This chapter is dedicated in memory of James B. Nachman, MD.
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and adolescence, with approximately 3500 new cases diagnosed annually in North America in patients 21 years of age and younger. ALL is defined as the presence of 25% or more malignant lymphoblasts (“blasts”) in the bone marrow. The diagnosis of ALL is often initially suspected by the presence of circulating blasts in the peripheral blood that often occurs in the setting of concomitant anemia and thrombocytopenia. Leukemia cells may also infiltrate extramedullary sites (eg, central nervous system [CNS], testes, lymphatic system, solid organs). Patients with extramedullary lymphoid masses, but less than 25% blasts in the bone marrow, are considered to have lymphoblastic lymphoma. ALL may arise from precursor B cells (B-ALL) or T cells (T-ALL).
The incidence of childhood ALL peaks between 2 and 3 years of age (Table 445-1) and is slightly more common in males than females. The incidence of leukemia is substantially higher in white children compared to black children, with the highest rates in children of Hispanic ethnicity. With the exception of Down syndrome and rare familial leukemia predisposition syndromes, causal factors of childhood ALL remain largely unknown. Epidemiologic studies have also investigated various environmental factors (eg, viral infections, parental smoking, living near power lines) potentially associated with increased risk of childhood ALL, although definitive associations have not been proven. Exposure to very high doses of ionizing radiation, chemicals such as benzene, and certain chemotherapies have been associated with an increased risk of acute myeloid leukemia (AML), but not ALL.
TABLE 445-1DEMOGRAPHICS OF CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA ||Download (.pdf) TABLE 445-1DEMOGRAPHICS OF CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA
|Feature ||% |
|B Lineage ||80% |
|T Lineage ||15% |
|Other ||5% |
|Male ||59% |
|Female ||41% |
|< 1 y ||2% |
|1–9 y ||75% |
|> 10 y ||23% |
|White ||75% |
|Hispanic ||14% |
|Black ||7% |
|Other ||4% |
|White Cell Count at Diagnosis |
|< 50,000/µL ||77% |
|50,000–100,000/µL ||10% |
|> 100,000/µL ||13% |
Remarkable progress has been made in the treatment of children with ALL during the past 6 decades. This success is largely attributable to improved understanding of key biologic and genetic features of childhood ALL that has informed risk stratification of patients, as well as to appropriate therapeutic intensification for children with high-risk disease. Enhanced supportive care has also decreased morbidity and mortality and contributed to improved outcomes. In the 1960s, fewer than 10% of children with ALL were cured. In 2016, more than 90% of all children with newly diagnosed ALL can be cured with modern frontline therapy (Fig. 445-1). Relapse-free survival exceeds 95% for a subset of patients with the most favorable genetic features and treatment response. Patients are generally considered cured if they remain in remission more than 5 years from completion of therapy.
Improved outcomes for children with acute lymphoblastic leukemia (ALL) over successive treatment eras.
In normal T- and B-cell development, lymphocyte maturation and differentiation occurs independently of antigenic stimulation. Subsequent interaction of T and B cells with their specific antigens results in lymphocyte proliferation and differentiation, resulting in (1) effector T cells capable of cytotoxicity, cytokine secretion, and B-cell help, (2) long-lived memory T cells for sustained antigen recognition, and (3) plasma cells of B-cell origin involved in antibody secretion.
Eighty percent of cases of childhood ALL are of B-cell lineage, whereas 15% are of T-cell lineage. T-cell ALL comprises 10% of ALL in children ages 1 to 9 years and 20% of ALL in adolescents and young adults. Approximately 98% of B-ALL results from arrest at an immature B-precursor cell stage, which confers a distinct immunophenotype (Fig. 445-2). Rarely, mature B-cell leukemias can occur, which are a form of Burkitt lymphoma and require different treatment (discussed in detail in Chapter 447). The various stages of B-cell development cannot be judged by cell morphology but require classification by patterns of cell surface antigen expression. The earliest stage in B-cell development is the pro-B cell, which is characterized by surface expression of the histocompatibility complex HLA-DR, lack of CD10 (CALLA, common ALL antigen), and lack of cytoplasmic immunoglobulins. The slightly more mature pre-B cell expresses cytoplasmic immunoglobulin and may or may not express CD10. Most childhood ALL arises from pre-B cells, while the pro-B immunophenotype is most often seen in infants with ALL (Fig. 445-2). In T-ALL, cases are evenly distributed among the early, mid, and late thymocyte states classified by the presence or absence of various T-cell antigens, including CD2, CD4, CD5, CD7, CD8, and cytoplasmic CD3. Rarely, ALL cases may show a mixed phenotype (most commonly T/myeloid or B/myeloid) or a natural killer cell immunophenotype.
Childhood acute lymphoblastic leukemia (ALL) pathogenesis. HSC, hematopoietic stem cell.
Many leukemia-associated somatic alterations are prognostic with respect to clinical outcomes (Table 445-2). Characterization of the cytogenetics and other molecular mutations within ALL cells are thus important factors for assignment of patients to appropriately intensive therapy. To determine cytogenetic abnormalities in childhood ALL, chromosomal metaphase preparations of leukemic cells (“spreads”) are analyzed to identify potential abnormalities in chromosome number and structure. It is now well known that certain genetic abnormalities cannot be detected by routine cytogenetic analysis. An additional cytogenetic assay called fluorescent in situ hybridization (FISH) uses dye-conjugated probes to identify specific chromosomal losses, gains, or translocations (rearrangement or exchange of genetic material between nonhomologous chromosomes) within leukemic cell spreads. Newer molecular assays using DNA- or RNA-based array and sequencing technologies can now also identify cytogenetically cryptic point mutations or gene fusions, many of which have prognostic significance and therapeutic implications.
TABLE 445-2PROGNOSTIC FACTORS IN CHILDHOOD B-ALL ||Download (.pdf) TABLE 445-2PROGNOSTIC FACTORS IN CHILDHOOD B-ALL
|I. Initial Risk Groups |
| A. NCI standard risk: ||1–9 years and < 50,000/μL presenting WBC |
| ||No central nervous system or testicular disease |
| B. NCI high risk: ||≥ 10 years OR ≥ 50,000/μL presenting WBC |
|II. Blast Cytogenetics |
| A. Favorable: ||t(12;21) (ETV6-RUNX1) |
| ||Hyperdiploidy with +4, +10 |
| B. Neutral: ||Other or normal |
| C. Unfavorable: ||t(9;22) translocation (BCR-ABL1) |
| ||Hypodiploidy < 44 chromosomes |
| ||KMT2A (MLL) rearrangements |
| ||iAMP21 |
|III. Early Treatment Response |
| A. Rapid response: ||< 0.01% marrow MRD on day 29 induction |
| B. Slow response: ||≥ 1% blood MRD on day 8 induction, if NCI standard risk |
| ||≥ 0.01% marrow MRD on day 29 induction |
Most cases of B-ALL have detectable chromosomal abnormalities by either standard cytogenetic or molecular techniques. These abnormalities may include gains or losses of whole chromosomes, structural abnormalities involving individual chromosomes, or translocations involving 2 or more chromosomes. The 2 most common genetic aberrations in childhood B-lineage ALL are (1) hyperdiploidy (usually 51–67 chromosomes) and (2) translocation between chromosomes 12 and 21 that results in ETV6-RUNX1 fusion. High hyperdiploidy and t(12;21) each comprise 20% to 25% of alterations in younger children with B-ALL. Both abnormalities are most common in children 1 to 9 years of age and are associated with a good prognosis. Hypodiploidy (< 44 chromosomes) occurs rarely in childhood ALL, although this subtype is associated with a poor prognosis. Survival analyses have further demonstrated increasingly inferior survival with increasing chromosomal loss; worse outcomes occur for children with near-haploid (24–31 chromosomes) or low hypodiploid (32–39 chromosomes) ALL.
Translocation between chromosomes 9 and 22 resulting in BCR-ABL1 fusion (the Philadelphia chromosome) is another uncommon genetic abnormality (occurring in 3–4% of childhood B-ALL) that was historically associated with a very poor prognosis prior to addition of tyrosine kinase inhibitor therapy (discussed below). The incidence of Philadelphia chromosome-positive (Ph+) ALL increases during adolescence and accounts for a major subset of adult ALL.
A new subtype of B-ALL known as BCR-ABL1–like or Philadelphia chromosome–like (Ph-like) was recently identified. Ph-like ALL is characterized by an activated kinase gene expression profile similar to that observed in Ph+ ALL, although the BCR-ABL1 fusion is not present. The Ph-like subset comprises 10% to 20% of B-ALL occurring in children and adolescents and is associated with a variety of genetic alterations that activate kinase signaling. Children with Ph-like ALL have poor clinical outcomes when treated with standard chemotherapy, but these leukemias may be amenable to treatment with the addition of kinase inhibitors (discussed below), similar to the approach now taken in Ph+ ALL.
Another common translocation in childhood B-ALL is between chromosomes 1 and 19, which results in TCF3-PBX1 fusion. Although the t(1;19) was historically associated with intermediate outcomes, it is no longer considered prognostic in the era of modern risk-based chemotherapy. Another recurrent translocation involves rearrangement of KMT2A (formerly MLL) on the long arm of chromosome 11 (at 11q23) with 1 of more than 75 known gene partners. KMT2A-rearranged ALL occurs in approximately 75% of infants less than 1 year of age and carries an extremely poor prognosis even with intensive chemotherapy. The incidence of KMT2A-rearranged ALL is much lower in noninfants, accounting for 5% to 6% of B-ALL cases occurring in children and adolescents. While older children with KMT2A-rearranged ALL do not fare quite as poorly as infants, they are treated as high risk with more intensive chemotherapy, given their inferior outcomes. Finally, intrachromosomal amplification of part of chromosome 21 (iAMP21) occurs in approximately 2% of children with B-ALL. This genetic alteration is also considered high risk, and children with iAMP21 ALL are also treated more intensively. Other less common recurrent genetic abnormalities also occur in childhood B-ALL, some of which have prognostic significance.
In T-ALL, it is uncommon to detect leukemia-associated abnormalities based on routine cytogenetic analyses. However, FISH and other molecular testing often reveal recurrent abnormalities. For example, mutations in NOTCH1 occur in approximately 50% of cases of childhood T-ALL and appear to be associated with more favorable prognoses. The prognostic significance of most recurrent alterations in T-ALL remains unknown, however, so they are not presently used for risk stratification.
In many cases of childhood ALL, production of the various types of blood cells other than lymphocytes is seriously impaired. Children may present with decreased hemoglobin and hematocrit (anemia), manifesting as pallor or fatigue. Decreased platelets (thrombocytopenia) can lead to bruising and spontaneous bleeding. Low white blood cell (WBC) counts can lead to serious bacterial, fungal, or viral infections manifesting with fever, particularly in the context of prolonged neutropenia or lymphopenia. The triad of fever, pallor, and bruising is a common presentation of ALL, particularly in younger children. Some children also initially present with bone pain or refusal to walk due to leukemic infiltration of the bone marrow. Many patients with ALL present with palpable lymphadenopathy, hepatomegaly, or splenomegaly due to infiltration of organs by leukemic blasts. Children and adolescents with ALL less commonly present with respiratory compromise due to the presence of a large anterior mediastinal mass, which is more common in patients with T-ALL. Large mediastinal masses causing respiratory distress are considered a medical emergency and often require immediate intervention. The presence of lytic bone lesions diagnosed by radiography or magnetic resonance imaging (MRI) is another rare presentation of ALL. Prior to performing a biopsy of a lytic bone lesion, a complete blood count and a careful review of the peripheral blood smear should be performed.
Many patients with ALL have evidence of circulating blasts that can be seen on a peripheral blood smear, but the specific diagnosis must be made by flow cytometry analysis. ALL blasts are characterized by a high nuclear-to-cytoplasmic ratio, clumpy nuclear chromatin, and few small nucleoli. Even if peripheral blasts are present, performing a bone marrow aspiration is highly recommended to obtain optimal leukemia specimens for flow cytometric determination of immunophenotype, cytogenetic and FISH analyses, as well as other molecular genetic testing. Classification of leukemia immunophenotype and specific cytogenetic translocations are necessary for the risk stratification and treatment of childhood ALL. Most cases of childhood ALL are of B-cell or T-cell origin that can be readily identified by flow cytometric delineation of specific cell surface antigens. However, both B-ALL and T-ALL may rarely have aberrant concomitant expression of myeloid antigens consistent with mixed phenotype acute leukemia, which can be a diagnostic dilemma and is generally associated with an inferior treatment response.
As part of the routine diagnostic evaluation, a lumbar puncture (LP) should be performed to assess whether blasts are present in the cerebrospinal fluid (CSF). Ideally, the initial LP (or spinal tap) should be performed by an experienced physician using sedation for younger patients to minimize the possibility of a traumatic tap that may alter proper risk stratification. Patients with < 5 WBCs per μL in CSF and no evidence of microscopic ALL involvement on a cytocentrifuged (cytospin) specimen are classified as CNS negative (CNS 1). In a nontraumatic LP, the presence of ≥ 5 WBC/μL in the CSF and the presence of leukemic blasts on cytospin are needed to make a diagnosis of overt CNS involvement (CNS 3). Patients with < 5 WBC/μL in the CSF, but with detectable leukemic blasts on cytospin, are classified as CNS 2. Patients who present with neurologic dysfunction (eg, cranial neuropathies, altered mental status, back pain) should undergo brain or spine computed tomography (CT) or MRI prior to an LP to assess potential CNS infiltration with leukemia and to ensure safety in performing the procedure. Rarely, patients can present with retinal hemorrhages or with vision changes due to leukemic infiltration of the optic nerves. Any patient with ocular symptoms should also be evaluated immediately by formal ophthalmologic exam and MRI of the brain and orbits. Urgent radiotherapy can preserve vision in some patients with acute-onset vision loss and optic nerve infiltration with leukemia. Testicular examination to assess for masses and asymmetry should be performed in all males at diagnosis and during therapy as testicular infiltration with leukemia may occur, more commonly at relapse than at diagnosis. Testicular biopsy is indicated in boys with suspected testicular involvement if the findings persist after the first course of therapy. If confirmed, testicular radiotherapy may be incorporated into the treatment plan.
A number of prognostic factors are utilized for risk stratification of patients and allocation to treatment of appropriate intensity (Table 445-2). Prognostic factors can generally be divided into 3 groups: (1) host-related factors, (2) disease-related factors, and (3) treatment response factors.
Age is an important prognostic factor in childhood B-ALL. Generally, children ages 1 to 9 years have better prognoses and outcomes than those younger than 1 year or older than 10 years of age at time of diagnosis. This difference is in part related to the significantly higher incidence of favorable cytogenetic subtypes of ALL (eg, hyperdiploidy, ETV6-RUNX1 translocation) that comprise 50% to 60% of recurrent genetic alterations in B-ALL in younger children. As previously mentioned, infants less than 1 year of age with KMT2A-rearranged ALL have inferior clinical outcomes.
Presenting WBC count is another important prognostic factor in B-ALL. Many pediatric oncology consortia utilize a cutoff of 50,000 WBC/μL at diagnosis to determine risk group assignment. Extreme hyperleukocytosis (WBC > 200,000/μL) is often associated with unfavorable leukemia cytogenetics and generally portends a poorer clinical prognosis. Overt CNS involvement of leukemia is a less favorable prognostic factor, and testicular involvement with leukemia in males is also considered high risk.
The combination of age and WBC is currently used for initial risk group allocation in patients with B-ALL. Standard risk B-ALL is defined as age > 1 and < 10 years and a WBC of < 50,000/μL, while high-risk B-ALL is defined as age ≥ 10 years and/or initial WBC ≥ 50,000/μL. Children with CNS positivity (CNS 3) are also generally considered high risk. Hepatosplenomegaly and other extramedullary involvement at diagnosis have no independent prognostic significance.
Race and ethnicity have been evaluated as prognostic factors in many studies, but are not considered prognostic with modern anti-ALL therapy. However, emerging data demonstrate that specific genetic variations and mutations that confer increased chemosensitivity or are associated with increased toxicity are more common in certain racial and ethnic groups of patients.
In the past, pretherapy factors such as age, initial WBC count, and blast cytogenetics were used to determine risk group and treatment assignment. However, rapidity of response to induction chemotherapy is now recognized as the most important factor determining clinical outcome. Several large clinical trials have demonstrated that children who achieve remission with no detectable minimal residual disease (MRD) at the end of induction therapy have significantly better outcomes compared to those with higher levels of MRD. Therefore, children with ALL are currently assigned to an initial induction treatment based on age, WBC count, and immunophenotype. Treatment is subsequently modified at the end of induction based on depth of achieved remission (as measured by MRD) and by leukemia-associated genetic results (Fig. 445-3).
Current Children’s Oncology Group risk algorithm for postinduction treatment assignment in children with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL). Infants and children with T-cell ALL (T-ALL) are risk classified and treated on separate regimens. MRD, minimal residual disease; NCI, National Cancer Institute.
In some studies, the morphologic response in the peripheral blood following a 7-day treatment prophase with prednisone alone and a single dose of intrathecal chemotherapy has demonstrated prognostic significance. Patients with fewer than 1000 blasts/μL in peripheral blood on day 8 had a cure rate greater than 70%, whereas patients with greater than 1000 blasts/μL had a cure rate of approximately 30%. Historically, patients with 25% or greater blasts in the bone marrow on day 8 of induction therapy (“slow early response,” or SER) also had a significantly worse prognosis compared to patients with less than 25% blasts on the day 8 bone marrow evaluation. Subsequent treatment of SER patients with more aggressive treatment strategies has resulted in improved outcomes in some studies.
Morphologic assessment of response by light microscopic examination of post-treatment bone marrow tissue remains an imprecise technique, as it reliably allows detection of only relatively high levels of residual ALL. Newer, more sensitive genetic- and flow cytometry–based MRD assays are capable of detecting submicroscopic amounts of residual leukemia. Because ALL is a malignant clonal disorder, each cell in the clone has a unique immunoglobulin gene rearrangement. This rearrangement can be identified by polymerase chain reaction (PCR) and sequenced to determine the percentage of cells in peripheral blood or marrow with the unique leukemia-associated rearrangement. Polymerase chain reaction–based MRD techniques have a sensitivity of 0.01%, meaning that such assays can identify 1 ALL cell among 10,000 normal cells. In addition, most ALL cells have unique immunophenotypes that can be distinguished from normal B or T cells by flow cytometry. Flow cytometric MRD analyses also have a sensitivity of approximately 1 in 10,000 cells (0.01%). Regardless of the detection assay used, patients with high levels of MRD at the end of induction therapy have worse outcomes than those patients with very low or undetectable levels. New assays using next-generation sequencing technologies are currently in clinical development and have demonstrated even greater sensitivity for MRD detection in childhood ALL.
With rare exception, emergent treatment with chemotherapy is not necessary and may actually be contraindicated. Patients often present with severe metabolic abnormalities, hematologic abnormalities, or infectious complications that must be adequately managed before antileukemia treatment can be safely initiated. Initial assessment of the newly diagnosed patient should begin with a careful determination of the vital signs. A patient with ALL and a large mediastinal mass may present with respiratory distress due to tracheal compression; if untreated, this can progress to respiratory arrest. Sedation of such patients carries a significant risk of cardiac arrest due to impediment of venous blood return to the heart. Many patients with ALL will present with fever that is commonly associated with neutropenia (absolute neutrophil count < 500/μL), which puts them at high risk for bacterial sepsis. In patients with fever and neutropenia, broad-spectrum antibiotic coverage should be promptly initiated after blood and any other clinically indicated cultures are obtained.
Tumor lysis syndrome (TLS) refers to the release of intracellular by-products from leukemic cells, including uric acid and phosphorus. Patients with ALL and high WBC counts or large extramedullary masses often present with an elevated blood uric acid level. In rare cases, patients may present with significant renal compromise due to uric acid nephropathy. In any patient with ALL and an initial high uric acid level, renal function (serum creatinine) should be carefully assessed, and medications such as allopurinol should be started to lower the uric acid level. Even if uric acid levels are initially normal, they may rise to high levels as chemotherapy is initiated and leukemia cells break down. All patients should thus receive therapy to prevent the development of uric acid nephropathy even if uric acid levels are not elevated at presentation. For patients with high tumor burdens and/or hyperuricemia, use of rasburicase (urate oxidase) is recommended instead of allopurinol. Rasburicase degrades uric acid to harmless metabolites, and blood levels of uric acid fall precipitously following a single dose. Short-term dialysis may rarely be required for patients with renal dysfunction who do not show rapid improvement in renal function with intravenous fluid hyperhydration, and initiation of allopurinol or rasburicase. Serum phosphate levels, although rarely significantly elevated at diagnosis, may rise as treatment is initiated. This hyperphosphatemia can lead to hypocalcemia and precipitation of calcium phosphate in the renal tubules. Addition of medications to bind excess phosphorus can be used, such as aluminum hydroxide or sevelamer.
Patients with ALL are often anemic at diagnosis. Development of anemia in ALL is often a chronic process. For severely anemic patients, packed red blood cell (PRBC) transfusions should be approached with caution. Small aliquots of PRBCs can initially be given to raise the hemoglobin concentration to 7 to 8 g/dL. If necessary, a diuretic may be given to control fluid volume. In patients with very high WBC counts, increasing hemoglobin levels beyond 7 to 8 g/dL may significantly increase viscosity and increase risk of thrombosis.
Patients can present with hyperleukocytosis that requires urgent treatment. Extreme leukocytosis (WBC > 200,000/μL) is usually asymptomatic but may be associated with CNS symptoms and/or thrombosis. A diagnosis of leukemia can often be established rapidly by peripheral blood flow cytometry in these circumstances, and treatment with corticosteroids can be initiated to lower the WBC. In these situations, patients should be very carefully monitored for TLS. Leukopheresis can also be performed for temporary reduction of WBC count, but the overall additional efficacy of this procedure remains unknown.
Patients with ALL (most commonly T-ALL) can present with a large anterior mediastinal mass and risk of airway compromise. Sedation and anesthesia should be avoided in such situations. Initiation of steroid therapy will generally shrink the mass rapidly, but may increase the risk for TLS. Low-dose radiation to a small field around the airway can also be considered. Following the initiation of radiation, significant improvement in respiratory status is usually seen within 12 hours.
Ten-year overall survival rates now exceed 90% for childhood ALL (see Fig. 445-1). This remarkable success can be attributed to several fundamental observations and principles from early treatment eras that have continued to provide the foundation for contemporary therapy. One of the first essential observations from early treatment eras was the recognition that cure requires the sustained delivery of therapy beyond an initial remission. Additional advances have included (1) the establishment of the efficacy of combination chemotherapy, (2) the recognition of the critical need for presymptomatic treatment of the CNS sanctuary site, and (3) the value of later intensification of therapy to eradicate remaining residual disease, especially among children with slow initial treatment responses. More recently, risk-directed treatment approaches have been adopted and refined.
Modern treatment for childhood ALL consists of multiagent chemotherapy administered in several phases: induction, consolidation, intensification, and maintenance phases of therapy (Table 445-3). The induction phase of treatment generally lasts 1 month, and over 95% of children achieve a remission at the end of this phase. The next phases of treatment (consolidation and intensification) are designed to intensify systemic and CNS-directed therapy to eradicate any residual disease. The final and longest phase of treatment (maintenance) is designed to prevent disease recurrence. In general, treatment is 2 to 3 years in duration. Some earlier ALL studies treated boys for longer than girls because male gender was associated with inferior outcomes. Treatment duration is now the same for boys and girls, as contemporary regimens have abrogated the prognostic impact of male gender.
TABLE 445-3COMPARISON OF STANDARD THERAPY, BFM THERAPY, AND AUGMENTED BFM THERAPY FOR ACUTE LYMPHOBLASTIC LEUKEMIA ||Download (.pdf) TABLE 445-3COMPARISON OF STANDARD THERAPY, BFM THERAPY, AND AUGMENTED BFM THERAPY FOR ACUTE LYMPHOBLASTIC LEUKEMIA
Among children with newly diagnosed ALL, specific treatment approaches have generally been developed based on immunophenotype (B-ALL vs T-ALL) and age (infants < 1 year of age vs older children). Unique genetic subtypes of ALL, such as Ph+ ALL, are treated with separate regimens that include a tyrosine kinase inhibitor. Several studies have now shown that outcomes are improved for adolescents and young adults treated with pediatric protocol-inspired regimens. Accordingly, many “pediatric” ALL clinical trials now treat patients up to 30 years of age.
In an ongoing effort to reduce the risk for late treatment effects, there has been a growing trend to minimize the use of cranial radiotherapy. CNS prophylaxis for the majority of children now consists of intrathecal chemotherapy and systemic agents that penetrate the CNS, such as dexamethasone and high-dose methotrexate. Radiotherapy tends to be limited to those children who have CNS 3 leukemic involvement at diagnosis. Some treating groups, however, have eliminated the use of radiotherapy entirely.
The current paradigm for systemic treatment of patients with B-ALL begins by assigning patients to either a standard or a high-risk group based on age and initial WBC count. Within the Children’s Oncology Group (COG), children ages 1 to 9 years who have an initial WBC count of less than 50,000/μL are assigned to a standard risk group and receive a 3-drug induction that includes vincristine, asparaginase, and dexamethasone. All other patients are considered high risk and receive a 4-drug induction that also includes an anthracycline such as daunomycin. High-risk patients ages 1 to 9 years have been shown to benefit from dexamethasone as the induction steroid, whereas older patients have not derived the same benefit and receive prednisone.
Patients are reclassified at the end of induction based on their initial risk group, blast cytogenetics, and early response as assessed by flow cytometric or PCR-based measurement of MRD during and at the end of induction (Fig. 445-3). Patients with hypodiploidy (< 44 chromosomes in the blast population) are considered very high risk regardless of initial risk group or early response and often undergo hematopoietic stem cell transplantation (HSCT) in first remission. Patients with Ph+ ALL receive a tyrosine kinase inhibitor, which inhibits the BCR-ABL1 fusion protein, in conjunction with intensive chemotherapy. End-induction MRD is the most significant predictor of outcome, and patients who have MRD ≥ 0.01% are treated more intensively following induction. Patients with rapid responses and MRD < 0.01% at the end of induction are assigned to treatment regimens based on initial risk group and blast cytogenetics. Standard-risk rapid responders with either the ETV6-RUNX1 translocation or hyperdiploidy with extra copies of chromosomes 4 and 10 and no extramedullary disease have a projected event-free survival (EFS) of greater than 95% and are treated with a lower-risk regimen with less exposure to anthracyclines and no exposure to cyclophosphamide.
Several advances have been made in the treatment of standard-risk B-ALL patients, and their 5-year EFS now exceeds 90%. Survival rates approaching 100% are observed in certain very favorable low-risk subsets, including standard-risk patients with favorable cytogenetics and rapid MRD responses. For standard-risk patients who are MRD positive at the end of induction, improved outcomes can be achieved with intensification of postinduction therapy.
A recent trial for children with high-risk ALL compared dexamethasone to prednisone during the induction phase of treatment and high-dose methotrexate to escalating lower doses of intravenous methotrexate without leucovorin rescue in interim maintenance and demonstrated the superiority of high-dose methotrexate among all age groups. The superiority of dexamethasone for 14 days during induction was also observed in high-risk patients less than 10 years of age. This modified augmented Berlin-Frankfurt-MÜnster (BFM) treatment regimen has now become a standard in COG high-risk ALL protocols. The prognostic role of MRD response has also been further defined. Persistent MRD on day 29 of induction is the most robust prognostic factor, but later time point MRD also significantly influences prognosis such that patients who are MRD positive at the end of induction, but achieve MRD negativity at the end of consolidation or its equivalent, have favorable outcomes with EFS of approximately 80%. In contrast, patients with MRD ≥ 0.01% at the end of consolidation fare quite poorly, with estimated EFS rates of 39%. Many treating groups consider HSCT or alternative treatment approaches after remission is achieved for these patients.
Infants less than 1 year of age with ALL pose a unique challenge. The majority of patients less than 6 months of age have KMT2A (formerly MLL) gene rearrangements, most commonly a translocation between chromosomes 4 and 11, and have poor outcomes. Infants without KMT2A gene rearrangements have a significantly better outcome. Currently, infants with ALL are treated with intensive chemotherapy for 2 years. Benefits for HSCT have not been established, and current trials are focusing on the inclusion of targeted therapy directed at the unique biological pathway activation in this subtype of ALL, including epigenetic modulators.
Substantial recent advances have also occurred in the treatment of T-ALL. Whereas T-ALL has historically been more challenging to treat, outcomes now approach those observed in B-lineage disease with several international treating consortia reporting overall survival rates of approximately 90%. Intensive therapy, very similar to that employed in high-risk B-ALL, is required to achieve cure, and recent clinical trials are investigating new agents targeting unique underlying biological pathways. Recent trials have also demonstrated that, like B-ALL, cranial radiation can be safely eliminated in the majority of patients. The superiority of dexamethasone versus prednisone in reducing relapse risk has also been demonstrated. The kinetic pattern of disease regression is unique in T-ALL with slower initial responses. Similar to B-ALL, the persistence of MRD at the end of consolidation is a negative prognostic factor and an indication for treatment intensification. Unlike B-ALL, presenting WBC count is not prognostically significant in T-ALL, so children receive a common high-risk 4-drug induction regardless of initial WBC or age at diagnosis.
While most children with ALL are now cured, relapses may occur in favorable-risk patients and are often unpredictable. The current focus in ALL therapy has therefore centered upon further refining risk prediction. Comprehensive genomic analyses have been pivotal in this regard and have identified new subtypes of ALL, such as Ph-like ALL, where targeted agents are being introduced in an effort to improve cure rates. Efforts to further optimize the delivery of standard chemotherapy agents and to introduce promising new immunotherapeutic agents for these children who are at the highest risk for disease recurrence are presently underway. Finally, for rare leukemia subtypes, such as Ph+ ALL and infant ALL, international collaborations to address the unique challenges among these populations are in progress.
Despite numerous advances in the treatment and supportive care for children with ALL, 2% to 3% will die of infectious or other toxic complications, 1% will develop a second malignant neoplasm, and 10% to 15% will relapse. Recurrent or relapsed ALL remains a significant challenge, as fewer than 50% of patients will survive long term. Relapse can occur in the bone marrow or extramedullary sites, with CNS and testes being most common, or in both locations. The most important prognostic factors for recurrent ALL are the site and timing of the recurrence relative to the initial diagnosis. In general, isolated bone marrow relapse carries a worse prognosis compared to extramedullary or combined relapse. Early relapse (< 36 months from initial diagnosis) has a worse outcome than late relapse. Relapses of T-ALL are particularly challenging to treat and have very few long-term survivors.
The general treatment strategy for early isolated or combined bone marrow and extramedullary relapse is to reinduce remission with intensive chemotherapy. Once remission is achieved, allogeneic HSCT is generally recommended for early marrow relapses as this has been shown to increase chances of cure when compared to ongoing treatment with chemotherapy alone. Late isolated extramedullary relapse carries a more favorable prognosis and is generally treated with chemotherapy and local therapy (treatment directed to the extramedullary site). Treatment for late bone marrow and early extramedullary relapse varies, and most cooperative groups utilize early MRD response to determine whether to continue intensive chemotherapy alone or to pursue allogeneic HSCT after a second remission is achieved.
Current intensive therapy regimens have reached the limit of tolerability with or without HSCT for children with relapsed ALL, and further improvements in outcomes are likely not possible without development of new treatment approaches. Several new promising immunotherapeutic agents have thus been developed in recent years. Monoclonal antibody therapies (some conjugated to drug toxins) directed against leukemic cell surface antigens have shown promising early results. Bi-specific T-cell–engaging (BiTE) antibodies that simultaneously target a cell surface antigen on leukemic blasts and a target antigen on cytotoxic T cells have also been developed. This bridging effect facilitates more direct contact of effector T cells to kill leukemia cells. Similarly, chimeric antigen receptor (CAR) T-cell therapy has been developed where autologous T cells are harvested and engineered to express a chimeric receptor targeting leukemic cell surface antigens. Very promising initial response rates of 90% have been observed with CD19-redirected CAR T-cell therapy in children with relapsed or refractory B-ALL, but the long-term success of such therapies is not yet known. These and other new immunotherapies are under active investigation in clinical trials in children with relapsed and refractory B-ALL.
COMPLICATIONS AND LATE EFFECTS
Survival rates for children with newly-diagnosed ALL now exceed 90%. However, this achievement requires 2 to 3 years of intensive chemotherapy, which can come at a significant cost in terms of acute and long-term toxicities. There are many ongoing efforts to better understand the spectrum of acute and late treatment-related effects of therapy and to improve the quality of ALL survivorship.
Infectious complications are the most common acute toxicities in children undergoing ALL therapy and the most common cause of treatment-related deaths. During treatment, patients with ALL often have extremely low lymphocyte counts and are at risk for pulmonary or disseminated infection with Pneumocystis jirovecii (formerly Pneumocystis carinii), which can be fatal. All patients with ALL thus receive prophylactic trimethoprim/sulfamethoxazole therapy 2 to 3 days per week. Supportive care guidelines routinely include surveillance for infection during all phases of treatment with prompt initiation of broad-spectrum antimicrobial therapy for fever and neutropenia. Such guidelines and treatment modifications have been developed to minimize the risk for infectious complications among the most vulnerable ALL populations, including infants and children with Down syndrome.
One of the most significant causes of acute and long-term morbidity in patients undergoing ALL therapy is osteonecrosis, occurring in 1% to 2% of young children and up to 15% to 20% of adolescents. Osteonecrosis is disabling in many children and most commonly affects weight-bearing joints. It frequently occurs in multiple joints and requires surgical intervention in more than 25% of cases. While the onset of osteonecrosis is typically during treatment, symptoms can persist long-term. Risk factors for osteonecrosis include steroid exposure (especially dexamethasone), adolescent age, female sex, and high body mass index. Recently, several host genetic polymorphisms in a diversity of biological pathways have been linked to a higher risk of osteonecrosis. Results from a recently completed COG trial for high-risk ALL suggest that alternate week dosing of dexamethasone is 1 successful strategy to reduce the risk of osteonecrosis, while preserving treatment efficacy. Other studies are assessing potential contribution of other common ALL agents, such as methotrexate and asparaginase, to development of osteonecrosis.
Cardiac late effects from anthracyclines can be observed in ALL survivors and have been the focus of many recent studies. Contemporary ALL protocols have limited the cumulative exposure to anthracyclines compared to past regimens; however, even lower exposures can lead to asymptomatic echocardiographic changes. One successful strategy to mitigate these effects has been use of the cardioprotectant dexrazoxane, which is an iron-chelating agent designed to prevent free radical formation. This agent has been shown to protect children from anthracycline-related heart damage without compromising the effectiveness of ALL therapy or increasing the risk for secondary leukemia.
One of the most significant concerns about ALL therapy is the short- and long-term impact on neurocognitive outcomes. Early treatment regimens in the 1970s and 1980s commonly included higher doses (24 Gy or higher) of cranial radiotherapy, which has been associated with a risk for secondary brain tumors, decline in cognitive functioning, and endocrinopathies. Cranial radiation is now delivered at much lower doses (12–18 Gy) on contemporary treatment regimens, and radiotherapy has been eliminated altogether in the vast majority of children. This has raised the question of late neurocognitive outcomes among children treated with systemic and intrathecal chemotherapy alone. Most studies have shown that, while the toxicities are fewer than observed with higher doses of cranial radiation, late effects still occur. Recent studies have shown, for example, that children who have been exposed to intrathecal chemotherapy and higher doses of methotrexate are at risk for attention problems and impairment in executive functioning, although their intelligence is generally unchanged from that of the general population. As the number of adult long-term survivors of childhood ALL continues to increase, concerted efforts to minimize the risk for treatment-related complications and late effects are underway.
It is an exciting time in the treatment of childhood ALL with several major recent advances in the understanding of disease biology and host determinants of response, toxicity profiles, and outcomes. Breakthroughs in the genomic characterization of disease, coupled with the development of new targeted medications, have fostered the development of new precision medicine approaches for several ALL subtypes. Refinements in risk classification and MRD assessment have now identified subgroups of favorable risk patients who have outstanding chances for cure with less toxic regimens. While relapsed leukemia remains a significant challenge, several new immunotherapeutic treatment approaches have been developed, and active investigation to understand the longer-term impact of these therapies is ongoing. Finally, as survival rates now exceed 90% for children with ALL, dedicated efforts are in progress to reduce the risk for treatment-related long-term effects and to improve the quality of ALL survivorship.
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