 14 marrow morphology and end-induction MRD assessment, and cytogenetics are subsequently used to determine the intensity of postinduction therapy. NCI standard-risk patients with rapid morphologic response (day 14 M1 marrow) and MRD less than 0.1% and an M1 marrow on day 29 are assigned to one of two groups based on cytogenetics. Patients with favorable cytogenetics (either t(12;21) or trisomies of chromosomes 4, 10, and 17) are considered "standard risk-low" while patients with neither favorable nor unfavorable cytogenetics (t[9;22], or hypodiploidy [<44 chromosomes]) are considered "standard risk-average." Standard-risk patients with either slow morphologic response (either day 7 or day 14 M1 marrow) and/or MRD more than 0.1% on day 29 are assigned to a third group (standard risk-high) and receive more intensive postinduction treatment. High-risk patients with precursor B-cell ALL are divided into rapid-responder (rapid morphologic response and low MRD) or slow-responder groups. Patients are classified as very high risk if they have any of the following features (regardless of initial risk group):
The Dana-Farber Cancer Institute ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially classified as either standard risk or high risk based on age, presenting leukocyte count, and the presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥0.01) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.01) continue to receive treatment based on their initial risk-group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive a tyrosine kinase inhibitor (imatinib) beginning mid-induction and are eligible for an allogeneic stem cell transplant in first remission.
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. [60]
Treatment of childhood acute lymphoblastic leukemia (ALL) typically involves both inpatient and outpatient chemotherapy given for 2 to 3 years. Since myelosuppression and generalized immunosuppression are an anticipated consequence of both leukemia and its treatment with chemotherapy, 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 infectious and other complications throughout all phases of therapy. Approximately 1% of patients die during induction therapy and another 1% to 3% die during first remission from treatment-related complications. [1] [2] Such specialized care is best accomplished in 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 into three phases: (1) remission induction, (2) consolidation or intensification and, (3) maintenance or continuation, with central nervous system (CNS) sanctuary therapy generally provided in each stage. The intensity of both the induction and postinduction phases is determined by prognostic factors utilized for risk-based treatment assignment. [4] With this treatment approach, approximately 80% of patients aged 1 to18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors. [5] [6] [7] [8]
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. In COG protocols, a subset of the known prognostic factors (e.g., age, white blood cell [WBC] count at diagnosis) 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 and WBC count <50,000/μL); in children meeting high-risk age and WBC criteria, EFS rates are approximately 70%. [5] [6] [7] [8] [9] 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 and WBC count, can identify patient groups with expected EFS rates ranging from less than 40% to more than 95%. [9] [10]
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 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, however, 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, CNS-penetrant systemic chemotherapy (such as high-dose methotrexate) and cranial radiation. At present, most newly diagnosed children with ALL are treated without cranial radiation; many groups administer cranial radiation only to those patients to be considered 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. [11] In two trials, overall EFS was not compromised when frequent dosing of intrathecal chemotherapy and high-dose methotrexate replaced cranial radiation in these high-risk patients. [7] [8]
Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear. [12] [13] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation. [12] The Children's Oncology Group (COG) has also adopted this strategy.
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, with the poorest prognosis for those with MLL gene rearrangements. [14] [15] 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% even with a more intensive therapeutic approach. [15] [16] [17] Infants with MLL-gene rearrangements 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 (SCT) in first remission. [16] [18] [19] [20] 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 leukocyte count) or poor early treatment response. [21] [22] However, a COG study demonstrated a 3-year EFS rate of 80.5% in Ph+ patients treated with intensive chemotherapy and a tyrosine kinase inhibitor (imatinib). [23] 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.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Three-drug induction therapy using vincristine, corticosteroid (prednisone or dexamethasone) and L-asparaginase in conjunction with intrathecal therapy (IT), results in complete remission 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] and 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-drug induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered. [2] [4] [5] Because of the likelihood of increased toxicity with four-drug induction therapy, Children's Oncology Group (COG) protocols for National Cancer Institute (NCI) standard-risk precursor B-cell ALL currently utilize a three-drug induction consisting of dexamethasone, vincristine, and L-asparaginase, and add a fourth drug (daunorubicin) for higher risk patients. 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 a four-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 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, a third randomized trial (conducted in Japan) did not confirm a survival advantage with dexamethasone. [11] This discrepant result might have been due to the use of a higher dose of prednisolone during induction therapy, the use of a more intensive backbone chemotherapy regimen, and/or the smaller number of patients included in that trial.
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. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens. [12] [13] 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, [14] and has been associated with a higher risk of osteonecrosis, especially in adolescent patients. [15]
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 E. 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, allowing it to produce asparagine depletion with less frequent administration. [16] A single intramuscular 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 intramuscular E. coli L-asparaginase (three times a week for 3 weeks). [17] Studies have shown that a single dose of PEG-L-asparaginase given as part of multiagent induction results in potentially therapeutic serum enzyme activity (>100 IU/mL) in nearly all patients for at least 2 to 3 weeks. [17] [18] [19] 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. [20] 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. [17] PEG-L-asparaginase has been safely administered intravenously in pediatric patients. [18] [19] There does not appear to be significant difference between intramuscular and intravenous administration of PEG-L-asparaginase in terms of pharmacokinetics and toxicity. [19]
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). [16] If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose. 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. [21] [22] 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. [23]
More than 95% of children with newly diagnosed ALL will achieve a complete remission within the first 4 weeks of treatment. Of the 2% to 4% of patients who fail to achieve complete remission 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). [22] [24] [25]; [26][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 complete remission is achieved. [27] [28] [29]
For patients whose disease achieves complete remission, measures of the rapidity and extent of response to induction chemotherapy have important prognostic significance, as discussed in Cellular Classification and Prognostic Variables section. Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher relapse risk, [30] and has been used by the COG to risk-stratify patients. Similarly, end-induction levels of submicroscopic minimal residual disease (MRD), assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcomes. [31] [32] [33] Intensification of postinduction therapy for patients with high levels of end-induction MRD is currently under investigation by many groups. MRD levels earlier in induction (e.g., days 8 and 15), as well at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance. [33] [34] [35]
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 intrathecal 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. To that end, cranial radiation is used much less frequently in current regimens than it has been in the past.
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 often continued throughout the maintenance phase. IT chemotherapy typically consists of either methotrexate alone or methotrexate with cytarabine and hydrocortisone. [36] Unlike IT cytarabine, IT methotrexate has a significant systemic effect which may contribute to prevention of marrow relapse. [37]
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, high-dose methotrexate, and high-dose cytarabine provide some degree of CNS protection. 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]
IT chemotherapy, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL. [4] [24] [38] [39] [40] [41] The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients. The DFCI ALL Consortium 95-01 trial (DFCI-95001) (1996–2000) randomized standard-risk patients to receive either 18 Gy of cranial irradiation with IT chemotherapy or more frequently dosed IT chemotherapy alone (without radiation) and demonstrated no significant difference in EFS between the two arms. [22]
The relative efficacy and toxicity of triple IT chemotherapy (methotrexate, prednisone, cytarabine) IT therapy and single (methotrexate alone) in nonirradiated standard-risk patients was studied in a randomized fashion as part of the CCG-1952 clinical trial (1996-2000). [42] 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 fewer than 5 WBC/hpf on CSF cell count); the isolated CNS relapse rate was 7.7% ± 5.3% for CNS2 patients who received triple intrathecal chemotherapy compared with 23.0% ± 9.5% for those who received IT methotrexate alone (P = 0.04). 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. [42]
Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) are at increased risk of CNS relapse, [43] although this risk appears to be nearly fully abrogated if they receive more intensive IT chemotherapy, especially during the induction phase. [44] 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 should also receive more intensive IT chemotherapy. [44] [45]
Controversy exists as to which, if any, high-risk patients should be treated with cranial radiation. 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, including those with T cell phenotype and subsets of patients with high-risk precursor B-cell ALL, including those with extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities. [46] Both the proportion of patients receiving radiation and the dose of radiation administered have decreased over the last 2 decades. For example, in a trial conducted between 1990–1995, 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. [25] In the follow-up trial conducted by that group between 1995–2000 (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. [40] 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. [40]
Two recent studies, one conducted by the SJCRH and the other by the Dutch Childhood Oncology Group (DCOG), omitted cranial radiation for all patients, including those high-risk subsets typically irradiated by other groups. [4] [41] Each of these studies included four doses of high-dose methotrexate administered every 2 weeks during postinduction consolidation, as well as an increased frequency of IT chemotherapy and frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy. The 5-year cumulative incidence of isolated CNS relapse on each trial was between 2% and 3%, although some patient subsets had a significantly higher incidence. 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 any CNS-involvement at diagnosis, defined as CNS2, CNS3 or traumatic LP with blasts. [41] The overall EFS for these studies was 85.6% (SJCRH) and 81% (DCOG), in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation. Of note, 33 of 498 (6.6%) of patients treated on the SJCRH study received an allogeneic stem cell transplant in first remission for high-risk features (including 26 with high MRD, six with Philadelphia chromosome–positive ALL, and one with near haploidy). [41]
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). [22] [40] 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%). [41] 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.
Toxic effects of CNS-directed therapy for childhood ALL can be divided into 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. [47] [48] [49]
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. [50] [51] [52] [53] [54] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation. [55] [56] [57] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys. [56] [57] [58] 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 to 28 Gy) on clinical trials conducted in the 1970s and 1980s. [59] 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. [60]; [61][Level of evidence: 1iiC] On current clinical trials, many patients who receive cranial radiation are now 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.
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential. [49] [62] [63] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered. [64] In general, high-dose or intermediate-dose methotrexate should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
The most common 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. [41] Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to IT chemotherapy. [65] 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. [66] Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities. [66]
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. [61] [67] [68] [69] This modest decline is especially seen in young children and girls. [70] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances, [71] 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. [72]
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.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
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 continuous maintenance therapy. Intensification may involve use of the following:
In children with standard-risk disease, there has been an attempt to limit exposure to drugs, such as anthracyclines and alkylating agents, that are 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 disease. [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]
Postinduction consolidation for regimens using a German Berlin-Frankfurt-Muenster "BFM-backbone," such as those of the Children's Oncology Group (COG), include a delayed intensification phase, during which patients receive a 4 week reinduction (including anthracycline) and a cyclophosphamide-containing reconsolidation regimen at approximately 3 months after remission is achieved. [1] [14] [15] Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of delayed intensification improved outcome for children with standard-risk ALL, in comparison to that achieved without an intensification phase. [14] [16] [17] In a Children's Cancer Group (CCG) study, which included a three-drug induction and utilized prednisone as the corticosteroid throughout all treatment phases, two blocks of delayed intensification produced a small event-free survival (EFS) benefit compared with one block of delayed intensification in intermediate-risk patients. [18] The benefit of two blocks of delayed intensification, however, may depend, in part, on the type of corticosteroid used (prednisone vs. dexamethasone). In a subsequent CCG study for standard-risk ALL in which dexamethasone was used instead of prednisone, two blocks of delayed intensification were not associated with a survival benefit in patients who were rapid early responders. [19]
In high-risk patients, a number of different approaches have been used with comparable efficacy. [7] [20] [21]; [15][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. Clinical trials conducted by the former CCG demonstrated that an augmentation of the BFM treatment backbone, including intensified interim maintenance and delayed intensification phases, improved outcome for high-risk patients. [14] [19] [22] In a randomized CCG trial of high-risk patients with slow early response (M3 marrow on day 7 of induction), an augmented BFM regimen was associated with a superior EFS compared with a more standard BFM treatment backbone. [22] The augmented BFM regimen in that trial included two courses of delayed intensification (instead of one). Therapy was also intensified by the inclusion of repeated courses of intravenous methotrexate (without leucovorin rescue) given with vincristine and asparaginase as well as additional vincristine/L-asparaginase pulses during the consolidation and delayed intensification phases. 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 prednisone. [23] Of note, there is a significant incidence of osteonecrosis of bone in teenaged patients who receive the augmented BFM regimen. [24]
The augmented BFM regimen has also been evaluated in children with high-risk ALL and a rapid early response to induction therapy. For these children, augmented intensity during consolidation, interim maintenance, and delayed intensification resulted in a higher EFS rate than that achieved with standard-intensity treatment. Increased duration of intensive therapy was not beneficial, and a single application of delayed intensification was as effective as two applications. [25][Level of evidence: 1iiA]
Approximately 10% to 20% of patients with ALL are classified as very high risk, including infants, those with adverse cytogenetic abnormalities (e.g., t[4;11] or low hypodiploidy) 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). [15] [26] These patients have been treated with multiple cycles of intensive chemotherapy during the consolidation phase, often including agents not typically used in up-front ALL regimens for standard and high-risk patients, such as high-dose cytarabine, ifosfamide and etoposide. [15] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset. [15] [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 an 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 = 0.02); however, there was no significant difference in overall survival (OS) (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = 0.12) . 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]
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral methotrexate. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. Clinical trials generally call for giving oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS. [30] 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] Because of the risk of hepatic complications, 6-TG is no longer utilized in maintenance therapy in any protocol. It remains unknown if short term use of 6-TG can improve outcome without excessive toxicity.
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 somewhat controversial. A CCG randomized trial demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses, [38] and a meta-analysis combining data from six clinical trials showed an EFS advantage for vincristine/prednisone pulses. [39] However, 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. [40] When 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] [41] On that trial, patients randomized to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate. [14] [41] 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. [42] The benefit of using dexamethasone in adolescents requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group. [24] [43]
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] [15] Extending the duration of maintenance therapy beyond 3 years does not improve outcome. [39]
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.
The current COG standard-risk ALL study divides patients into rapid-responder and slow-responder subgroups. Rapid responders are assigned to two separate groups based on cytogenetics. Patients with triple trisomy (chromosomes 4, 10, and 17) or a TEL-AML1 translocation are considered low risk. These patients are randomly assigned to receive standard therapy (simple consolidation, interim maintenance, delayed intensification, and maintenance) with or without additional PEG-L-asparaginase during consolidation and interim maintenance. Patients with ALL and rapid response, who do not have triple trisomy or TEL-AML1 (classified as standard-risk average group), are randomly assigned to receive treatment in a 2 × 2 factorial design to evaluate various components of the hemiaugmented BFM regimen. Some regimens extend maintenance therapy for boys based on the high risk of relapse, however, it is not clear that longer maintenance reduces relapse risk in boys, especially in the context of current intense therapies. [15][Level of evidence: 2Di]
Standard-risk ALL patients with slow early response disease receive the fully augmented BFM regimen.
In the COG trials, patients with ALL and rapid response to induction therapy receive hemiaugmented BFM, while patients with slow response receive the fully augmented BFM regimen. There are two randomized groups in the COG high-risk precursor B-cell ALL protocol (COG-AALL0232). During induction, patients aged 1 to 9 years are randomly assigned to receive either dexamethasone (14 days) or prednisone (28 days). Patients aged 10 years and older receive prednisone during induction. All patients are randomized to receive either Capizzi methotrexate or high-dose methotrexate with leucovorin rescue as given in BFM protocols during the first interim maintenance phase.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
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]
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 backbone for this protocol was based on the DFCI 87-001 regimen. [2] Results of an interim analysis of the POG protocol led investigators to conclude that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen results in significantly improved EFS, due in large measure to a decrease in the rate of central nervous system (CNS) relapse (estimated 3-year EFS, 80%). [3] This POG study was the first clinical trial to provide convincing evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase and doxorubicin were also important components of this regimen. [1] [3]
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-Munster (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%). [4] 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 [5] used cranial radiation for every patient while CCG-1961 used cranial radiation only for patients with slow morphologic response. [3] Among children with NCI standard-risk T-cell ALL, the EFS for children treated on CCG-1952 and COG-C1991 studies was inferior to the EFS for children treated on the POG-9404 study. [6]
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. All patients with T-cell ALL are considered high risk regardless of age and WBC count. Pilot studies from this group have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [7] [8] in the context of a BFM backbone for patients with newly diagnosed T-cell ALL; efficacy will be evaluated in the current trial. [9]
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.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL. [10] 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. [11] [12] [13] Despite intensification of therapy, long-term EFS rates from recent trials remain below 50%, and for those infants with MLL gene rearrangement the EFS rates continue to be in the 17% to 40% range. [11] [12] [14] [15] [16][Level of evidence: 2A] Factors predicting poor outcome for MLL-rearranged infants include a very young age (<6 months), extremely high presenting leukocyte count (300,000/μL or greater), and high levels of MRD at the end of induction and consolidation phases of treatment. [12]; [17][Level of evidence: 3iDii]
Treating infants with and without MLL gene rearrangements with different treatment protocols has been evaluated in a Japanese study. A favorable outcome was obtained with antimetabolite-based therapy for MLL-germline (nonrearranged) patients, while outcome remained unfavorable, despite intensive chemotherapy, for infants with MLL gene rearrangements. [14] An additional study from Japan confirms the good outcome of infants without MLL gene rearrangements. [14] This raises the question whether infants with B-lineage immunophenotype and germline MLL configuration should be treated on the same protocols as similar patients older than 1 year, although infants without MLL gene rearrangements treated on the ICU-INTERFANT99 also had favorable outcome (4-year EFS of 74%). [12]
The role of bone marrow transplantation in infants with MLL-rearranged ALL remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective. [18] [19] [20]; [21][Level of evidence: 3iA] One problem in the interpretation of these studies is the high rate of early relapse, especially in infants with very high-risk features. In a retrospective analysis of 256 patients initially treated between 1983 and 1995, no benefit was observed for any type of allogeneic stem cell transplant compared with intensive chemotherapy without transplant. [22] Similarly, in the ICU-INTERFANT99 study, after adjusting for waiting time to transplantation, high-risk patients who underwent hematopoietic SCT (HSCT) had 4-year disease-free survival (DFS) rates that did not significantly differ from those of high-risk patients treated with chemotherapy alone. [12] A COG study of infants with ALL observed that patients with MLL gene rearrangements who underwent transplantation in first remission as per protocol had outcome inferior to a comparable group of infants who completed treatment with chemotherapy. [11]
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.
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. [23] [24] These patients have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed for them. [25] A study from France of 15- to 20-year old patients 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). [26] Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens. [24] [27] [28] [29]; [30][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. [24] In the COG high-risk study (CCG-1961), the 5-year EFS rate for patients aged 16 to 21 years was 71.5%. [31][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%. 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. [30][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 with chemotherapy in these patients, there seems to be no role for the routine use of allogeneic SCT in first remission for adolescents and young adults with ALL. [31]
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. [27] Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis. [24] [32] [33] [34] High body mass index is also a risk factor for osteonecrosis, [35] and may be associated with a higher relapse rate in older patients. [36]
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:
Prior to use of imatinib mesylate (see below),HSCT from a matched sibling donor was the treatment of choice for patients with Philadelphia chromosome–positive (Ph+) ALL. [37] [38] [39] 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. [40] In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. More rigorous human leukocyte antigen (HLA) matching by molecular high-resolution typing, however, has significantly improved outcome for patients receiving matched unrelated donor transplants. [41]
Early response measures have been shown to be prognostically significant in patients with Ph+ ALL. [42] [43] Patients with Ph+ ALL who show a rapid morphologic response to induction therapy have an improved outcome compared with patients who show a slow response. [42] 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. [44] [45] [46]
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. [47] [48] Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy. [49] [50] [51] Preliminary outcome for results for adults with Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant. [52] [53] [54]
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 was 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. [51] Longer follow-up is necessary to determine if this novel treatment improves cure rate or merely prolongs DFS.
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:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the time from diagnosis and site of relapse. [1] [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]; [13][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. Although there is general agreement that time to relapse is an important predictor of outcome, no evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) improves outcome. [14]
In addition to site and timing of relapse, other factors have been reported to predict survival after relapse in patients with B-precursor ALL. The Berlin-Frankfurt-Muenster (BFM) group has reported that patients who have combined marrow/extramedullary relapses fare better than those with isolated marrow relapses. [5] Others have not confirmed this finding. The 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. [15]
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). [16][Level of evidence: 2Di] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL. [16] [17] [18] [19]; [20][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.
Initial treatment of relapse consists of induction therapy to achieve a CR2. The Children's Oncology Group (COG) has developed a reinduction platform that is effective in inducing remission in 68% of patients with early relapse and 96% with late relapse of precursor B-cell ALL (overall CR2 rate, 81%). [16][Level of evidence: 2Di] The first month of therapy on that platform consists of a four-drug induction that is very similar to that administered to newly diagnosed high-risk patients. The BFM group has reported an overall CR2 rate of 87% for patients with a marrow relapse (96% for those with a late relapse) using a reinduction regimen that included high-dose methotrexate and high-dose cytarabine in addition to vincristine, dexamethasone and L-asparaginase. [5] Similar results were reported by the SJCRH utilizing an oral etoposide-based reinduction. [21]
The COG four-drug reinduction platform does not appear to be effective for patients with relapsed T-cell ALL (five of seven patients failed to achieve a CR2). [16] Treatment of children with relapsed T-cell ALL with the T-cell selective agent nelarabine has demonstrated a response rate of approximately 50%. [22]
The selection of post-CR2 therapy for the child whose marrow relapse occurs on or shortly after the completion of therapy depends on many factors including prior treatment and other individual patient considerations. Aggressive approaches, including hematopoietic stem cell transplantation (HSCT), should be strongly considered for patients with early-relapsing precursor B-cell ALL and patients with relapse of T-cell ALL occurring at any time. [23] [24] 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] [20] [25] [26] [27] [28] [29] [30] [31] However, even with transplantation, survival rates for patients with early marrow relapses are less than 50%.
For B-precursor patients with a late marrow relapse, 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] [32] [33] Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction treatment requires additional study.
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. [25] [34] [35] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent, [36] although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary. [37] 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. [19] [38] [39]
Outcome following matched unrelated donor transplants has improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants. [29] [40] [41] [42] [43]; [44][Level of evidence: 2A] Rates of clinically extensive graft-versus-host disease and treatment-related mortality remain higher with unrelated than with matched sibling transplants. [30] [40] [45] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate.. [46] A Center for International Blood and Marrow Transplant Research 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. [47] 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. [48] For T-cell–depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells and/or allogeneic cells from a natural killer cell (NK)-reactive donor, may have a better outcome than those who receive paternal stem cells. [49][Level of evidence: 3iiA] There are a number of new options for documenting and preventing subsequent relapse after transplantation, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and NK cell therapy. [50]
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. [51] Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term event-free survival (EFS). [51] [52] [53] 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. [52] [53] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT. [54]; [55][Level of evidence: 3iiiA]
With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated central nervous system (CNS) relapse is less than 5% and testicular relapse is less than 1% to 2%. [56] [57] [58] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse. [59] In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques, [60] and successful treatment strategies must effectively control both local and systemic disease. The level of submicroscopic marrow involvement may also predict response to postrelapse therapy. [60]
While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission. [61] [62] [63] [64] 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. [63] 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 intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only. [64] 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. [65] [66] 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). [67][Level of evidence: 3iiiDii] The use of post-HSCT intrathecal chemotherapy has been controversial, although the most current data would suggest no benefit. [68]
The standard approach for treating isolated testicular relapse is to administer chemotherapy plus radiation therapy. While there are limited clinical data concerning outcome without the use of radiation therapy, 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. 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. [69] A study that looked at testicular biopsy at the end of therapy failed to demonstrate a survival benefit for patients with early detection of occult disease. [70]
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.
Children's Oncology Group (COG)
The COG has divided patients with relapse into three risk categories as outlined in Table 1. Clinical trials in all risk categories are available.
| Isolated CNS or Testicular Relapse [Clinical Trial] | Bone Marrow or Combined Relapse [Clinical Trial] | |
|---|---|---|
| <18 months from diagnosis | Intermediate risk [COG-AALL0433] | High risk [COG-ADVL04P2] |
| 18 to 36 months from diagnosis | Low risk [COG-AALL02P2] | High risk [COG-ADVL04P2] |
| >36 months from diagnosis | Low risk [COG-AALL02P2] | Intermediate risk [COG-AALL0433] |
| Note: All relapsed T-cell ALL is considered high risk—COG-AALL07P1 | ||
| aAll intermediate-risk patients with matched siblings choosing allogeneic transplant, and all high-risk patients undergoing related or unrelated transplantation are encouraged to enroll in ASCT0431 (see below) after completion of the three induction blocks associated with these protocols. | ||
For patients with isolated testicular relapse, the hypothesis of this protocol is that testicular radiation is not necessary if intensive systemic chemotherapy, including high-dose methotrexate, is administered. Patients will initially receive high-dose methotrexate followed by standard induction therapy. With complete clinical response, treatment with intensive chemotherapy as per a prior successful relapse protocol (POG-9412) [64] will be administered. Testicular radiation therapy is not given.
For patients with isolated CNS relapse, the hypothesis of this protocol is that reduced-dose cranial radiation (12 Gy) will be adequate to prevent subsequent CNS relapse when combined with a protocol of intensive systemic and coordinated intrathecal therapy. Treatment will be similar to that successfully utilized in POG-9412.
Other clinical trials investigating new agents and new combinations of agents are available for children with recurrent ALL and should be considered. [71] [72] [73] Targeted therapies specific for ALL are being developed, including monoclonal antibody-based therapies and using drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Call 1-800-4-CANCER
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. A trained Cancer Information Specialist is available to answer your questions.
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The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
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For more information from the NCI, please write to this address:
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
Find Publications
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
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.
This summary was comprehensively reviewed and extensively revised.
About PDQ
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This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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