Pediatric Acute Lymphoblastic Leukemia 

Updated: Jan 03, 2019
Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Jennifer Reikes Willert, MD 

Overview

Practice Essentials

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing more than a quarter of all pediatric cancers. The image below depicts bone marrow aspirate from a child with T-cell acute lymphoblastic leukemia.

Bone marrow aspirate from a child with T-cell acut Bone marrow aspirate from a child with T-cell acute lymphoblastic leukemia. The marrow is replaced with lymphoblasts of various sizes. No myeloid or erythroid precursors are seen. Megakaryocytes are absent.

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.

Also, see the Childhood Acute Lymphoblastic Leukemia: Diagnosis, Management, and Complications slideshow to help recognize and treat this disease and its associated complications.

Signs and symptoms

Children with acute lymphoblastic leukemia (ALL) often present with signs and symptoms that reflect bone marrow infiltration and/or extramedullary disease. When leukemic blasts replace the bone marrow, patients present with signs of bone marrow failure, including anemia, thrombocytopenia, and neutropenia.

Other presenting signs and symptoms of pediatric ALL include the following:

  • Patients with B-precursor ALL: Bone pain, arthritis, limping; fevers (low or high); neutropenia; fatigue, pallor, petechiae, and bleeding; lymphadenopathy and hepatosplenomegaly

  • Patients with mature-B ALL: Extramedullary masses in the abdomen or head/neck; CNS involvement (eg, headache, vomiting, lethargy, nuchal rigidity)

  • Patients with T-lineage ALL: Respiratory distress/stridor due to a mediastinal mass

Symptoms of CNS involvement are rarely noted at initial diagnosis but are more common in T-lineage and mature B cell ALL.[1] Testicular involvement at diagnosis is also rare; if present, it appears as unilateral painless testicular enlargement.

See Clinical Presentation for more detail.

Diagnosis

Testing

Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary to establish the diagnosis of ALL.

Routine laboratory studies in pediatric ALL include the following:

  • CBC count

  • Peripheral blood smear

  • Serum chemistries (eg, potassium, phosphorus, calcium)

  • Uric acid level

  • LDH level

  • Coagulation studies, such as PT, aPTT, levels of fibrinogen and D-dimer

Laboratory tests that help classify the type of ALL include the following:

  • Immunophenotyping - To detect surface immunoglobulin on leukemic blasts (diagnosis of mature B-cell leukemia) or the expression of T-cell–associated surface antigens (diagnosis of T-lineage ALL)

  • Cytogenetic studies - To identify specific genetic alterations in leukemic blasts

  • Molecular studies (eg, FISH, RT-PCR, Southern blot analysis) - To identify translocations more rapidly and those not detected on routine karyotype analysis; to distinguish lesions that appear cytogenetically identical but are molecularly different

  • Minimal residual disease studies[2] - To detect chimeric transcripts generated by fusion genes, detect clonal TCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or identify a phenotype specific to the leukemic blasts

  • Genome-wide association studies - To detect the presence of genetic changes where routine techniques are unhelpful (eg, activated tyrosine kinase pathways in Ph-like ALL), not in clinical use yet

See Acute Lymphoblastic Leukemia Staging for more complete information.

Imaging studies

No other imaging studies other than chest radiography to evaluate for a mediastinal mass are routinely required in pediatric ALL. However, the following radiologic studies can be helpful:

  • Ultrasonography: To evaluate for testicular infiltration in boys with enlarged testes; to evaluate for leukemic kidney involvement as a risk assessment for tumor lysis syndrome

  • ECG, echocardiogram: To identify any preexisting cardiac dysfunction before administration of anthracyclines (baseline studies); to monitor heart function during treatment with anthracyclines

Procedures

  • Lumbar puncture with cytospin morphologic analysis: To assess for CNS involvement before administration of systemic chemotherapy; to administer intrathecal chemotherapy

  • Bone marrow aspiration and biopsy: To confirm the diagnosis of ALL

CNS disease is divided into the following groups:

  • CNS 1: Absence of blasts on CSF cytospin preparation, regardless of the WBC count

  • CNS 2: WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL but negative by Steinherz-Bleyer algorithm findings (if traumatic tap)

  • CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic syndrome)

See Workup for more detail.

Management

Leukemia is a systemic disease, and treatment is primarily based on chemotherapy. However, the different forms of ALL require different approaches for optimal results. Treatment of subclinical CNS leukemia is an essential component of ALL therapy.

Treatment for ALL typically consists of the following phases:

  • Remission-induction phase (eg, dexamethasone or prednisone, vincristine, asparaginase, daunorubicin)

  • Intensification/consolidation phase: The importance of this phase is undisputed, but consensus is scarce on the best regimens and duration of treatment. Current Children's Oncology Group (COG) ALL protocols use a therapeutic backbone that was originally introduced in Berlin-Frankfurt-Muenster (BFM) clinical trials in the 1980s. This includes administration of cytarabine, cyclophosphamide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, 6-thiouguanine, and vincristine.

  • CNS-directed therapy consists of systemic chemotherapy that enters the CSF, as well as intrathecal chemotherapy administered throughout the entire course of treatment, which is primarily MTX but sometimes includes hydrocortisone and cytarabine (“triple-intrathecal therapy”).

  • Continuation therapy targeted at eliminating residual disease (eg, MTX, 6-MP, vincristine and glucocorticoid pulses)

Pharmacotherapy

Medications used in the treatment of pediatric ALL include the following:

  • Antineoplastics (eg, vincristine, asparaginase Escherichia coli, asparaginase Erwinia chrysanthemi, calaspargase pegol, daunorubicin, doxorubicin, MTX, 6-MP, cytarabine, cyclophosphamide, dasatinib, imatinib)

  • Corticosteroids (eg, prednisone, dexamethasone)

  • Antimicrobials (eg, TMX/SMP, pentamidine)

  • Antifungals (eg, fluconazole)

Treatment of T-cell ALL may benefit from high dose methotrexate and the addition of nelarabine, but clinical trial data regarding these two interventions is still pending. Mature B-cell ALL needs to be treated in the same way as disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose MTX, cytarabine, and cyclophosphamide over a 6-month period.

Blood transfusions or antibiotics may be required to deal with complications of ALL therapy. Do not administer folate supplementation owing to interactions with MTX.

Nonpharmacologic therapy

Other treatments involved in managing pediatric ALL may include the following:

  • Initial administration of IV fluids: Without potassium, with or without sodium bicarbonate

  • Cranial irradiation: Effectively prevents overt CNS relapse but potentially causes neurotoxicity and brain tumors; largely replaced by intensive intrathecal and systemic chemotherapy

  • Allogeneic HSCT (hematopoietic stem cell transplant): Usually following second complete remission after relapse (if early) or first remission in high risk patients; potentially prevents relapse and/or mortality vs chemotherapy alone.

Surgical options

In generally, surgical care is not required in the treatment of ALL. However, placement of a central venous catheter is needed for administering chemotherapy, blood products, and antibiotics, as well as for obtaining blood samples.

See Treatment and Medication for more detail.

Background

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children, representing one quarter of all pediatric cancers. The annual incidence of acute lymphoblastic leukemia within the United States is 3.7-4.9 cases per 100,000 children age 0-14 years,[3] with a peak incidence in children aged 2-5 years.

Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.[4]

With improvements in diagnosis and treatment, overall cure rates for children with acute lymphoblastic leukemia have reached 90%.[5] The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity of therapy. This article summarizes the current diagnosis and treatment of childhood acute lymphoblastic leukemia.

Pathophysiology

In acute lymphoblastic leukemia (ALL), a lymphoid progenitor cell becomes genetically altered and subsequently undergoes dysregulated proliferation, with clonal expansion. In ALL, the transformed lymphoid cells reflect the altered expression of genes usually involved in the normal development of B cells and T cells. Several studies indicate that leukemic stem cells are present in certain types of ALL.

Epidemiology

Annually, around 3000 children in the United States are diagnosed with ALL. The annual incidence of ALL within the United States is 3.7-4.9 cases per 100,000 children 0-14 years of age[3] with a similar estimated worldwide incidence, although it has been questioned whether the incidence may be less in low-income countries.[6] White children are more frequently affected than black children, and there is a slight male preponderance, which is most pronounced for T-cell acute lymphoblastic leukemia. The incidence of acute lymphoblastic leukemia peaks in children aged 2-5 years and subsequently decreases with age.

Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown.[4] Environmental risk factors such as exposure to ionizing radiation and electromagnetic fields and parental use of alcohol and tobacco have not been shown to cause pediatric acute lymphoblastic leukemia. In addition, no direct link has been established between viral exposure and the development of childhood leukemia.

Prognosis

The likelihood of long-term cure in ALL depends on the clinical and laboratory features and the treatment. Prognostic risk assessment includes clinical features (age and white blood cell [WBC] count at diagnosis), biologic characteristics of the leukemic blasts, response to the induction chemotherapy, and minimal residual disease (MRD) burden. Based on these criteria, patients can be effectively stratified into low risk, average or standard risk, high risk, and very high-risk.[7]

Standard-risk patients are aged 1-9.9 years with WBC of less than 50,000 at presentation, lack unfavorable cytogenetic features, and show a good response to initial chemotherapy. The Children’s Oncology Group (COG) defines standard risk as less than 1% blasts in peripheral blood by 8 days and less than 0.01% blasts in bone marrow by 29 days (rapid early response). Low-risk patients have < 0.01% blasts for both time points and have favorable cytogenetics (eg, trisomy 4, 10). High-risk patients do not meet these criteria or have extramedullary involvement that makes it inappropriate for them to be treated as standard risk. Very-high-risk patients have unfavorable cytogenetic features (Philadelphia chromosome, hypodiploidy (n < 44), MLL gene rearrangement or poor response to initial chemotherapy (induction failure or Day 29 bone marrow with MRD >0.01%).

Patients younger than 1 year with acute leukemia have disease that is biologically distinct with a poor outcome.[8]

The 5-year event-free survival (EFS) varies considerably depending on risk category, from 95% (low risk) to 30-80% (very high risk), with infant leukemia having the worst outcomes: 20% for patients younger than 90 days. COG redefined very high risk to include high risk patients ≥13 years of age, which made the range of outcomes wider for this subgroup. Overall, the cure rate for childhood acute lymphoblastic leukemia (ALL) is more than 80%.

Five-year survival rates for children diagnosed with ALL rose to 90% from 2000-2005, which was up from 84% in 1990-1994.[5] Improvement in survival was observed for all age groups of children, except for infants younger than 1 year. In low-income countries (LIC), therapeutic results for pediatric ALL have been less encouraging due to delayed diagnosis, abandonment of therapy, and death from toxicity due to suboptimal supportive care. Nevertheless, current 4-year event-free survival rates are 61% in India,[8] and over 78% in Lebanon,[9] demonstrating that pediatric ALL is curable in LIC.

An analysis of long-term survival among 21,626 children with ALL treated in COG trials from 1990-2005 found that 10-year survival rose to almost 84% in 1995-1999 from 80% in 1990-1994. The analysis also found that survival improved for almost all groups, including older children and black children.[5]

Acute complications may involve all organ systems and include the following:

  • Tumor lysis syndrome

  • Renal failure

  • Sepsis

  • Bleeding

  • Thrombosis

  • Typhlitis

  • Neuropathy

  • Encephalopathy

  • Seizures

In addition, lifelong follow-up is necessary, because survivors may experience late effects from treatment for this condition, such as the following:[1]

  • Secondary malignancy

  • Short stature (if craniospinal radiation)

  • Growth hormone deficiency

  • Learning disability

  • Cognitive defects

Patient Education

Ensure that the patient's parents and guardians understand that ALL usually does not have a known cause, that accurate stratification helps guide therapy, and that participating in institutional or consortium-based clinical trials may help lead to better outcomes in the future. In addition, parents and guardians must know the expected adverse effects of each medication and be able to recognize signs and symptoms that require immediate medical attention, such as those for anemia, thrombocytopenia, and infection. Furthermore, parents and patients must know how to quickly access medical help from the oncology team.

For patient education information, see Cancer and Tumors Center, as well as Leukemia.

 

Presentation

History

Children with acute lymphoblastic leukemia (ALL) often present with signs and symptoms that reflect bone marrow infiltration and/or extramedullary disease. When leukemic blasts replace the bone marrow, patients present with signs of bone marrow failure, including anemia, thrombocytopenia, and neutropenia. In patients with B-precursor ALL, bone pain, arthritis, and limping may be presenting symptoms and in 5% of patients are the only symptoms, leading to delays in diagnosis.[10] Fevers, whether low- or high-grade, are common at presentation, but despite neutropenia, sepsis is rarely seen. Other common clinical manifestations include fatigue, pallor, petechiae, and bleeding. In addition, leukemic spread may manifest as lymphadenopathy and hepatosplenomegaly.

Mature-B ALL may be associated with extramedullary masses in the abdomen or head and neck and central nervous system (CNS) involvement.

In patients with T-lineage ALL, respiratory distress and stridor secondary to a mediastinal mass may be a presenting symptom.

Symptoms of CNS involvement, such as headache, vomiting, lethargy, and nuchal rigidity are rarely noted at initial diagnosis but are more common in T-lineage and mature B cell ALL.[1] Cranial nerve deficits are an important sign of CNS involvement. Testicular involvement at diagnosis is also rare; if present, it appears as unilateral painless testicular enlargement.

Physical Examination

Physical findings in children with acute lymphoblastic leukemia (ALL) reflect bone marrow infiltration, as well as extramedullary disease. Patients commonly present with pallor caused by anemia and petechiae and bruising secondary to thrombocytopenia. Leukemic infiltration may manifest as lymphadenopathy and hepatosplenomegaly. If it involves the central nervous system (CNS), papilledema, nuchal rigidity, and cranial nerve palsy is sometimes found. Testicular examination in males is critical; leukemic infiltration usually manifests as unilateral painless testicular enlargement.

The presence of stridor is cause for concern and may signify a mediastinal mass, found in half of patients with T-lineage ALL, with a risk of imminent respiratory arrest. Attempts to lay the patient flat or perform intubation should be avoided, and the patient should commence steroid therapy and be transferred to the PICU for close observation while workup is underway.

 

DDx

Diagnostic Considerations

Complete morphologic, immunologic, and genetic examination of the leukemic cells is necessary to establish the diagnosis of acute lymphoblastic leukemia.

The following are other conditions to consider when evaluating a child with suspected acute lymphoblastic leukemia (ALL):

  • Acute myeloid leukemia

  • Aplastic anemia

  • Acute anemia

  • Idiopathic thrombocytopenic purpura (ITP)

Differential Diagnoses

 

Workup

Approach Considerations

Upon initial presentation, ensure the patient is clinically stable and work to establish a diagnosis. Obtain a complete blood cell (CBC) count with peripheral smear to be evaluated by a hematologist or hematopathologist for the presence of blasts. If significant number of blasts are seen, flow cytometry may rapidly confirm whether T-lineage or B-lineage acute lymphoblastic leukemia (ALL) is present. Blood chemistry drawn should include serum levels of uric acid, potassium, phosphorus, calcium, and lactate dehydrogenase (LDH) to determine the level of tumor lysis.

No imaging studies other than chest radiography to evaluate for a mediastinal mass should be required. If the physical examination reveals enlarged testes, perform ultrasonography to evaluate for testicular infiltration.

A bone marrow aspirate and biopsy performed under sedation will confirm the diagnosis with special stains (immunohistochemistry), and immunophenotyping, and allow collection of adequate sample for cytogenetics and molecular studies. A lumbar puncture with cytospin morphologic analysis to assess for central nervous system (CNS) involvement and to administer intrathecal chemotherapy is often performed at the same time.

Bone marrow and CSF studies are performed before any systemic chemotherapy, including oral steroid, is administered. In addition, if anthracyclines are to be administered, obtain a baseline echocardiogram and an electrocardiogram (ECG). Wherever possible, a central venous line should be placed prior to starting chemotherapy.

 

 

 

Immunophenotyping

Acute lymphoblastic leukemia (ALL) cells rearrange their immunoglobulin and T-cell receptor (TCR) genes and express antigen receptor molecules that correspond to such processes in normal developing B and T lymphocytes, so that ALL can be classified as B-lineage or T-lineage ALL.

Mature B-cell ALL should be differentiated from other B-lineage ALL and accounts for only 1-3% of childhood ALL. Diagnosis depends on the detection of surface immunoglobulin on leukemic blasts, as well as distinctive morphology, with deeply basophilic cytoplasm containing prominent vacuoles, designated L3 in the French-American-British (FAB) system (see Histologic Features).

B-lineage ALL accounts for 80% of childhood ALL and involves lymphoblasts that have cell-surface expression of 2 or more B-lineage–associated antigens (ie, CD19, CD20, CD24, CD22, CD21, or CD79).[4] CD10 is commonly expressed, which makes it a useful diagnostic marker, and the presence of aberrant myeloid markers (eg, CD7) is occasionally noted but has little prognostic impact. B-cell precursors of ALL can be further subclassified as early pre–B-cell, pre–B-cell, or transitional pre–B-cell, but distinguishing these subtypes is usually not clinically relevant.

T-lineage ALL accounts for 10-15% of childhood ALL, and is identified by the expression of T-cell–associated surface antigens, of which cytoplasmic CD3 is specific. T-cell ALL cases can be classified by early, mid, or late thymocytes, and 10% of cases are early T-precursor (ETP) ALL characterized by absent CD1a and CD8, weak CD5, and one or more myeloid or stem cell markers (eg, CD117, CD34, CD13, CD33). ETP ALL is thought to have worse prognosis, but this assumption may not be valid on modern T-cell ALL chemotherapy protocols.

The overall outcome for T-lineage and high risk B-lineage ALL is similar, provided intensive chemotherapy is used.

Cytogenetic and Molecular Studies

In 80% of pediatric acute lymphoblastic leukemia (ALL) cases, specific genetic alterations can be found in leukemic blasts using routine karyotype analysis and molecular techniques, such as fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and Southern blot analysis. Important diagnostic, therapeutic, and prognostic implications are associated with the abnormalities described.[11]

See Acute Lymphoblastic Leukemia Staging for summarized information.

B-lineage ALL has a variety of chromosomal abnormalities, which in almost half of cases confer favorable outcomes:

  • t(12;21)(p13;q22) or ETV6-RUNX1 (formerly known as TEL-AML1) (20-25% cases)

  • Hyperdiploidy (>50 chromosomes/cell) (25% cases) associated with non-random trisomies X, 4, 6, 10, 14, 17, 18 and 21. Trisomy 4 and 10 alone (and in the past with trisomy 17 or "triple trisomy”) has been found to confer benefit. It is very important to confirm that "hyperdiploidy" does not represent doubling of a near-haploid clone, which has a poor prognosis

Other, less common, chromosomal abnormalities confer a poor outcome:

  • Extreme hypodiploidy with < 44 chromosomes/cell (1% of cases) which can be subdivided into near-haploid ALL (24–31 chromosomes) harboring mutations affecting receptor tyrosine kinase and RAS signaling, and low-hypodiploid ALL (32–39 chromosomes) characterized by alterations in TP53 as a manifestation of Li-Fraumeni Syndrome.

  • MLL gene rearrangement eg t(4;11)(q21;q23) (6% cases)

  • Philadelphia chromosome positivity t(9;22)(q34;q11) (3% cases)

  • Internal amplification of chromosome 21 (iAMP 21) (2% cases)

And some chromosomal abnormalities are of uncertain significance:

  • t(1;19)(q23;p13) or TCF3-PBX1 (formerly known as E2A-PBX1) (4% cases) was thought to confer poor prognosis with increased risk of CNS relapse, but this is no longer true with contemporary treatment.

Genome-wide association studies (GWAS) use techniques that are not widely available to define genetic abnormalities in the 20% of B-lineage ALL cases where routine testing is unrevealing, demonstrating changes associated with poor outcome:

  • "Ph-like" ALL (10-15% of cases) with gene expression similar to Ph+ ALL which commonly have IZKF1 alteration, and in half of cases cryptic rearrangements of CRLF2 (cytokine receptor like factor 2). Approximately half of CRLF2 -rearranged cases have point mutations in Janus kinase (JAK) family members JAK1 and JAK2

  • Increased CRLF2 (cytokine receptor like factor 2) expression, which may have an underlying CRLF2 mutation (5-7% of cases). Interestingly, increased CRLF2 expression is also seen in 50% of the patients with Down syndrome and ALL, where its prognostic value is uncertain.

T-lineage ALL also has a variety of chromosomal abnormalities with less well-defined prognostic value:

  • Constitutive activation of NOTCH1 signaling is the most common abnormality and secondary to activating mutations in NOTCH1 (>50% of cases of T-ALL), FBXW7 mutations (15% of cases), and t(7;9)(q34;q34.3) (< 1% of cases), and may convey favorable outcome.

  • Genetic lesions also include homeobox (HOX), LMO, and bHLH family members. Amongst the HOX genes TLX1 rearrangement t(10;14)(q24;q11) was thought to confer a favorable prognosis (5-10% cases) and TLX3 rearrangement t(5;14)(q35;q32) less favorable (20-25% cases).

Minimal Residual Disease Studies

Historically, the response to leukemia treatment was assessed morphologically, which can be challenging when looking for small numbers of leukemic cells, especially in bone marrow specimens recovering from chemotherapy or after transplantation.

Studies of minimal residual disease (MRD) may be based on the detection of chimeric transcripts generated by fusion genes, the detection of clonal TCR or immunoglobulin heavy-chain (IgH) gene rearrangements, or the identification of a immunophenotype specific to the leukemic blasts.[2] All of the methods for detecting MRD have a much higher sensitivity than that of morphology, and all studies using MRD techniques have shown significant correlations between end-of-induction leukemia burden and outcome.[12] As a result, current treatment protocols use MRD measurements for acute lymphoblastic leukemia risk assignment.[13]

For B-lineage ALL patients, the significance of MRD was quantitatively different among genetic subgroups and NCI risk groups, with the time point for measurement varying between studies:

  • On COG P9904/5/6 clinical trials, multivariate analysis found Day 29 (end of induction) bone marrow (BM) MRD measured by flow cytometry with a cut-off of 0.01% was the most significant predictor of outcome in patients with B-ALL. The  These studies also found that Day 8 peripheral blood MRD level was an independent predictor of outcome in multivariate analysis.

  • The UK ALL 2003 clinical trial also confirmed MRD as the single most important predictor of relapse, and patients with day 29 BM MRD ≥ 0.01% had a threefold higher relapse rate (5-year EFS 79%) compared with low-risk patients (5-year EFS 94-95%).

  • The St Jude Total XV trials confirmed that BM MRD on Day 19 and Day 46 of induction therapy were important predictors of relapse with Day 19 BM MRD of < 1% detecting a favorable risk group (10-year EFS 95-100%) and day 19 BM MRD of >1% who still had >0.01% at day 46 having poor outcomes (10-year EFS 25-69%)

For T-lineage ALL patients:

  • The Italian Association of Pediatric Haematology-Oncology (AIEOP)-Berlin-Frankfurt-Muenster (BFM) 2000 study used PCR to measure MRD on Day 33 (end induction) and Day 78 (end of consolidation, EOC) and found EOC MRD a better predictor of adverse outcome in T-lineage ALL. Regardless of Day 33 MRD, patients who had EOC MRD < .01% had a 7-year EFS of at least 80%, in contrast to patients with EOC MRD >.01% who had a7-year EFS of 49%.

Ultrasonography

Perform testicular ultrasonography if the testes are enlarged upon physical examination.

Some clinicians use renal ultrasonography to evaluate for leukemic kidney involvement as an assessment of risk for tumor lysis syndrome.

Bone Marrow Aspiration and Biopsy

Bone marrow aspirate and biopsy results confirm the diagnosis of acute lymphoblastic leukemia (ALL). In addition, special stains (immunohistochemistry), immunophenotyping, cytogenetic analysis, and molecular analysis help in classifying each case. See the images below for examples of bone marrow aspirate findings.

Bone marrow aspirate from a child with B-precursor Bone marrow aspirate from a child with B-precursor acute lymphoblastic leukemia. The marrow is replaced primarily with small, immature lymphoblasts that show open chromatin, scant cytoplasm, and a high nuclear-cytoplasmic ratio.
Bone marrow aspirate from a child with T-cell acut Bone marrow aspirate from a child with T-cell acute lymphoblastic leukemia. The marrow is replaced with lymphoblasts of various sizes. No myeloid or erythroid precursors are seen. Megakaryocytes are absent.
Bone marrow aspirate from a child with B-cell acut Bone marrow aspirate from a child with B-cell acute lymphoblastic leukemia. The lymphoblasts are large and have basophilic cytoplasm with prominent vacuoles.

Histologic Features

Historically, the French-American-British (FAB) classification system allocated acute lymphoblastic leukemia (ALL) into 3 groups based on morphology, as described below. Only L3 morphology retains diagnostic relevance.

  • L1: The lymphoblast cells are usually small, with scant cytoplasm and inconspicuous nucleoli. L1 accounts for 85% of all cases of childhood acute lymphoblastic leukemia.

  • L2: The lymphoblast cells are larger than in L1. The cells demonstrate considerable heterogeneity in size, with prominent nucleoli, and abundant cytoplasm. L2 accounts for 14% of all childhood acute lymphoblastic leukemia.

  • L3: The lymphoblast cells are large with deep cytoplasmic basophilia. They frequently have prominent cytoplasmic vacuolation and are morphologically identical to Burkitt lymphoma cells. L3 accounts for 1% of childhood acute lymphoblastic leukemia cases.

See Acute Lymphoblastic Leukemia Staging for more complete information.

Laboratory Studies

An elevated leukocyte count of more than 10 × 109/L (>10 × 103/µL) occurs in only half of patients with pediatric acute lymphoblastic leukemia (ALL). Neutropenia, anemia, and thrombocytopenia are common in ALL but it is often observed secondary to inhibition of normal hematopoiesis by leukemic infiltration. It is important to recognize that 20% of patients with ALL initially present with pancytopenia and no evidence of peripheral blasts.[14]

Various metabolic abnormalities may include increased serum levels of uric acid, potassium, phosphorus, calcium, and lactate dehydrogenase (LDH). The degree of abnormality reflects the leukemic cell burden and destruction (lysis). Coagulation studies can be helpful in patients with T-lineage ALL and should include tests of the prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, and D-dimer level to assess for disseminated intravascular coagulation (DIC).

 

Treatment

Approach Considerations

Acute lymphoblastic leukemia (ALL) is a systemic disease, and treatment is primarily based on chemotherapy. Thus, surgical care is generally not required in the treatment of ALL, except for the placement of a central venous catheter for administering chemotherapy, blood products, and antibiotics, and for obtaining blood samples.

Different forms of ALL require different approaches for optimal results, nevertheless ALL treatment typically consists of a remission-induction phase, intensification (consolidation) phase, and continuation therapy targeted at eliminating residual disease. Central Nervous system (CNS) directed therapy is critical for improved survival rates. The addition of cyclophosphamide and asparaginase is also beneficial in the treatment of T-cell ALL. Mature B-cell ALL needs to be treated like disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide over a 6-month period. Because of the use of MTX, avoid folate supplementation.

Initially transfer children to a facility in which they can be in the care of a pediatric oncologist, preferably a center that participates in multi-institutional clinical trials. Immediately admit any patient who is neutropenic and who develops chills or fever to administer intravenous (IV) broad-spectrum antibiotics. Frequent hospitalizations may be required to deal with complications of ALL therapy, including the need for blood transfusions or antibiotics.

Tumor Lysis Syndrome

Before and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome, which refers to the metabolic derangements caused by the systemic and rapid release of intracellular contents as chemotherapy destroys leukemic blasts. Because some cells can die before therapy, such metabolic changes can occur even before therapy begins.

Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia, and hyperkalemia. Hyperuricemia can lead to crystal formation with tubular obstruction and acute renal failure requiring dialysis. Therefore, electrolyte and uric acid levels should be closely monitored throughout initial therapy.

To prevent complications of tumor lysis syndrome, patients should initially receive intravenous (IV) fluids at approximately twice the maintenance rates without potassium; this rate may vary depending on the condition of the patient.

Sodium bicarbonate may be added to the IV fluid to achieve moderate alkalinization of the urine (pH level, 7.5-8) to enhance the excretion of uric acid. A urine pH level higher than this should be avoided to prevent crystallization of hypoxanthine or calcium phosphate.

The standard prophylactic treatment for malignancy-associated hyperuricemia includes allopurinol. By blocking the enzyme xanthine oxidase, allopurinol blocks uric acid formation. Patients at high risk for tumor lysis still need to excrete pre-existing uric acid, which is unaffected by the use of allopurinol. Rasburicase, a recombinant urate oxidase, has the ability to catalyze the enzymatic oxidation of uric acid to a much more urine soluble product, allantoin, and is invaluable is situations with high uric acid build up (eg, ALL with hyperleukocytosis). Due to its expense, rasburicase is not routinely recommended for every ALL patient.

By definition, hyperleukocytosis refers to WBC counts in excess of 100,000/mcL (100 x 109/L), but patients with ALL (unlike patients with AML) are unlikely to suffer severe complications until WBC counts exceed 300,000/mcL (300 x 109/L). St Jude Children’s Research Hospital was unable to demonstrate a clear benefit from leukophoresis for newly diagnosed patients with ALL with WBC counts exceeding 200,000/mcL (200 x 109/L), and it is therefore no longer routinely recommended.

Chemotherapy

The phases and duration of chemotherapy for acute lymphoblastic leukemia (ALL) are briefly discussed in this section.

Phases of therapy

The treatment of childhood ALL, with the exception of mature B-cell ALL, commonly has several components: induction, consolidation, interim maintenance, delayed intensification, and maintenance.

The goal of induction is to achieve remission, previously defined as less than 5% blasts in the bone marrow, recovery of blood counts and no evidence of leukemia at other sites. Induction therapy generally consists of 3 or 4 drugs, which includes a glucocorticoid, vincristine, asparaginase, and possibly an anthracycline. This type of therapy induces complete remission based on morphology in more than 98% of patients. However, the measurement of minimal residual disease (MRD) by flow cytometry or polymerase chain reaction (PCR) has been shown to be much more specific and sensitive than the morphologic examination of blast cells, and the goal is to have less than 0.01% at the end of induction.

Current childhood ALL clinical trials incorporate MRD as a criterion for determining rapid early responder versus slow early responder status during induction chemotherapy. Based on MRD measurements, treatment may be intensified in patients with high amounts of residual blasts at the end of induction therapy.

Consolidation therapy is given soon after remission is achieved to further reduce the leukemic cell burden before the emergence of drug resistance and relapse in sanctuary sites (ie, testes, central nervous system [CNS]). In this phase of therapy, the patient is given different drugs (eg, cyclophosphamide, cytarabine and/or 6-mercaptopurine [6-MP]). Consolidation therapy improves the long-term survival of patients with standard-risk disease.

Interim maintenance involves non-myelosuppressive chemotherapy (eg, vincristine and intravenous MTX) that are administered to maintain remission and allow the bone marrow to recover. This occurs for 4-8 weeks.

Delayed intensification, is a repeat of the first two months of induction and consolidation in high-risk and very-high-risk ALL protocols that includes some new agents (substituting dexamethasone for prednisone, doxorubicin for daunorubicin, and 6-thioguanine for 6-MP and repeating others). The goal is to eliminate residual drug-resistant cells. Pioneered by Dr Riehm and the BFM group, this phase was found to be beneficial for patients in all risk groups, including standard-risk and low-risk ALL.

Maintenance (or continuation therapy) is the last and longest phase of treatment. This consists of intrathecal MTX at least every 3 months, vincristine and steroid pulses every 1-3 months, daily 6-MP, and weekly MTX. The doses of last 2 agents are adjusted based on peripheral neutrophil counts, in order to optimize therapy. Although vincristine and steroid pulses improve outcomes, they can be associated with avascular necrosis of the bone and vincristine neuropathy, and the current COG standard risk ALL trial is evaluating whether these 2 agents can be given every 3 months.

Duration of therapy

Whereas mature B-cell acute lymphoblastic leukemia (ALL) is treated with a 6-month to 8-month course of intensive therapy, achieving acceptable cure rates for patients with B-lineage and T-lineage ALL requires approximately 2-2.5 years of continuation therapy. Attempts to reduce this duration resulted in high relapse rates after therapy was stopped. In the United States, in current B-ALL clinical trials, the total duration of continuation therapy for girls is 2 years from the start of interim maintenance; for boys, it is 3 years from the start of interim maintenance.

The use of continuous dexamethasone in adolescents has been associated with an unacceptably high rate of osteonecrosis of the hips of around 40%,[15] and this medication is therefore omitted from induction and continuation therapy in older children. No data support the hypothesis that a second block of delayed intensification confers any extra benefit.

Management of CNS Disease

Central nervous system (CNS) disease is divided into the following:

  • CNS 1 - Absence of blasts on cytospin preparation of cerebrospinal fluid (CSF), regardless of the number of white blood cells (WBCs)

  • CNS 2 - WBC count of less than 5/mL and blasts on cytospin findings, or WBC count of more than 5/mL but negative by Steinherz-Bleyer algorithm findings* (if traumatic tap)

  • CNS 3 - WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia, such as facial nerve palsy, brain/eye involvement, and hypothalamic syndrome (Additional intrathecal therapy is only given for CNS 3 disease.)

*If the patient has blasts in the peripheral blood and the lumbar puncture is traumatic (containing ≥5/mL WBCs and blasts), treat as CNS 3 if the CSF WBC count divided by the CSF red blood cell (RBC) count is greater than 2 times the blood WBC count divided by the blood RBC count.

CNS-2 patients are probably at increased risk for relapse. Although the Dutch Cancer and Leukemia Study group (DCLSG) demonstrated that for 526 patients on protocols ALL-7 and ALL-8, CNS-2 accounted for approximately 20% of patients and was not associated with inferior outcome.[16] More recent data from the COG Standard Risk ALL protocol suggests patients with CNS-2 had inferior outcome. Traumatic lumbar puncture at diagnosis with blasts present is also associated with poor outcome, and this has been confirmed by several study groups. For patients with ALL, the initial diagnostic lumbar puncture should be done with an adequate platelet count by an experienced pediatric oncologist.

Treatment of subclinical CNS leukemia is an essential component of acute lymphoblastic leukemia therapy. Risk factors for CNS relapse included genetic abnormality, CNS involvement at diagnosis, and T-cell immunophenotype.

Cranial irradiation

Although cranial irradiation (CXRT) effectively prevents overt CNS relapse, concern about subsequent neurotoxicity and brain tumors led to a desire to replace this modality with intensive intrathecal and systemic chemotherapy.

The UKALL XI trial (1990-97) administered high-dose intravenous methotrexate (HDMTX) (6–8 g/m2) with intrathecal methotrexate (ITMTX) compared with ITMTX alone, and demonstrated decreased isolated and combined CNS relapse for patients with standard risk ALL with the former. For patients with high risk ALL, HDMTX with ITMTX were compared with CXRT and ITMTX, and although CNS relapses were significantly fewer with the latter, 10-year EFS was not significantly different (55·2% vs 52·1%).[17]

The DLCSG ALL-7 and ALL-8 trials (1988-1997) omitted CXRT except for 2% of patients who had overt CNS-3 disease and were still able to demonstrate an overall CNS relapse rate of only 5.5%.[18]

Pui et al confirmed these findings in the study Total XV (2000-2007); prophylactic CXRT was omitted from treatment for all groups of patients, including CNS-3, with an overall CNS relapse rate of 3.9%.[15]

Currently, whether prophylactic CXRT is necessary for patients with very-high-risk ALL is unclear. The current COG VHR ALL and Ph+ ALL trials do not routinely administer prophylactic CXRT, although patients with CNS-3 continue to receive CXRT.

Management of High-Risk Disease

The optimal treatment for patients with very high-risk (VHR) acute lymphoblastic leukemia (ALL) has not been determined;[19] however, some centers recommend allogeneic hematopoietic stem cell transplantation (HSCT) soon after first remission (CR1) is achieved. For the subset of patients with BCR-ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival results equivalent to allogeneic HSCT.[20] In addition, the ongoing COG randomized trial AALL1131 is evaluating the use of the experimental agent clofarabine in conjunction with intensified chemotherapy for VHR ALL.

A review of 1,041 patients with ALL and induction failure showed this population to be highly heterogeneous in their clinical features. Patients with T-cell ALL appeared to have a better outcome with allogeneic HSCT, whereas for patients with B-cell ALL and either age younger than 6 years or high hyperdiploidy, the value of HSCT was less certain.[21] For patients without a matched family donor, HSCT from an unrelated donor would therefore no longer be a reasonable treatment option for that subset, although it may be for other patients with VHR ALL. Large, multi-institutional, controlled trials are needed to confirm this recommendation.

Management of Down syndrome with ALL

Patients with Down Syndrome and ALL (DS-ALL) constitute only 2-3% of all patients diagnosed with ALL, but are highly vulnerable to toxicity from the chemotherapy agents used as well as infection.[22]

Methotrexate is linked to systemic toxicity and neurotoxicity and patients are usually treated on a modified ALL protocol with omission of high-dose methotrexate, leucovorin rescue after intrathecal methotrexate, and decreased exposure to dexamethasone and vincristine.

Death from infection is a significant risk, and patients with DS-ALL are kept inpatient during the induction phase, febrile patients receive early antibiotics (or antifungals as needed), and serum IgG levels are carefully monitored throughout the course of treatment with IVIG infused as needed.

Management of relapse

Relapse occurs in 20% of children with ALL, when blasts reappear after complete remission (CR) is achieved. The site of relapse in the vast majority of cases involves the bone marrow, but other sites include the CNS or testes. Isolated CNS relapse (< 5% of total relapse) or isolated testicular relapse (1-2% of total relapse) is rare with current ALL therapy, but if it occurs more than 18 months from diagnosis, it has good outcome with local and aggressive systemic chemotherapy. Patients at high risk for further relapse and poor survival are those with B-lineage ALL with early relapse in bone marrow (which may be combined with other sites, such as CNS) or all T-lineage ALL.[23]

Early relapse is defined as bone marrow relapse that occurs within 36 months of initial diagnosis or within 6 months of completion of primary therapy; outcomes are poor, with only 35-40% of these patients achieving long-term remission. Late relapse occurs outside this time frame, and outcomes are better than for early relapse, with over half of these patients achieving long-term remission. Unfortunately, the vast majority of patients with T-lineage ALL suffer early relapse.

In patients with relapsed ALL, a multidrug-resistant clone has been selected so that leukemia cells are more resistant to chemotherapy.[24] Nevertheless, patients often respond to the same agents initially used for induction; the problem is in keeping them in remission. Standard treatment phases for ALL with first relapse is reinduction chemotherapy to get patients back into remission (CR2), followed by postreinduction consolidation therapy for patients who achieve CR2, discussed below.

Blinatumomab

Blinatumomab (Blincyto) was approved in December 2014 for adults with Ph- relapsed or refractory B-precursor ALL. Data are emerging for pediatric patients. The prescribing information describes a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor ALL (median age was 6 yr [range: 2-17 yr]) with doses ranging from 5-30 mcg/m2/day.[25]

In a phase 2 study of pediatric patients who relapsed following bone marrow transplant, Schelegel et al recommended a dosage regimen of 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles.[26]

At a higher dose, a fatal cardiac failure event was described in the setting of life-threatening cytokine release syndrome.[25] The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on body surface area (BSA)-based regimens.[25]

Reinduction

Most standard regimens use a 4-drug induction backbone, with glucocorticoid, vincristine, an anthracycline (such as daunorubicin or doxorubicin) and asparaginase; this was shown as early as the 1980s to achieve second remission in more than 90% of relapsed ALL patients in a Pediatric Oncology Group Study (POG 8303). COG AALL01P2 used this 4-drug treatment regimen, and gave additional blocks of intensive chemotherapy with cyclophosphamide/etoposide and/or high dose cytarabine. Using this regimen, of the 63 patients in early relapse, 68% achieved CR2, and of 54 patients in late relapse, 96% achieved CR2.

The UK ALL R3 regimen studied 212 patients with relapsed ALL and compared the anthracycline drug mitoxantrone to idarubicin in a four-drug induction regimen, and obtained a long-term progression-free survival rate of 64% at 3 years in 103 patients with relapsed ALL on the mitoxantrone arm.[27]

Consolidation

After reinduction, consolidation treatment is intended to prevent further relapse and achieve long-term cure. For patients with an early relapse HSCT is desirable. Patients with elevated MRD prior to HSCT are more likely to suffer relapse; however, whether multiple cycles of intensive chemotherapy with or without newer agents (such as bortezomib or clofarabine) can ameliorate this risk factor is unclear.[28]

For patients with late relapse the risks of HSCT often outweigh potential benefit, and intensified chemotherapy alone is recommended to achieve long-term remission (>50% of patients). Standard drugs are used in higher doses, along with additional agents, such as etoposide.

Second relapse or refractory disease

Despite successful reinduction and consolidation, many patients with ALL eventually relapse a second time. With regard to second and subsequent relapse, no standard treatment regimen has been established; oncologists must choose among various combinations of drugs. Long-term survival for all patients with ALL after a second relapse remains poor, in the range of 10-20% and some families may opt for palliative care.

The FDA approved the first CAR T-cell therapy in August 2017. Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged 25 years or younger with B-cell precursor ALL that is refractory or in second or later relapse.[29]

Hematopoietic stem cell transplantation (HSCT)

HSCT has been used in very high risk patients in first remission (CR1) as well as in patients with ALL relapse at high risk for further relapse (eg, early BM relapse). Although most patients with relapse achieve second remission (CR2), because two thirds of patients with early relapse eventually have a second relapse, this makes HSCT a recommended option for this group of patients. The improved outcomes of VHR ALL for some categories of patients, such as Ph+ ALL receiving chemotherapy incorporating imatinib, means the role of HSCT in patients with VHR ALL is still debated.[19]

In a collaborative study between the COG and the Center for International Blood and Marrow Transplant Research (CIBMTR), Eapen et al studied 374 children with ALL in CR2 after a marrow relapse who received either a matched sibling donor hematopoietic stem cell transplant (MSD HSCT) (n=186) or ongoing chemotherapy (n=188).[30] The study confirmed better leukemia-free survival in patients with early relapse who received total body irradiation (TBI) based conditioning regimens. The presence of MRD before HSCT is a negative predictor of outcome after HSCT; however, whether aggressive attempts to reduce MRD before HSCT translate into improved long-term survival remains unclear.

Similarly, in the ALL-REZ BFM 90 trial, MSD HSCT benefited patients with higher risk relapse (10-year EFS 40% vs 20% for chemotherapy alone) but did not improve 10-year EFS for lower-risk patients (10-year EFS 52% vs 49% for chemotherapy alone).

With advances in HSCT technique and supportive care, alternative donors (eg, matched unrelated donors) can also be used with equivalent survival outcomes if a MSD is not available.

Molecular-targeted therapy

A drug targeted at the underlying molecular defect that is unique to certain leukemias can have potent and specific antileukemic activity while producing minimal toxicity to normal cells.[31] The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, that is standard front-line treatment for Ph-positive chronic myeloid leukemia (CML). Combination regimens with imatinib and conventional chemotherapy have shown efficacy in Ph-positive acute lymphoblastic leukemia.[32, 20]

Imatinib is approved for children newly diagnosed with Ph+ ALL. Its approval was based on a trial involving 92 patients in which children (1 year or older) and young adults were divided into 5 groups to receive different durations of imatinib therapy along with conventional chemotherapy. Among the 50 children receiving the longest duration of imatinib, the 4-year progression-free survival rate was 70%. Increasing duration of imatinib therapy was associated with lower overall mortality.[20]

The use of tyrosine kinase inhibitor or JAK2 inhibitor therapy for Ph-like ALL will be evaluated in future clinical trials.

Cellular therapy

Although HSCT with its graft versus leukemia (GVL) effect is the most commonly used cellular therapy, several other interventions are possible, as follows:[33]

  • Donor leukocyte infusion (DLI): T-cell DLI in a postallogeneic HSCT setting, provide GVL benefit for relapsed chronic myeloid leukemia and EBV-induced lymphoproliferative disease and, rarely, for induced durable remissions in relapsed ALL.

  • Natural killer (NK) cell infusion: NK cell infusions in the setting of haploidentical transplantations and killer cell Ig–like receptor (KIR) ligand mismatches has shown benefit in a minority of AML patients, but the value in ALL is uncertain.

  • In chimeric antigen receptor (CAR) T-cell therapy, the patient's own T-cells are collected from peripheral blood and genetically engineered to express a CAR that targets a specific molecule on cancer cells. The modified T-cells are then expanded and reinfused into the patient, after lymphodepletion with conditioning chemotherapy.[34] Studies of treatment with CAR T-cells targeting CD19 have reported high rates of complete and long-lasting remissions in patients with refractory acute lymphoblastic leukemia (ALL). Toxicities, which can be fatal, include cytokine release syndrome (CRS), B-cell aplasia, and cerebral edema.[34] ) 

    In August 2017, the US Food and Drug Administration (FDA) approved the anti-CD19 CAR T-cell therapy agent tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Because of the risk of adverse effects, the FDA approval includes a risk evaluation and mitigation strategy, which requires special certification for hospitals and clinics that administer the treatment and additional training for their physicians and other staff.[35, 29]

    Approval of tisagenlecleucel was based on results of an open-label, multicenter single-arm trial (Study B2202). Eighty-eight children and young adults were enrolled, 68 were treated, and 63 were evaluable for efficacy. Among the 63 treated patients, 52 responded. Of these 52 responders, 40 patients (63%) had a complete response within the first 3 months after infusion, and 12 (19%) had a complete remission with incomplete blood count recovery. All of these were associated with minimum residual disease–negative status in the bone marrow.[36]

    In conjunction with the approval of tisagenlecleucel, the FDA also expanded the approval of tocilizumab to include the treatment of severe or life-threatening CRS resulting from CAR T-cell therapy in patients 2 years of age or older. In clinical trials, 69% of patients with CRS related to CAR T-cell therapy had complete resolution of CRS within 2 weeks after receiving one or two doses of tocilizumab.[29]

Genetic studies and future challenges

More than 80% of children with ALL now can be cured.[1] However, the cause of treatment failure in the remaining 20% of patients is largely unknown, although several clues have emerged from GWAS. Poor outcome has been correlated with alteration of IKZF1, which encodes the lymphoid transcription factor IKAROS,[37] and Janus kinase mutations have been associated with a high risk of treatment failure.[38]

Because of the diverse nature of the disease, use of risk-directed therapy for all patients on the basis of molecular and pharmacogenetic characterization of the leukemic cells at the time of diagnosis is favored, and the COG is looking at a clinical trial to evaluate the use of tyrosine kinase inhibitors for Ph-like ALL.

Consultations

Numerous consultations may be obtained, depending on the clinical circumstances of patients with newly diagnosed ALL, including the following:

  • Pediatric surgeon: Patients require placement of a central venous catheter.

  • Psychosocial team: Involve psychologists and social workers in the care of patients with acute lymphoblastic leukemia to aid them and their families in navigating all of the difficult issues surrounding their care.

  • Radiation oncologist: Consultation may be appropriate if there is extramedullary disease not responding to induction therapy (eg, testicular involvement) or that associated with high-risk disease (eg, CNS-3 in patients with T-lineage ALL).

  • Other subspecialists: Consultations with other specialists (ie, infectious disease specialist, nephrologist) may be appropriate, depending on the clinical circumstances.

Long-Term Monitoring

Frequent clinic visits are required to administer outpatient chemotherapy, to monitor blood counts, and to evaluate new symptoms. In addition, all patients should be on trimethoprim- sulfamethoxazole (TMP-SMZ) or a similar agent, such as monthly IV pentamidine, to prevent Pneumocystis carinii pneumonia (PCP). Patients with infant leukemia may benefit from being on oral fluconazole prophylaxis to reduce the risk of candidiasis.

 

Medication

Medication Summary

Drugs commonly used during remission induction therapy include dexamethasone or prednisone, vincristine, asparaginase, and daunorubicin. Consolidation therapy often includes methotrexate (MTX) and 6-mercaptopurine (6-MP) or cyclophosphamide and cytarabine. Drugs used for intensification include cytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, and vincristine. Continuation therapy is based on oral 6-MP and MTX with pulses of vincristine and glucocorticoid (prednisone or dexamethasone). Intrathecal chemotherapy includes primarily MTX, which may also be combined with hydrocortisone and cytarabine (“triple-intrathecal therapy”). Imatinib and dasatinib are also approved for children with newly diagnosed with Ph+ ALL.[39, 11, 58]

It is important to note that corticosteroids can adversely suppress the function of the hypothalamic-pituitary-adrenal (HPA) axis and such suppression can have adverse effects on a patient's ability to respond to different stresses, such as severe infection. A Cochrane Database review of 7 studies showed adrenal insufficiency occurred in nearly all ALL patients in the first days after cessation of glucocorticoid therapy. Although the majority of patients recovered within a few weeks, a small number of patients had adrenal insufficiency lasting up to 34 weeks.[39]

Tyrosine kinase inhibitors (TKIs) have emerged as treatment options for patients with the B-cell ALL subtype known as Philadelphia chromosome-like ALL (Ph-like ALL). According to a genomic profiling study of 1725 children, adolescents, and young adults with B-precursor ALL, investigators found that 15% of these patients had Ph-like ALL and that within this subgroup, 91% exhibited kinase-activating gene changes. The investigators also reported that, based on in vitro testing, leukemia cells expressing ABL1, ABL2, CSF1R, and PDGFRB gene fusion were sensitive to the TKI dasatinib, while EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and leukemia cells expressing ETV6 -NTRK3 fusion were sensitive to crizotinib.[40, 41, 58, 59]

Drug therapies for relapsed or refractory ALL include cell-based gene therapy (eg, tisagenlecleucel)[36] and reinduction regimens.

Antineoplastic Agents

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

Cell-division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may be decreased in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant ones and is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents act at specific phases of the cell cycle, whereas others (ie, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Vincristine (Vincasar PFS)

Vincristine is a chemotherapeutic agent derived from the periwinkle plant. This agent acts by inhibiting microtubule formation in mitotic spindles, causing metaphase arrest.

Daunorubicin (Cerubidine)

Daunorubicin is an anthracycline that intercalates with DNA and interferes with DNA synthesis.

Methotrexate (Trexall)

Methotrexate is a folate analogue that competitively inhibits dihydrofolate reductase, thus inhibiting DNA, RNA, and protein synthesis.

Mercaptopurine (Purinethol)

Mercaptopurine is a synthetic purine analogue that kills cells by incorporating into DNA as a false base.

Cytarabine

Cytarabine is a synthetic analogue of nucleoside deoxycytidine. This agent undergoes phosphorylation to arabinofuranosyl-cytarabine-triphosphate (ara-CTP), a competitive inhibitor of DNA polymerase.

Etoposide (Toposar)

Etoposide inhibits topoisomerase II and breaks DNA strands, causing cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

Cyclophosphamide

Cyclophosphamide is chemically related to the nitrogen mustards. When this drug is used as an alkylating agent, the mechanism of action of its active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Nelarabine (Arranon)

Nelarabine is a prodrug of 9-beta-D-arabinofuranosylguanine (ara-G). This agent is converted to the active arabinofuranosyl-guanine-5'-triphosphate (ara-GTP), a T-cell–selective nucleoside analogue. Leukemic blast cells accumulate ara-GTP, which allows for incorporation into DNA, leading to inhibition of DNA synthesis and cell death.

Nelarabine was approved by the US Food and Drug Administration [FDA] as an orphan drug to treat T-cell lymphoblastic lymphoma (a type of non-Hodgkin lymphoma [NHL]) that does not respond or that relapses with at least 2 chemotherapy regimens.

Clofarabine (Clolar)

Clofarabine is a purine nucleoside antimetabolite that inhibits DNA synthesis and is indicated for relapsed or refractory acute lymphoblastic leukemia in pediatric patients. Pools of cellular deoxynucleotide triphosphate are decreased by inhibiting ribonucleotide reductase and terminating DNA chain elongation and repair. This agent also disrupts mitochondrial membrane integrity.

Immunomodulators

Class Summary

Immunomodulators (eg, interleukin 6 [IL-6] inhibitors) may be needed for therapies resulting in cytokine release.

Tocilizumab (Actemra)

Interleukin-6 receptor antagonist. Decreases C-reactive protein, rheumatoid factor, erythrocyte sedimentation rate, and amyloid A. It is indicated for treatment of cytokine release syndrome (CRS) resulting from tisagenlecleucel therapy. Clinical signs of CRS correlate with T-cell activation and high levels of cytokines, including interleukin 6 (IL-6).

Enzymes, Oncology

Class Summary

Asparaginase derivatives catalyze conversion of L-asparagine into aspartic acid and ammonia. The pharmacological effect is thought to be based on selective killing of leukemic cells owing to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize L-asparagine, and therefore depend on an exogenous source of L-asparagine for survival.

Asparaginase Erwinia chrysanthemi (Erwinaze)

Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing circulating levels of asparagine. Lack of asparagine synthetase activity results in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine. Indicated as part of a multiagent chemotherapeutic regimen for the estimated 15-20% patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli –derived asparaginase.

Pegaspargase (Oncaspar, PEG L Asparaginase)

Catalyzes deamidation of asparagine to aspartic acid and ammonia, thereby reducing circulating levels of asparagine. Lack of asparagine synthetase activity results in cytotoxicity specific for leukemic cells that depend on an exogenous source of the amino acid asparagine. Pegylation of the molecule prolongs the duration of action to 2-3 weeks.

Calaspargase pegol (Asparlas, calaspargase pegol-mknl)

Indicated as part of a multiagent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients aged 1 month to 21 years. This product provides a longer interval between doses and an extended shelf-life compared with other asparaginase products.

Antineoplastics, Tyrosine Kinase Inhibitor

Class Summary

When added to chemotherapy, tyrosine kinase inhibitors (TKIs) have been shown to improve progression-free survival in newly diagnosed patients with Ph+ ALL.[58, 59]

Imatinib (Gleevec)

Imatinib is a selective BCR-ABL tyrosine kinase inhibitor. It is indicated for newly diagnosed children aged 1 y or older with Ph+ ALL in combination with chemotherapy.

Dasatinib (Sprycel)

Second generation TKI indicated for newly diagnosed children aged 1 y or older with Philadelphia chromosome positive (Ph+) ALL in combination with chemotherapy. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones.

CAR T-Cell Therapies

Class Summary

In chimeric antigen receptor (CAR) T-cell therapy, autologous T-cells are collected from peripheral blood and genetically engineered to express a CAR that targets a specific molecule on cancer cells. The modified T-cells are then expanded and reinfused into the patient, after lymphodepletion with conditioning chemotherapy.

Tisagenlecleucel (Kymriah)

CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged 25 years or younger with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

Antimicrobials

Class Summary

Prophylactic antimicrobial drugs are given to prevent infection in patients receiving chemotherapy.

Sulfamethoxazole and trimethoprim (Septra, Bactrim)

Sulfamethoxazole and trimethoprim inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. All immunocompromised patients can be given cotrimoxazole to prevent Pneumocystis carinii pneumonia (PCP).

Pentamidine

Immunocompromised patients who do not tolerate cotrimoxazole due to myelosuppression may receive IV pentamidine to prevent Pneumocystis carinii pneumonia (PCP).

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body’s immune response to diverse stimuli. These agents are significantly toxic to lymphoblasts, and two thirds of patients with pediatric ALL who receive steroid therapy alone go into remission.

Prednisone

Prednisone is a corticosteroid and an important chemotherapeutic agent in the treatment of acute lymphoblastic leukemia (ALL). This agent is used in induction therapy and is also given as intermittent pulses during continuation therapy.

Dexamethasone (Baycadron, Maxidex, Ozurdex)

Dexamethasone is another corticosteroid that acts as an important chemotherapeutic agent in the treatment of ALL. Like prednisone, this agent is used in induction and reinduction therapy and is also given as intermittent pulses during continuation therapy.

Antifungals

Class Summary

These agents may change the permeability of the fungal cell, resulting in a fungicidal effect.

Fluconazole

Fluconazole may be used in patients at high risk (eg, infant ALL) to prevent fungal infections. It is a synthetic triazole that inhibits fungal cell growth by inhibiting CYP-dependent synthesis of ergosterol, a vital component of fungal cell membranes.

 

Questions & Answers

Overview

What is the prevalence of pediatric acute lymphoblastic leukemia (ALL)?

What are the signs and symptoms of pediatric acute lymphoblastic leukemia (ALL)?

Which routine lab tests are performed in the workup of pediatric acute lymphoblastic leukemia (ALL)?

Which lab tests are performed to classify pediatric acute lymphoblastic leukemia (ALL) type?

Which imaging studies are performed in the workup of pediatric acute lymphoblastic leukemia (ALL)?

Which procedures are performed in the workup of pediatric acute lymphoblastic leukemia (ALL)?

How is CNS disease categorized in pediatric acute lymphoblastic leukemia (ALL)?

What are the phases of treatment for pediatric acute lymphoblastic leukemia (ALL)?

Which medications are used in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

Which nonpharmacologic therapies are used in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of a central venous catheter in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is pediatric acute lymphoblastic leukemia (ALL)?

What is the pathophysiology of pediatric acute lymphoblastic leukemia (ALL)?

What is the prevalence of pediatric acute lymphoblastic leukemia (ALL) in the US?

What causes pediatric acute lymphoblastic leukemia (ALL)?

What is the prognosis of pediatric acute lymphoblastic leukemia (ALL)?

What are the acute complications of pediatric acute lymphoblastic leukemia (ALL)?

What are the possible complications of pediatric acute lymphoblastic leukemia (ALL) treatment?

What is included in patient education about pediatric acute lymphoblastic leukemia (ALL)?

Presentation

Which clinical history findings are characteristic of pediatric acute lymphoblastic leukemia (ALL)?

Which physical findings are characteristic of pediatric acute lymphoblastic leukemia (ALL)?

DDX

Which conditions are included in the differential diagnoses of acute lymphoblastic leukemia (ALL)?

Workup

How is acute lymphoblastic leukemia (ALL) diagnosed?

What is the role of immunophenotyping in the workup of pediatric acute lymphoblastic leukemia (ALL)?

What is the prevalence of genetic alterations in leukemic blasts of pediatric acute lymphoblastic leukemia (ALL)?

Which chromosomal abnormalities are associated with favorable outcomes in pediatric acute lymphoblastic leukemia (ALL)?

Which chromosomal abnormalities are associated with poor outcomes in pediatric acute lymphoblastic leukemia (ALL)?

Which chromosomal abnormalities have uncertain prognostic value in pediatric acute lymphoblastic leukemia (ALL)?

Which chromosomal abnormalities associated with pediatric acute lymphoblastic leukemia (ALL) are not revealed on routine testing?

Which chromosomal abnormalities are found in T-lineage pediatric acute lymphoblastic leukemia (ALL)?

What is the role of minimal residual disease studies in the workup of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of ultrasonography in the workup of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of bone marrow aspiration and biopsy in the workup of pediatric acute lymphoblastic leukemia (ALL)?

Which histologic findings are characteristic of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of lab tests in the workup of pediatric acute lymphoblastic leukemia (ALL)?

Treatment

How is pediatric acute lymphoblastic leukemia (ALL) treated?

How is tumor lysis syndrome treated in pediatric acute lymphoblastic leukemia (ALL)?

What is the role of chemotherapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of consolidation therapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of interim maintenance therapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of delayed intensification therapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of maintenance therapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the duration of chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL)?

How is CNS disease treated in pediatric acute lymphoblastic leukemia (ALL)?

What is the role of cranial irradiation in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

How is high-risk pediatric acute lymphoblastic leukemia (ALL) treated?

How is pediatric acute lymphoblastic leukemia (ALL) treated in patients with Down syndrome?

How is relapsed pediatric acute lymphoblastic leukemia (ALL) treated?

What is the role of blinatumomab (Blincyto) in the treatment of relapsed pediatric acute lymphoblastic leukemia (ALL)?

Which chemotherapy agents are used to treat relapsed pediatric acute lymphoblastic leukemia (ALL)?

When is HSCT indicated in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

How is a second relapse or refractory pediatric acute lymphoblastic leukemia (ALL) treated?

What is the role of HSCT in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of molecular targeted therapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the role of cellular therapy in the treatment of pediatric acute lymphoblastic leukemia (ALL)?

What is the likely cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL)?

Which specialist consultations are beneficial to patients with pediatric acute lymphoblastic leukemia (ALL)?

What is included in the long-term monitoring of pediatric acute lymphoblastic leukemia (ALL)?

Medications

Which medications are used in the treatment of pediatric acute lymphoblastic leukemia (ALL)?