INTRODUCTION — Acute lymphoblastic leukemia/lymphoma (ALL/LBL) is the most common cancer in children, accounting for nearly one-third of all childhood malignancies. ALL and LBL are considered to be the same entity, distinguished only by the primary location of the disease [1,2].
Overall survival for children with ALL/LBL is >90 percent and has improved dramatically since the 1980s due, in part, to successive research protocols that improved clinical outcomes while reducing adverse events (AEs). Optimizing outcomes with pediatric ALL/LBL, while limiting short-term and long-term AEs requires adherence to a contemporary treatment protocol. Treatment should be administered at a center with substantial experience with pediatric malignancies or in consultation with childhood leukemia experts.
Initial treatment of ALL/LBL in children and adolescents is presented here.
The epidemiology, presentation, classification, risk group stratification, and outcomes of childhood ALL/LBL are discussed separately.
●(See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)
●(See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
●(See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
TREATMENT PRINCIPLES — Therapy for ALL/LBL is intensive, complex, and prolonged. Optimal outcomes are associated with strict adherence to a contemporary research protocol.
●Treatment phases – Broadly speaking, treatment can be grouped into:
•Central nervous system (CNS) management – All children with ALL/LBL require treatment to reduce the risk of CNS relapse (algorithm 1). CNS management is incorporated into all phases of treatment and is guided by findings from the initial lumbar puncture (LP) and clinical and pathologic features. (See 'CNS management' below.)
•Remission induction – Remission induction seeks to reduce the burden of disease, achieve a complete remission (CR), and restore normal hematopoiesis. Remission induction therapy is stratified according to clinical and pathologic features at presentation. (See 'Remission induction' below.)
•Consolidation/late intensification – Consolidation/late intensification is administered to consolidate or achieve CR and is stratified according to pathologic features and the response to induction therapy. (See 'Consolidation/intensification' below.)
•Maintenance – Maintenance therapy is lower-intensity chemotherapy that lasts for two to three years. (See 'Maintenance therapy' below.)
●Adherence to protocol – Treatment of pediatric ALL/LBL varies with the leukemic immunophenotype (B cell versus T cell), cytogenetic/molecular features of the leukemic blasts, and early disease response (assessed by measurable residual disease [MRD]), all of which contribute to an individual patient's risk of relapse.
Importantly, details of risk stratification and treatment protocols (eg, drug choices, doses, schedule, and treatment duration) vary among clinical trial groups. Treatment should adhere to the chosen protocol and the associated stratification scheme; it is not advisable to "mix and match" components of care from different treatment protocols. Treatment should be administered or overseen by an experienced pediatric hematologist/oncologist.
●Special scenarios – Certain categories of ALL/LBL and populations of children require distinctive management:
•Distinctive cytogenetic/molecular features – T cell ALL/LBL, Philadelphia chromosome positive (Ph+) ALL/LBL, and Ph-like ALL/LBL require specific treatments. (See 'Special scenarios' below.)
•Down syndrome – Patients with trisomy 21/Down syndrome (DS) who develop ALL/LBL require specific treatment considerations because they are particularly susceptible to treatment-related toxicities and increased mortality. (See 'Down syndrome' below.)
•Infants – ALL/LBL in infants is aggressive, has an adverse prognosis, and requires distinctive treatment. (See 'Infant ALL/LBL' below.)
•Adolescents/young adults (AYA) – AYA patients with ALL/LBL have distinctive aspects of disease biology, susceptibility to chemotherapy toxicity, and response to treatment. They are usually treated on high-risk arms of standard protocols (See 'Adolescents/young adults' below.)
PRETREATMENT EVALUATION — Initial evaluation and diagnostic work-up for children and adolescents with suspected ALL/LBL are described separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)
Clinical and laboratory evaluation
Clinical — Clinical manifestations of ALL/LBL are often nonspecific.
●History – The child and/or caregivers should be asked about fever, headache, musculoskeletal pain, and findings associated with a mediastinal mass/superior vena cava (SVC) syndrome (eg, dysphagia, dyspnea, swelling of face, neck, or upper extremities).
●Physical examination – The child should be evaluated for hepatosplenomegaly and lymphadenopathy. The neurologic examination should include evaluation of cranial nerves. Boys should be evaluated for swelling, firmness, or other abnormalities of the testicles. Details of the clinical manifestations of ALL/LBL in children are presented separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Presentation'.)
Down syndrome (DS) and other genetic conditions influence treatment of ALL/LBL. The clinical evaluation should consider findings that might be associated with DS and other genetic conditions. (See 'Down syndrome' below and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial ALL disorders'.)
•Hematology – Complete blood count (CBC) with differential count.
•Chemistries – Serum electrolytes (including potassium, phosphorus, calcium), glucose, creatinine, and liver function tests.
•Coagulation – Prothrombin time (PT), partial thromboplastin time, (PTT), D-dimer, and fibrinogen.
•Tumor lysis panel – Lactate dehydrogenase (LDH), uric acid, in addition to electrolytes noted above.
•Viral testing – Testing for hepatitis B, hepatitis C, human immunodeficiency virus (HIV), cytomegalovirus (CMV), varicella-zoster virus (VZV), and/or Epstein Barr virus (EBV) varies among institutions.
•Pharmacogenomics – Testing for TPMT (thiopurine methyltransferase) and NUDT15 variants. Although testing is recommended, it is not required and practice varies among institutions.
•Pregnancy testing – As appropriate.
●Pathology – The pretreatment bone marrow (BM) specimen enables categorization according to World Health Organization (WHO) criteria (table 1), establishes a baseline for assessing measurable residual disease (MRD), and is used for ALL/LBL risk stratification (table 2). MRD testing can be performed on peripheral blood if there are sufficient leukemia cells in the specimen (eg, >1000 blasts/microL), but a bone marrow specimen is also needed for enrollment on most clinical trials (See 'Risk stratification' below and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in children'.)
BM evaluation includes morphologic examination, immunophenotyping by flow cytometry, and identification of molecular/genetic abnormalities. Initial evaluation and diagnostic criteria for ALL/LBL are described separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)
●Other evaluation and management
•Chest radiograph – Chest radiograph to exclude a mediastinal mass.
•Cardiac – Echocardiogram to assess left ventricular function (especially if anthracyclines are part of the treatment plan) and electrocardiogram (ECG) to detect prolongation of the QTc interval.
•Other imaging (as clinically indicated):
-Computed tomography (CT) – CT of neck/chest/abdomen/pelvis with intravenous contrast, if indicated for suspicion of lymphomatous disease.
-Positron emission tomography (PET) – If lymphomatous involvement is suspected (eg, primarily nodal enlargement, mediastinal mass, or bone lesions).
-Brain and/or spine CT or magnetic resonance imaging (MRI) – If neurologic abnormalities are present.
-Scrotal ultrasound – For suspected testicular involvement.
-Central venous access device placement
-Fertility counseling and preservation – (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
•Transplant eligibility – Patients with features of high-risk disease should be referred for consideration of hematopoietic cell transplantation (HCT) and to initiate a donor search. (See 'Risk stratification' below.)
Lumbar puncture — A diagnostic lumbar puncture (LP) is required to establish the status of the central nervous system (CNS).
All patients should have an LP shortly after diagnosis and, ideally, prior to systemic therapy. The diagnostic LP is generally coupled with the first intrathecal (IT) chemotherapy treatment. (See 'CNS management' below.)
●Diagnostic LP – An experienced clinician should perform the LP, often with the patient under moderate sedation or general anesthesia.
We generally perform the first diagnostic LP without regard for the level of circulating blasts. Some institutions favor a modest delay until the blast count declines with the initiation of systemic therapy.
It is important to avoid a traumatic LP, especially at diagnosis, when most patients have circulating leukemic blasts that can contaminate the cerebrospinal fluid (CSF) sample. A traumatic lumbar puncture leads to difficulty establishing the CNS status, may increase the risk of CNS relapse, and can adversely affect IT treatment (eg, due to collapse of the thecal sac, scarring or segmentation of the subarachnoid membrane, creation of a hematoma or CSF collection). The most common problem is contamination of CSF with blood cells, which makes determination of CNS status more complex (see below).
Platelets should be transfused before the LP if the patient is bleeding or has significant thrombocytopenia; the platelet threshold varies among institutions (eg, <10,000/microL to <50,000/microL). Fresh frozen plasma and/or cryoprecipitate can be transfused for patients with a coagulopathy.
●Analysis of CSF:
•Routine testing – Cell count and cytospin.
•Detection of blasts – Blasts are typically detected by microscopy of cytospin specimens. Flow cytometric analysis of CSF improves blast detection, but it is not routinely performed in all centers. It is important to distinguish circulating blasts caused by a traumatic LP (described below) from leukemic meningitis.
●Classification of CNS status – Findings from the initial LP are used to classify CSF , as follows:
•CNS1 – <5 leukocytes/microL CSF with no CSF blasts on cytospin
•CNS2 – <5 leukocytes/microL CSF with <5 blasts on cytospin
•CNS3 – ≥5 leukocytes/microL with blasts, or clinical or imaging findings of CNS involvement
•TLP+ – Traumatic lumbar puncture (ie, red blood cell [RBC] count ≥10/microL) with blasts, but not meeting criteria for CNS3
Risk stratification — Treatment of pediatric ALL/LBL is stratified according to the risk of relapse. For children with favorable prognosis, risk stratification enables lower treatment intensity and fewer treatment-related adverse effects, while preserving excellent outcomes. For patients with higher-risk features, treatment is intensified.
Importantly, different pediatric cooperative groups and consortia have developed different criteria for risk stratification based on their treatment protocols. The approach to risk stratification for a patient should be the same as that applied in the chosen study group treatment protocol.
Features that are commonly used for risk stratification in pediatric ALL/LBL include:
•Clinical features – White blood cell (WBC) count <50,000/microL, age ≥1 year to <10 years .
•Genetic features – Hyperdiploid karyotype (>50 chromosomes [in particular with trisomy of chromosomes 4 and 10, according to some groups]), ETV6::RUNX1-fusion.
•Clinical features – WBC ≥50,000/microL, age <1 year to ≥10 years.
Note that infants are treated using separate protocols, as described below. (See 'Infant ALL/LBL' below.)
•Genetic features – Hypodiploid karyotype (<44 chromosomes), Philadelphia chromosome positivity (Ph+), Ph-like phenotype, or KMT2A-rearrangement.
Note that T cell ALL/LBL and Ph+ ALL/LBL require distinctive treatment, as described below. (See 'T cell ALL/LBL' below and 'Ph+ B-ALL/LBL' below.)
Additional discussion of ALL/LBL risk factors is presented separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
Risk stratification affects all stages of treatment:
●Remission induction therapy – Induction therapy is stratified according to clinical features (ie, age, WBC count), leukemic immunophenotype (ie, B cell versus T cell), and cytogenetic/molecular features. (See 'Remission induction' below.)
●Subsequent phases – Subsequent therapy is guided by achievement of complete remission and the level of measurable residual disease at the end of induction and/or at the end of consolidation. (See 'Response assessment' below.)
COMPLICATIONS OF ALL/LBL AND TREATMENT — ALL/LBL and its treatment may be associated with life-threatening complications, including:
●Tumor lysis syndrome – Acute tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis and release of large amounts of potassium, phosphate, uric acid, and nucleic acids into blood.
Laboratory findings may include hyperkalemia, hyperphosphatemia, hypocalcemia (caused by precipitation of calcium phosphate), hyperuricemia, increased lactate dehydrogenase (LDH), and acute kidney failure. ALL/LBL is associated with an intermediate- to high-risk for TLS . (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)
•Prophylaxis – Preventive approaches include aggressive intravenous hydration and allopurinol (all patients) or rasburicase (recombinant uricase) for those with elevated uric acid . Rasburicase-associated adverse events include anaphylaxis, hemolysis, hemoglobinuria, methemoglobinemia, and interference with uric acid measurements; rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, because it can cause severe hemolysis .
Hemodialysis may be necessary to remove excess circulating uric acid and phosphate in patients who develop acute renal failure. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Prevention'.)
•Incidence and risk factors – The incidence of TLS varies among studies and depends on diagnostic criteria.
In one study, TLS was reported in nearly one-quarter of children during treatment of ALL/LBL . TLS was associated with age >10 years, splenomegaly, mediastinal mass, and presenting white blood cell (WBC) count ≥20,000/microL; absence of all four risk factors indicated a low risk for development of TLS, with a negative predictive value of 98 percent and a sensitivity of 96 percent.
●Infections – Infections are the most common cause of treatment-related mortality (TRM) in pediatric ALL/LBL.
Patients are susceptible to systemic bacterial, fungal, and viral infections due to functional neutropenia and lymphopenia at diagnosis and further myelosuppression from intensive and prolonged chemotherapy. Children receiving chemotherapy who have fevers or other signs/symptoms of infection must be promptly evaluated and treated with early initiation of broad-spectrum antibiotics.
•Prophylaxis – Prophylaxis for Pneumocystis jerovicii (eg, using sulfamethoxazole-trimethoprim, pentamidine, dapsone, or atovaquone) is routinely given, while administration of antifungal and antiviral agents varies among institutions.
There is no demonstrated survival benefit for routine use of granulocyte colony-stimulating factor (G-CSF) or other growth factors in this setting. A systematic review reported that children treated with G-CSF had fewer episodes of febrile neutropenia and infections and shorter hospitalization, but there was no shortening of neutropenia, decrease in treatment delays, or effect on survival . In a randomized, crossover study in 287 children with high-risk ALL/LBL, prophylactic G-CSF shortened periods of neutropenia, but did not reduce rates of febrile neutropenia, serious infections, or need for hospitalization; overall survival (OS) at six years was not affected . (See "Fever in children with chemotherapy-induced neutropenia".)
•Sepsis/infections – Septic deaths were reported in 2.4 percent of 3126 children in the prospective UKALL 2003 trial; these deaths accounted for two-thirds of TRM . Nearly half of infection-related mortality occurred during induction therapy (48 percent), but it also occurred during consolidation (9 percent), delayed intensification (23 percent), and maintenance therapy (20 percent). Most deaths occurred in neutropenic patients and within 48 hours of presentation with sepsis. Identified pathogens included bacteria (68 percent; eg, Pseudomonas spp, Eschericia coli, Enterococcus spp), fungi (20 percent; eg, Aspergillus spp, Candida spp), and viruses (12 percent).
A retrospective review reported infections in one-fifth of 425 children undergoing induction therapy and was especially common in children who were neutropenic or had an underlying condition (eg, Down syndrome, congenital heart disease, pre-existing immunodeficiency syndromes) . Infectious agents included 65 bacterial, 15 viral, and 5 fungal infections, but they caused death in only 1 percent of patients.
●Bleeding – Hemorrhage is usually caused by thrombocytopenia; patients with platelet counts <10,000/microL are at greatest risk. Bleeding from skin or mucous membranes is most common, while significant visceral bleeding is uncommon and intracranial hemorrhage is rare, but can be life-threatening. Transfusion of platelets to treat or prevent bleeding is discussed separately. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HSCT'.)
Patients can develop a vitamin K-dependent coagulopathy in association with prolonged antibiotic therapy. Children with an elevated prothrombin time (PT) are treated with either oral or intravenous vitamin K (2.5 to 5.0 mg/day by mouth; or if bleeding, 1 to 2 mg intravenously as a single dose); management in infants is discussed separately. (See "Overview of vitamin K", section on 'Vitamin K-deficient bleeding in newborns and young infants'.)
●Cytopenias – Many children present with cytopenias, which is compounded by cytotoxic agents and the prolonged nature of therapy.
Transfusion support for infants and children is discussed separately. (See "Red blood cell transfusion in infants and children: Selection of blood products".)
●Hypothalamic-pituitary-adrenal axis suppression – Daily administration of glucocorticoids during induction therapy suppresses the hypothalamic-pituitary-adrenal (HPA) axis in most patients . Children with infections, trauma, or surgery occurring during or shortly after induction therapy should receive glucocorticoid replacement therapy. In subsequent phases of therapy, glucocorticoid replacement may be needed during infections, trauma, or surgery that follow steroid pulses. (See "Treatment of adrenal insufficiency in children", section on 'Stress conditions'.)
A study of 64 patients reported that >80 percent of children had significant suppression of cortisol release by adrenocorticotropic hormone (ACTH) stimulation, but all patients recovered normal adrenal function within 10 weeks of induction therapy . However, another study reported that HPA axis suppression can last for up to 34 weeks . Stress-dose steroids should be administered if a patient has serious illness during induction or consolidation.
MANAGEMENT OF ALL/LBL — Treatment phases for pediatric ALL/LBL are described above. (See 'Treatment principles' above.)
It is important that criteria for risk stratification, central nervous system (CNS) management, and systemic therapy match the methods described in the chosen treatment protocol. It is not advisable to "mix-and-match" diagnostic and treatment components from different protocols.
CNS management — Treatment of the CNS is administered throughout the course of ALL/LBL therapy (ie, during remission induction, consolidation, intensification, and maintenance phases) (algorithm 1). Effective CNS management is essential for all children and has contributed to improved outcomes for pediatric ALL/LBL.
●Stratification of CNS risk – CNS management is stratified according to the risk for CNS relapse, but stratification criteria vary among research groups/protocols. Factors associated with increased risk for CNS relapse include:
•Higher risk – Leukemic cells detected by initial lumbar puncture (LP; ie, CNS2, CNS3, or TLP), hyperleukocytosis at presentation (>50,000/microL), T cell immunophenotype, high-risk genetic abnormalities (eg, Philadelphia chromosome positive [Ph+], Ph-like).
Categories of CNS involvement are defined above. (See 'Lumbar puncture' above.)
•Lower risk – B cell ALL/LBL with none of the above features.
●Selection of CNS-directed therapy – CNS management is guided by the chosen treatment protocol.
•Higher-risk patients – Management generally includes intrathecal (IT) therapy plus systemic treatment and/or cranial radiation therapy (RT).
Examples of treatment for higher-risk disease include:
-IT methotrexate (MTX) or "triple IT therapy" (ie, IT administration of MTX, cytarabine, and hydrocortisone) plus high-dose MTX with leucovorin rescue, increased doses of L-asparaginase, and/or cranial RT.
-Use of cranial RT is controversial and is increasingly limited to those with the highest risk of CNS relapse (eg, persistent CNS3 disease, selected patients with high risk T cell ALL/LBL) . Some institutions have eliminated CNS RT entirely.
-Patients with CNS2 disease may not require the same level of intensive therapy as the other higher-risk criteria; one approach is administration of IT cytarabine twice-weekly until one to three successive LPs reveal no blasts .
•Lower-risk patients – For patients with lower risk of CNS relapse, we suggest prophylaxis with IT MTX or triple IT therapy, rather than cranial RT; prophylaxis using RT is associated with unacceptable adverse effects (AEs), compared with IT therapy [18-20].
Prophylaxis using either IT MTX or triple IT therapy is associated with CNS relapse in <5 percent and grade ≥3 AEs in <10 percent. RT prophylaxis is not more efficacious than IT therapy, but it is associated with greater short-term and long-term toxicity (discussed below).
●Administration of CNS therapy
•Intrathecal therapy – The first IT treatment should be given at the time of the initial diagnostic LP.
We generally perform the first diagnostic LP/IT treatment in all children who have circulating blasts, regardless of the level, but some institutions favor a modest delay until a very high blast count declines with the initiation of systemic therapy. (See 'Lumbar puncture' above.)
•Systemic therapy – Intensification of systemic therapy contributes importantly to reducing relapses in higher-risk patients. Treatment intensification varies among protocols, but CNS-directed therapy and concurrent systemic treatment must follow the chosen treatment protocol.
Treatment intensification may include use of high-dose systemic MTX, additional asparaginase, or preference for dexamethasone rather than prednisone. In some phase 3 trials, dexamethasone was associated with lower rates of CNS relapse than prednisone, but this was offset by increased toxicity [21-23]. Trials that compared dexamethasone versus prednisone are discussed below. (See 'T cell ALL/LBL' below.)
•Radiation therapy – RT is generally reserved for children with frank CNS leukemia at diagnosis (eg, CNS3 disease) or other patients with very high risk.
Use of RT has declined because it is associated with substantial risk for long-term neurocognitive deficits, endocrinopathies, growth impairment, and CNS secondary malignancies. Contemporary cranial RT generally uses ≤18 gray (Gy) to limit AEs.
The reduced rate of CNS relapses with RT is offset by significant long-term morbidity, especially in younger children [24,25]. A meta-analysis from 10 international pediatric cooperative groups that pooled data on 16,623 patients with childhood ALL/LBL found that cranial RT reduced CNS relapse only in patients with CNS3 (ie, blasts in CSF at diagnosis); however, even for that subgroup, cranial RT was not associated with improved overall survival (OS) .
●Outcomes – Using contemporary treatments, CNS relapse occurs in <5 percent of children who achieve complete remission (CR); prior to the routine use of CNS prophylaxis, more than half of children who achieved CR relapsed with leukemic meningitis .
Outcomes with CNS-directed therapy include:
•IT prophylaxis – A study of nearly 600 children (both low-risk and high-risk for CNS relapse) who received intensified triple IT therapy (without cranial RT) reported 1.5 percent rate of CNS relapse after five years . Another study reported 1.4 percent seven-year cumulative risk of CNS relapse among 152 children treated with triple IT therapy .
IT MTX was directly compared with triple IT therapy in two phase 3 trials:
-In CCG 1952 (2027 patients), triple IT therapy was associated with a lower incidence of isolated CNS relapse at six years (3.4 percent compared with 5.9 percent with IT MTX; hazard ratio 0.53) and similar six-year event-free survival (EFS), but it was also associated with inferior six-year OS (90 versus 94 percent); primarily due to more bone marrow or testicular relapses). Grade ≥3 AEs were reported in 6 percent of children treated with IT MTX and 7 percent with triple therapy.
-In AALL1131, accrual was stopped when analysis revealed no difference between IT MTX and triple IT therapy for five-year OS (96 versus 97 percent, respectively) or disease-free survival (DFS; 93 versus 91 percent), relapses (isolated CNS, bone marrow only, or combined), or toxicity .
•Comparison of IT versus RT – Cranial RT is associated with increased toxicity, but it is not more effective than other approaches. RT was shown to prevent CNS relapse only for children with overt CNS involvement (ie, CNS3) at diagnosis [26,30].
Studies that reported RT was not more effective than other approaches for preventing CNS relapse include:
-The phase 3 DFCI ALL 95-01 trial randomly assigned children to either triple IT therapy versus 18 Gy cranial RT plus IT; the trial arms were associated with comparable rates of CNS relapse and five-year EFS .
-The St Jude Total XV Study reported that prophylactic cranial RT could be omitted without compromising OS in the setting of risk-adjusted treatment of pediatric ALL/LBL . However, compared with earlier St Jude studies that included RT, Total XV used more intensive systemic chemotherapy and more IT Therapy.
-In the phase 3 CCG-105 trial, CNS relapse and EFS were similar among 1388 children with intermediate-risk ALL/LBL who were randomly assigned to IT MTX alone versus RT (18 Gy during consolidation) plus IT MTX . However, this trial used less intensive systemic chemotherapy and reported higher rates of CNS relapse compared with contemporary studies.
•Toxicity – IT therapy can rarely cause seizures and/or leukoencephalopathy; IT therapy has also been associated with neurocognitive deficits in the longer-term.
Cranial RT is associated with considerably more short-term and long-term AEs, including neurocognitive deficits, endocrine and growth impairment, and secondary CNS tumors [34-38].
-Neurocognitive deficits – All forms of CNS therapy can cause neurocognitive deficits, especially when treatment includes RT. Strategies for educational and pharmacologic interventions have been developed to remediate cognitive dysfunction following treatment of childhood ALL/LBL .
Both triple IT therapy and RT plus IT therapy were associated with impaired cognitive function in DFCI ALL 95-01, but children who received RT had less fluent language output and were less able to modulate their behavior, according to their parents . A trial that randomly assigned 40 children to 18 Gy RT plus IT MTX versus high-dose MTX plus IT MTX reported no differences in 16 standardized memory measures but, collectively, the children had deficits in visual-spatial memory and verbal memory, compared with age-corrected norms .
A prospective study of 49 children in CR (for a mean of six years) after receiving either 18 Gy cranial RT plus IT MTX versus parenteral MTX reported comparable declines in neuropsychologic function, overall and verbal intelligence, and arithmetic achievement . More than half of children in the RT group had increased somnolence and four developed cerebral calcifications, while most of the children treated with systemic MTX had abnormal electroencephalograms and/or white matter hypodensities by CT. A study of 102 adult survivors of ALL/LBL who received cranial RT reported a progressive decline in attention and verbal functioning that persisted into adulthood . Impaired attention and cognitive function appear to be more significant in girls and in children who were radiated at a younger age (eg, <4 to 5 years) .
-Growth and development – RT is associated with impaired growth and a trend toward earlier onset of puberty . Irradiated patients had a greater loss in height compared with nonirradiated patients and this effect was greater with 24 Gy RT compared with 18 Gy . Treatment with ≤18 Gy RT has only a modest impact on final height, but younger patients (eg, <7 years), especially girls, remain at risk for clinically significant growth failure.
-CNS tumors – A retrospective cohort study of 9720 children reported 24 CNS neoplasms after median follow-up of 4.7 years; all tumors developed in children who received RT and the risk was especially increased in children who were ≤5 years of age at the time of cranial RT . (See "Delayed complications of cranial irradiation".)
Further discussion of long-term effects of cranial RT is presented separately. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS, mental health, and cognition' and "Delayed complications of cranial irradiation".)
Systemic treatment phases — Phases of systemic therapy for pediatric ALL/LBL are outlined above. (See 'Treatment principles' above.)
Remission induction — Remission induction therapy is stratified according to immunophenotype (B cell versus T cell), cytogenetic/molecular features of the leukemic blasts, and clinical risk factors (eg, age, presenting leukocyte count). For the individual child with ALL/LBL, risk stratification must use the criteria applied in the chosen treatment protocol. (See 'Risk stratification' above.)
Induction therapy requires four to six weeks. All regimens include a glucocorticoid, vincristine, and asparaginase; some groups/protocols also include an anthracycline for some or all categories of ALL/LBL.
Cooperative group protocols generally stratify treatment according to clinical and disease features at diagnosis, such as low-risk, standard-risk, intermediate-risk, and/or high-risk; some also use specific protocols for patients with T cell ALL/LBL.
Examples of stratified treatment protocols include:
●Low-risk B cell ALL/LBL 
●Standard-risk B cell ALL/LBL 
●High-risk B cell ALL/LBL [23,47]
●T cell ALL/LBL [48,49]
Certain categories (eg, T cell ALL/LBL, Ph+ ALL/LBL, infant ALL/LBL, Down syndrome-associated ALL/LBL) require distinctive therapy, as described below. (See 'Special scenarios' below.)
Ongoing clinical trials are evaluating the use of immunotherapy or other experimental approaches as a component of remission induction or post-induction therapy. However, these agents should not be used to treat ALL/LBL outside of a clinical trial, as benefits have not been proven and tolerability/safety of incorporating them into chemotherapy regimens have not yet been determined.
Administration and AEs of drugs used in remission induction therapy are discussed below. (See 'Chemotherapy' below.)
Response assessment — Bone marrow is examined at end-of-induction to determine if the patient has achieved CR by morphology and to assess the level of measurable residual disease (MRD). The response to induction therapy guides subsequent phases of treatment, including whether to proceed to consolidation phase and the nature of that treatment.
Response criteria are evolving to accommodate contemporary treatment protocols .
Historically, responses have been judged as follows:
●Complete remission – Criteria for CR include:
•Blasts – Clearance of blasts:
-Bone marrow blasts <5 percent
-No circulating blasts or extramedullary disease
•Recovery of blood counts – Restoration of hematopoiesis, including:
-Absolute neutrophil count (ANC) >1000/microL
•No relapse – No evidence of recurrence of ALL/LBL for four weeks.
•MRD criteria – Vary according to protocol (eg, blasts <0.01 to <0.1 percent).
Methods for assessing MRD in ALL/LBL are described separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)
●Less than CR – For patients who do not achieve CR according to the above criteria, further management is described separately. (See "Relapsed or refractory acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
Consolidation/intensification — Consolidation/late intensification is administered after achievement of CR.
Agents, doses, schedules, and even the labels for this phase of treatment differ among cooperative groups, but it generally includes consolidation, which is focused on deepening remission and intensive treatment of the CNS, followed by blocks of more intensive chemotherapy for four to eight months.
Consolidation/late intensification is stratified according to risk factors for relapse, including clinical and laboratory features at diagnosis and the level of MRD at the end of induction. MRD is measured for risk determination at the end of consolidation for some groups, including T cell ALL/LBL. Stratification criteria must correspond to those applied in the chosen treatment protocol.
Complete remission — For patients who are in CR at end-of-induction, consolidation therapy is stratified according to the risk category of ALL/LBL. Treatments differ among risk groups [19,42,51-54]; examples include:
●Low-risk and some standard-risk patients – Consolidation therapy consists of IT therapy, vincristine, and an antimetabolite (usually mercaptopurine [6-MP]).
●Standard- or intermediate-risk – Consolidation chemotherapy generally includes a glucocorticoid, cyclophosphamide, cytarabine, vincristine, asparaginase, 6-MP, and weekly MTX.
●High-risk/T cell ALL – Consolidation therapy is intensified, depending on the category of ALL/LBL; intensified chemotherapy (eg, cyclophosphamide, cytarabine, vincristine, asparaginase, 6-MP), high-dose MTX (5 g/m2) every two weeks, and additional glucocorticoids and anthracycline are common in high-risk protocols.
MRD-positive — Patients who are MRD-positive at end-of-induction often receive treatment that includes immunotherapy (eg, blinatumomab). (See 'Immunotherapy' below.)
MRD assessment may again be performed at end-of-consolidation, with subsequent treatment guided by the results. Outcomes are generally best when MRD is negative at end-of-induction, but for both B cell and T cell disease, outcomes are also favorable when MRD is negative at end-of-consolidation [48,49,55-57].
If bone marrow is still MRD-positive at end-of-consolidation, patients may be considered for allogeneic hematopoietic cell transplantation (HCT), especially if they have a slow response and/or high-risk cytogenetics. (See 'Allogeneic HCT' below.)
Maintenance therapy — Maintenance therapy (also called continuation therapy) is lower-intensity outpatient chemotherapy with ongoing CNS therapy that lasts for two to two and one-half years. Patients remain at increased risk for infections during maintenance therapy.
Details of maintenance therapy vary, but it generally includes daily 6-MP, weekly MTX, and periodic IT therapy; vincristine and glucocorticoid pulses every 3 months are included in some protocols. Patients with high-risk ALL/LBL may receive more aggressive or prolonged maintenance therapy.
●Importance of adherence to maintenance therapy – The importance of strictly adhering to maintenance therapy should be emphasized to children, families, and caregivers. Even modest reductions in 6-MP adherence can have substantial effects on relapse rates .
6-MP can be administered either as a tablet or an oral suspension. Better medication adherence is associated with a consistent daily routine that reflects the family's lifestyle (ie, selecting either morning or evening dosing) and permitting co-administration of 6-MP with food or milk products . Self-reporting frequently overestimates the true intake of 6-MP, particularly in poorly adherent patients . A cohort study reported that the rate of relapse was increased in patients with <90 percent adherence to 6-MP administration .
●Duration of maintenance phase – Maintenance phase usually lasts for two to two and one-half years. One study reported that <1 year of maintenance therapy was associated with a higher rate of relapse (39 percent at 12 years after diagnosis), but it still cured more than half of the children with ALL/LBL; some categories of ALL/LBL (eg, TCF3::PBX1 and ETV6::RUNX1 rearrangements) were associated with excellent disease-free survival (DFS) using this approach .
●Vincristine and steroid pulses – For standard-risk ALL/LBL, adding pulse therapy with vincristine and a glucocorticoid to daily 6-MP and weekly MTX was associated with more favorable long-term outcomes, compared with 6-MP and MTX alone . AALL0932, which enrolled 2,364 average-risk children and was associated with 96 percent five-year OS and 95 percent five-year DFS, reported that outcomes were not affected by decreasing the frequency of vincristine/dexamethasone pulses to every 12 weeks (rather than every 4 weeks), increasing the weekly dose of MTX to 40 mg/m2 (from 20 mg/m2) in maintenance therapy, or both changes . In another trial, outcomes were not improved by adding one-week pulses of dexamethasone with two doses of vincristine to maintenance therapy .
●Antimetabolite – Age, sex, and genetic polymorphisms affect 6-MP bioavailability [65-69]. To optimize dosing, we determine the genotype of TPMT and NUDT15; this is especially important in patients who experience myelosuppression at standard doses of 6-MP .
6-MP is metabolized to the bioactive compound, 6-thioguanine, but other pathways compete for 6-MP and can reduce levels of active metabolites. Heterozygosity for a common polymorphism at the TPMT locus (generally present in 5 to 10 percent of patients, but it varies among populations) is associated with reduced enzyme activity and increased toxicity [71-73]. NUDT15 deficiency is also associated with 6-MP intolerance.
●Ongoing risk for infections – Children remain at increased risk for infections throughout maintenance therapy.
Children who develop fever while receiving chemotherapy must be evaluated promptly and treated aggressively, especially if the patient is either neutropenic or has a central venous access device. Prophylaxis against Pneumocystis jerovicii (eg, trimethoprim-sulfamethoxazole, pentamidine, dapsone, or atovaquone) should be given throughout maintenance phase and is continued for at least three to six months after completion [64,74].
Children receiving chemotherapy should not be given live-virus immunizations while undergoing treatment; it is acceptable for family members to receive live-virus immunizations, except for oral polio vaccine [75,76]. Killed or recombinant vaccines are considered safe in this setting. (See 'Follow-up' below.)
Chemotherapy — Combination chemotherapy is the mainstay of treatment of ALL/LBL.
Induction chemotherapy — Remission induction therapy includes the following agents:
●Glucocorticoid – The dose, schedule, and type of glucocorticoid are determined by the patient's age, risk of relapse, and specifications of the chosen treatment protocol.
Compared with prednisone, dexamethasone has a longer half-life and better central nervous system (CNS) penetration, but it is associated with more frequent adverse effects (AEs), including more infections, fractures, osteonecrosis, mood/behavior problems, and myopathy . As a result, dexamethasone is generally reserved for higher-risk disease (eg, T cell ALL/LBL). Adolescents have a higher risk of osteonecrosis with dexamethasone .
Glucocorticoid-associated AEs can be mitigated with prophylactic antibiotics (eg, levofloxacin during periods of neutropenia) and/or alternative methods of administration (eg, altered schedules of dexamethasone or alternating hydrocortisone and dexamethasone to reduce osteonecrosis and neuropsychological AEs) [78-81].
Studies that compared dexamethasone with prednisone include:
•A meta-analysis that analyzed nearly 9000 children with ALL/LBL in eight randomized trials reported no difference in overall survival (OS) or relapses according to treatment with dexamethasone versus prednisone . Dexamethasone was associated with better event-free survival (EFS [ie, no death, relapse/refractory ALL/LBL, or secondary cancer]; relative risk [RR] 0.80 [95% CI 0.68-0.94]) but more treatment-related mortality (TRM) during induction (RR 2.31 [95% CI 1.46-3.66]), more neuropsychiatric AEs (RR 4.55 [95% CI 2.45–8.46]), and more myopathy (RR 7.05 [95% CI 3.00–16.58]). There was no significant difference in the incidence of osteonecrosis, sepsis, fungal infection, diabetes, or pancreatitis.
•The phase 3 ALL0232 trial of 2154 patients with high-risk B cell ALL/LBL reported that dexamethasone improved outcomes for patients age <10 years, but it was associated with a higher risk of osteonecrosis in patients ≥10 years .
•In a phase 3 trial (AIEOP-BFM ALL 2000) that included 3720 children, compared with prednisone, there was no difference in OS, but dexamethasone was associated with a lower five-year relapse rate (11 versus 16 percent) that was partially offset by more induction-related deaths (2.5 versus 0.9 percent) . The benefit with dexamethasone was mostly in patients with T cell ALL/LBL.
●Vincristine – Vincristine is administered weekly during induction therapy; the dose is typically capped at 2 mg to reduce the incidence and severity of peripheral neuropathy.
Vincristine-associated neuropathy involves both sensory and motor fibers and can be manifest as paresthesias, loss of reflexes, weakness, and autonomic neuropathies (including vocal cord paralysis). Virtually all patients have some degree of peripheral neuropathy; it is usually reversible, but improvement may take months. Children with mild neuropathy can usually continue to receive full doses of vincristine, but up to one-quarter of patients develop more severe neuropathy that interferes with activities of daily living and requires dose reduction or discontinuation. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vincristine'.)
The incidence of neuropathy is higher in patients with a single nucleotide polymorphism in the promoter region of CEP72 .
●Asparaginase – Pegaspargase (polyethylene glycol [PEG]-Escherichia coli-derived L-asparaginase) has largely replaced native E. coli L-asparaginase because of its longer half-life, lower incidence of hypersensitivity, and similar efficacy . However, pegaspargase can cause anaphylaxis, thrombosis, CNS toxicity, liver or pancreas toxicity, and other AEs.
•Anaphylaxis – Medications used to treat anaphylaxis should be readily available when asparaginase is given. Premedication with diphenhydramine and an H2-blocker can decrease the incidence of allergic reactions [85,86], but premedication may mask an allergic reaction that might herald development of inactivating antibodies.
Most allergic reactions occur after two or three doses and are thought to be caused by the PEG moiety, rather than the asparaginase, per se; this response may reflect prior exposure to PEG in laxatives or tablet coatings . A period of observation following administration of PEG-asparaginase is common practice at many institutions because anaphylaxis may be delayed by several hours. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase' and "Anaphylaxis: Emergency treatment".)
An adverse impact on outcomes had been demonstrated for patients with asparaginase discontinuation . For patients who experience PEG allergy/persistent anti-PEG antibodies, drug desensitization can be successful [89,90].
Recombinant Erwinia asparaginase has received US Food and Drug Administration (FDA) approval for patients with allergic reactions to PEG; it has a shorter half-life and requires more frequent administration compared to pegaspargase [91,92].
•Neutralizing antibodies – Neutralizing antibodies against E. coli asparaginase develop in 2 to 8 percent of children treated for ALL/LBL [93,94]. Neutralizing antibodies are generally associated with symptoms of hypersensitivity, but some patients with inactivating antibodies have no allergic manifestations, yet have silent inactivation. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)
Monitoring asparaginase activity can help to detect enzyme-inactivating antibodies; expert recommendations for monitoring asparaginase have been published .
Children who develop neutralizing antibodies can often be treated successfully with Erwinia asparaginase, since there is only approximately 10 percent antibody cross-reactivity between E. coli and Erwinia preparations .
•Thrombosis – Most thrombotic events (eg, deep vein thrombosis, pulmonary embolism, intracranial dural sinus thrombosis with hemorrhage) in children with ALL/LBL are associated with asparaginase-containing regimens . The risk of thromboembolic events increases with age, presence of a central venous catheter, and asparaginase therapy [98-102].
A meta-analysis of 1752 children in 17 studies of ALL/LBL reported that 5 percent of patients had a thromboembolic event during treatment (83 percent occurred during induction therapy)  and a prospective study of >1000 children (ages 1 to 18 years) reported thrombosis in 6 percent . Using contemporary treatment protocols, symptomatic thrombotic complications were reported in 1.8 percent of patients but rose to 15 percent in children with prothrombotic risk factors . E. coli-asparaginase and Erwinia-asparaginase appear to have equivalent risk of severe thrombosis, including CNS hemorrhage.
Consistent asparaginase activity levels >50 to 100 international units (IU)/L completely deplete serum asparagine , thereby inhibiting protein synthesis in leukemic cells but also reducing synthesis of coagulation-associated plasma proteins [105,106]. This can cause prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, and hypofibrinogenemia, with fibrinogen levels often less than 100 mg/dL. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)
●Anthracycline – Weekly dosing of an anthracycline is included in remission induction therapy in some regimens.
Inclusion of an anthracycline and the preferred agent differ among cooperative groups. Due to the potential impact on both short-term and long-term cardiac function, a pretreatment echocardiogram should be obtained in all patients prior to administration of anthracyclines. (See 'Clinical and laboratory evaluation' above.)
●Other agents – Targeted agents (eg, tyrosine kinase inhibitors [TKIs] for Philadelphia chromosome positive [Ph+] ALL/LBL) or additional chemotherapy (eg, nelarabine for T cell ALL/LBL) may be added for treatment in special scenarios, as described below. (See 'Special scenarios' below.)
Consolidation chemotherapy — Consolidation chemotherapy usually includes some combination of cyclophosphamide, cytarabine, vincristine, asparaginase, and 6-MP, along with intrathecal (IT) methotrexate. The intensity of consolidation is based on measurable residual disease (MRD) at end-of-induction [19,42,51-53]. (See 'Consolidation/intensification' above.)
Intensified consolidation chemotherapy for various subgroups of patients has yielded mixed results:
●Some reports indicated that more intensive treatment was associated with improved outcomes:
•UKALL 2003 – Among high-risk patients in UKALL 2003, augmented consolidation therapy achieved superior five-year EFS (90 versus 83 percent; odds ratio [OR] 0.61 [95% CI 0.39-0.98]) and a trend toward superior five-year OS (93 versus 89 percent) compared with standard consolidation, but was associated with more asparaginase hypersensitivity (7 versus 1 percent), pancreatitis, and MTX-associated mucositis and stomatitis .
•CCG-1961 – More intensive post-remission therapy was associated with improved outcomes for children with high-risk ALL/LBL in the phase 3 CCG-1961 trial . Intensified consolidation therapy achieved significantly superior five-year OS (89 versus 83 percent) and five-year EFS (81 versus 72 percent). Superior EFS was seen with B cell ALL/LBL, T cell ALL/LBL, children 1 to 9 years, and children >10 years. The trial also reported no advantage for treatment with two cycles of consolidation therapy, rather than one cycle.
●Other trials have not shown a benefit with intensified consolidation chemotherapy:
•AALL0331 – In the phase 3 COG AALL0331 trial of 5311 children, compared with four weeks of consolidation therapy, intensified therapy did not improve outcomes for children with standard-risk ALL/LBL, regardless of the level of MRD .
•AALL1131 – The phase 3 COG AALL1131 trial of children with very high-risk B cell ALL/LBL reported that substituting cyclophosphamide and etoposide for cyclophosphamide, cytarabine, and 6-MP did not affect four-year disease-free survival (DFS) [108,109]. The trial also reported that treatment that included clofarabine did not improve outcomes, but it was associated with excessive infections.
•NOPHO ALL 2008 – The phase 3 NOPHO ALL 2008 trial was stopped early when, compared with 30 weeks of asparaginase therapy in consolidation phase, 16 weeks of asparaginase achieved similar DFS (92 versus 91 percent) but with less asparaginase toxicity (9 versus 18 percent) .
●Lower-intensity therapy for children with low-risk ALL/LBL has been associated with mixed results:
•UKALL 2003, ALL 10 – In these two phase 3 trials, reduced intensity therapy did not affect outcomes for children with standard-risk ALL/LBL who were MRD-negative at end-of-induction [111,112].
•ALL 2000 – The phase 3 AIEOP-BFM ALL 2000 trial reported that for children with standard-risk ALL/LBL, reduced intensity of therapy led to inferior DFS due to increased relapses .
Maintenance chemotherapy — Maintenance therapy generally includes daily 6-MP, weekly MTX, and periodic IT therapy, with or without pulses of vincristine and a glucocorticoid [19,42,53]. Details of drug doses and schedules and duration of maintenance therapy vary among clinical trials groups; some protocols vary the intensity and/or duration of maintenance therapy for selected patients.
Studies that addressed aspects of maintenance therapy include:
●Vincristine/steroid pulses – The frequency and choice of steroid varies among protocols.
For patients with standard-risk ALL/LBL, adding pulses of vincristine and prednisone to 6-MP and weekly MTX achieved more favorable EFS, compared with 6-MP and MTX alone . A meta-analysis reported that adding pulses of vincristine plus prednisone (or prednisolone) to maintenance therapy was associated with improved five-year EFS (OR 0.71 [95% CI 0.61-0.84]) but did not affect OS among more than 1700 patients in 11 randomized trials . The meta-analysis also reported that pulses of vincristine plus dexamethasone did not affect EFS or OS among more than 3000 patients in eight randomized trials; the absence of effect with dexamethasone-containing pulses has been attributed to increased intensity of earlier phases of treatment in those trials.
AALL0932, which enrolled 2364 children with average-risk ALL/LBL, reported 96 percent five-year OS and 95 percent five-year DFS; outcomes were not affected by decreasing the frequency of vincristine/dexamethasone pulses to every 12 weeks (rather than every 4 weeks) or increasing the weekly dose of MTX to 40 mg/m2 (from 20 mg/m2) in maintenance therapy . In another trial, enhanced maintenance therapy (adding one-week pulses of dexamethasone with two doses of vincristine) did not improve outcomes .
●Antimetabolite – 6-MP is metabolized to the bioactive compound, 6-thioguanine. Drug and metabolite concentrations of oral 6-MP vary widely among patients, while age, sex, and genetic polymorphisms can affect bioavailability [65-69]. To optimize dosing, we determine the genotype of TPMT and NUDT15 prior to maintenance therapy (if was not previously determined).
Heterozygosity at the TPMT locus (present in 5 to 10 percent of patients, but the frequency varies vary among certain populations) has been associated with reduced thiopurine methyltransferase activity and increased toxicity [71-73]. NUDT15 deficiency is also associated with 6-MP intolerance.
A phase 3 trial of nearly 1500 children reported that, compared with 6-MP, 6-thioguanine caused excess toxicity without an apparent benefit . With six-year follow-up, there was no difference in OS or EFS between trial arms; 6-thioguanine was associated with fewer isolated CNS relapses (OR 0.53 [95% CI 0.30-0.92]), but this was offset by increased risk of death in remission (OR 2.22 [95% CI 1.20-4.14]), mainly due to infections during maintenance phase. 6-thioguanine was also associated with hepatic sinusoidal obstructive syndrome (SOS) in 11 percent of patients, including non-cirrhotic portal hypertension due to liver fibrosis or nodular regenerative hyperplasia [116,117]. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in children".)
Allogeneic HCT — Allogeneic hematopoietic cell transplantation (HCT) is used as consolidation therapy in first complete remission (CR1) only for selected patients. The decision to proceed with allogeneic HCT must be personalized.
Settings where transplantation may be considered include patients with MRD at end-of-consolidation, those with t(17;19), and some patients with induction failure .
Patient selection, timing of transplantation, and other aspects of HCT vary among institutions. However, myeloablative conditioning HCT is generally not used for children ≤1 year because of excessive non-relapse mortality (NRM).
●Graft choice – A human leukocyte antigen (HLA)-matched sibling donor (MSD) is the preferred graft source, but a matched unrelated donor (MUD) graft is used when a sibling donor is not available. A partially matched family member or umbilical cord blood may be an acceptable donor option for patients who do not have an HLA-matched donor.
Survival rates after allogeneic HCT appear to be comparable, regardless of the stem cell source (MSD, MUD, cord blood, or haploidentical donor) [119,120]. HCT using an MSD graft is associated with fewer severe infections and pulmonary complications than MUD grafts, but similar rates of OS, EFS, NRM, and relapse . (See "Donor selection for hematopoietic cell transplantation".)
●Transplantation versus other consolidation – No phase 3 trials have directly compared HCT with chemotherapy, but small prospective and retrospective studies suggest that allogeneic HCT in CR1 is associated with improved outcomes in patients with certain high-risk features and/or persistent disease.
As an example, in a prospective study, children with very high-risk ALL/LBL were assigned to consolidation chemotherapy or transplantation, according to the availability of a compatible related donor; among 357 children, 280 were assigned to chemotherapy and 77 to HCT . Compared with chemotherapy, HCT was associated with superior five-year DFS (57 versus 41 percent; HR 0.67 [95% CI 0.46-0.99]), but five-year OS (56 versus 50 percent, respectively; HR 0.73 [95% CI 0.49-1.09]) did not reach statistical significance.
Analysis of ALL BFM 90 and ALL BFM 95 reported that, compared with patients who received chemotherapy alone, children transplanted in CR1 had superior outcomes . Among the 179 patients who achieved CR, 36 were transplanted (23 with an MSD transplant, 8 with a MUD graft, and 5 with a mismatched related donor). Five-year OS was 67 percent for the 36 patients who underwent HCT, compared with 47 percent for the 120 patients treated with chemotherapy alone. Outcomes were comparable for patients who received MSD grafts versus MUD/mismatched related donor grafts, but relapses only occurred after MSD-HCT (8 of 23 patients), whereas transplant-related mortality (TRM) only occurred after the other graft sources (4 of 13 patients).
Use of allogeneic HCT for children and adolescents with relapsed or refractory ALL/LBL is discussed separately. (See "Relapsed or refractory acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
Immunotherapy — Several immunotherapies, including blinatumomab, inotuzumab ozogamicin, and tisagenlecleucel are effective and approved for use in the setting of relapsed/refractory (r/r) ALL/LBL. Ongoing clinical trials incorporate immunotherapy into upfront therapy within traditional chemotherapy backbones , but these agents should not be used for initial treatment of pediatric ALL/LBL outside of a clinical trial, as their benefits and toxicity have not yet been proven in this setting. (See 'Remission induction' above.)
●Blinatumomab – Blinatumomab is a bispecific T cell engaging (BiTE) antibody that directs CD3-positive effector memory T cells to CD19-positive blast cells. It is included as consolidation therapy for certain high-risk categories of de novo ALL/LBL and for r/r ALL/LBL.
Blinatumomab can cause cytokine release syndrome (CRS) and neurologic toxicity (eg, encephalopathy, convulsions, disorientation). CRS typically presents with fever, headache, nausea, asthenia, hypotension, increased transaminases, and increased total bilirubin within the first two days of treatment. Management of CRS and neurologic toxicity are described separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)
Blinatumomab is approved by the US Food and Drug Administration (FDA) for B cell ALL/LBL in first or second complete remission with MRD ≥0.1 percent.
●Inotuzumab ozogamicin – Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) that is being tested in clinical trials for high-risk patients with positive MRD at end-of-induction and is also used for r/r ALL/LBL.
Inotuzumab has been associated with hepatotoxicity, including fatal and life-threatening sinusoidal obstruction syndrome (SOS; also called veno-occlusive disease [VOD]); patients treated with inotuzumab prior to HCT have had increased rates of NRM. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in children".)
●Tisagenlecleucel – Tisagenlecleucel is a CD19-directed genetically modified chimeric antigen receptor (CAR)-T cell autologous T cell immunotherapy.
Tisagenlecleucel is associated with CRS and neurologic toxicity (described above); it is available in the United States only through a Risk Evaluation and Mitigation Strategy (REMS). (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)
Tisagenlecleucel is approved by the US FDA for treatment of r/r ALL/LBL in patients ≤25 years.
Use of immunotherapy for r/r ALL/LBL in children is discussed separately. (See "Relapsed or refractory acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
FOLLOW-UP — After completion of therapy, patients are monitored for relapse and to screen for long-term adverse effects (AEs) of treatment.
Most children with ALL/LBL are under the care of a pediatric oncologist for treatment, procedures, and monitoring during the entirety of the time they are receiving chemotherapy. Patients may be followed by their oncologist for several years after completing therapy, and transition to a long-term cancer survivor program, where available.
When therapy for ALL/LBL is completed, a primary care provider generally assumes health maintenance and other medical needs.
●Monitoring for relapse – Blood counts and measurable residual disease (MRD) are monitored regularly, as specified by the chosen treatment protocol. Patients are typically seen by their oncologist monthly for the first six months to one year after completing therapy and then at longer intervals for the next two to four years. After three to five years, patients are followed on an annual basis with a focus on long-term survivor issues.
Clinical manifestations of relapse are similar to those of the initial presentation of ALL/LBL (eg, fever, malaise, bleeding, bone pain). (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)
Potential sites of relapse include:
•Bone marrow – Bone marrow is the most common site of relapse; it may present as cytopenias, leukocytosis, or blasts on the complete blood count (CBC)/differential count or blood smear.
Bone marrow examination is warranted if there is a significant decline or persistence of unexplained cytopenias or other concerning hematologic abnormalities. This also applies for patients with a history of a hematopoietic cell transplantation (HCT).
•Central nervous system (CNS) – The CNS is the second most common site of relapse, although the incidence has diminished with routine use of effective CNS prophylaxis. CNS relapse may manifest with symptoms of increased intracranial pressure (headache, morning vomiting), nuchal rigidity, focal neurologic findings (particularly cranial nerve palsies), or papilledema.
CNS relapse may also be detected with routine evaluation of cerebrospinal fluid (CSF) in association with lumbar puncture (LP) for intrathecal (IT) chemotherapy administration. For this reason, it is imperative that a cytospin of the CSF sample is reviewed by a hematopathologist with every LP.
•Other sites – Testicular relapse is uncommon (<5 percent) with contemporary treatments, but it may present as unilateral, painless testicular enlargement . Diagnosis of relapse is made by testicular biopsy; bilateral biopsies should be performed because leukemic cells are frequently found in the contralateral testis .
Leukemic infiltrates rarely recur in other extramedullary sites, including the ovary, kidney, skin, and eye.
●Late effects of treatment – Treatment of pediatric ALL/LBL affects growth, development, and endocrine function and is associated with increased incidence of second cancers.
Specific late effects are influenced by patient age, treatment intensity, cranial or mediastinal radiation therapy, or allogeneic HCT. Details of late effects of treatment of pediatric ALL/LBL are presented separately. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Late effects'.)
●Routine care – The child should be monitored for growth, development, reproductive/gonadal function, and neurocognitive/psychosocial maturation. Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group, and are available at http://www.survivorshipguidelines.org.
Age-specific immunization is an important aspect of care for the patient who has been treated for ALL/LBL. Important aspects include:
•Immunizations are generally deferred for patients with ALL/LBL while receiving chemotherapy, partially because the effectiveness of vaccination in an immunocompromised patient is unclear . Live-virus vaccines, such as varicella, measles-mumps-rubella (MMR) and oral poliovirus, are contraindicated. About three to six months after completion of chemotherapy, the patient should begin to receive any missed vaccinations, including MMR and varicella.
•Annual influenza vaccination is given for children with ALL/LBL receiving chemotherapy. Household contacts should also receive influenza vaccine to prevent patient exposure during periods of neutropenia. Family members should not receive nasal influenza vaccine due to concerns that this live virus could spread to the child with leukemia.
•Cancer patients have variable responses to immunizations while immunosuppressed. Furthermore, children with ALL/LBL whose immunizations were up-to-date at the time of diagnosis may not maintain protective antibody titers after completion of chemotherapy [127,128]. For this reason, some centers routinely check antibody titers three to six months after completing chemotherapy; children with low antibody titers are generally be revaccinated [126,129]. (See "Immunizations in adults with cancer".)
•Patients who underwent HCT should repeat their immunization series beginning approximately one year after transplantation. Testing of immune function may provide evidence for safe immunization timing in these patients . (See "Immunizations in hematopoietic cell transplant candidates and recipients".)
SPECIAL SCENARIOS — Treatment of ALL/LBL is modified in the setting of specific leukemic features and for certain populations of children.
T cell ALL/LBL — T cell disease accounts for 15 percent of pediatric ALL/LBL. These children are more likely than others to have a mediastinal mass (60 percent) or central nervous system (CNS) involvement (10 percent) [130,131]. Although T cell ALL/LBL was historically associated with inferior outcomes, treatment intensification has achieved outcomes that are similar to B cell disease [132-134]. Patients with early T cell progenitor (ETP) ALL/LBL should be treated the same as children with T cell ALL/LBL .
T cell ALL/LBL is treated using more intensive therapy. Approaches generally include adding an anthracycline in remission induction therapy, use of dexamethasone (rather than prednisone), addition of nelarabine for intermediate and high-risk patients, and/or cranial radiation therapy (RT) to prevent CNS relapse. The most important prognostic factor for children with T cell ALL/LBL is the response to therapy after consolidation phase.
Noteworthy observations with T cell ALL/LBL include:
●Importance of intensified therapy – Intensified therapy is associated with improved outcomes in T cell ALL/LBL . An anthracycline is added to induction therapy, but the agent, dose, and schedule differ among cooperative groups . Anthracycline regimens have not been directly compared in prospective trials.
All groups use a four-drug, anthracycline-containing induction regimen for children with T cell ALL/LBL, based on the UKALL 2003 trial, which demonstrated superior outcomes compared with a three-drug regimen . Other studies also reported superior outcomes using a four-drug regimen, compared with earlier studies [48,136]. Randomized trials (CCG1882 and CCG-1961) demonstrated the benefit of an intensive consolidation phase in this setting [137,138].
●Dexamethasone as the preferred steroid – Although dexamethasone has been associated with increased infections, this is compensated for by greater potency and increased CNS penetration . Inclusion of dexamethasone might enable a reduced need for cranial RT and its attendant adverse effects (AEs).
UKALL2003, which included dexamethasone, was associated with superior overall survival (OS) and low rates of infections and avascular necrosis, compared with earlier studies [107,139]. AIEOP-BFM 2000 reported that, compared with prednisone, dexamethasone achieved a lower rate of five-year relapse (11 versus 16 percent) but increased toxicity and treatment-related mortality (TRM; 3 versus 1 percent) . DFCI ALL 00-01 suggested that inclusion of dexamethasone in intensification and continuation phases might also improve five-year event-free survival (EFS) .
●Nelarabine – Nelarabine is a purine deoxyguanosine analog that inhibits DNA synthesis.
Nelarabine is effective for treatment of high-risk T cell ALL/LBL, although its benefit for T cell lymphoblastic lymphoma (LBL) is less well demonstrated [49,55]. A nelarabine dose of 650 mg/m2/day for five days was optimal for treatment in children . AEs include neuropathy, dizziness, confusion, ataxia, seizures, mood alterations, and cytopenias .
In the phase 3 COG AALL0434 trial, for children with intermediate- and high-risk T cell ALL/LBL, addition of nelarabine achieved superior five-year disease-free survival (DFS; 88 versus 82 percent) and fewer CNS relapses (1 versus 7 percent) compared with no nelarabine . Nelarabine was well-tolerated and AEs were similar in both arms of the trial . The impact of nelarabine on outcomes for T cell LBL was not as clear, as AALL0434 was not powered to detect a difference in this subset of patients .
●Prognostic importance of measurable residual disease (MRD) – Response to treatment is the most important prognostic factor for children with T cell ALL/LBL ; unlike B cell disease, no other clinical or genetic features are independently associated with outcomes [132,134,143-145]. Many children with T cell ALL/LBL have a slower response to induction therapy with detectable MRD at end-of-induction, but outcomes remain favorable if they have low-level or undetectable MRD at the end of consolidation . The prognostic importance of end-of-consolidation MRD is even more striking for ETP ALL/LBL .
Treatment stratification has enabled outcomes with T cell disease that are similar to those of children with non-T cell ALL/LBL . Low/undetectable MRD at end-of-consolidation may identify patients with lower-risk T cell disease who can be treated with chemotherapy alone, whereas children with detectable MRD at end-of-consolidation may be offered allogeneic hematopoietic cell transplantation (HCT) . In AIEOP-BFM 2000, patients who were MRD-negative (<10-4) at end-of-consolidation had superior outcomes compared with those who were MRD-positive; importantly, outcomes for end-of-consolidation MRD-negative patients were similar regardless of MRD status at end-of-induction . Other groups have reported similar findings [147,148]. In the UKALL2003 trial, patients with end-of-induction MRD <10-4 had good outcomes using standard consolidation and maintenance therapy .
●CNS prophylaxis – There is no consensus for management of CNS risk in children with T cell ALL/LBL. We offer cranial RT only to patients with overt CNS disease (CNS3) at diagnosis because of its associated AEs.
AALL0434 compared two strategies of methotrexate (MTX) intensification in T cell ALL/LBL in a 2 x 2 randomized manner . Among those without overt CNS or testicular leukemia, children were randomly assigned to either escalating dose systemic MTX (without leucovorin) plus escalating pegaspargase versus high-dose systemic MTX with leucovorin rescue; all children, except those with low-risk features, also received prophylactic RT (12 Gy) and each group was further randomly assigned intermediate- and high-risk T cell ALL/LBL patients to receive or not receive a five-day course of nelarabine. Compared with high-dose MTX, the conventional-dose MTX arm achieved superior five-year OS (94 versus 89 percent) and DFS (92 versus 85 percent). The high-dose MTX arm was also associated with more relapses (59, including 23 with CNS involvement) than the conventional MTX dose (32 relapses, including 6 with CNS involvement). Outcomes for the 1189 evaluable patients in the trial (eg, 90 percent OS, 84 percent EFS) were superior to those from earlier trials of T cell ALL/LBL.
Ph+ B-ALL/LBL — The t(9;22) translocation (Philadelphia chromosome [Ph]) accounts for <5 percent of children with ALL/LBL, with a higher incidence in adolescents. The availability of BCR::ABL1 tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes for patients with Ph+ ALL/LBL, allowing many to avoid routine HCT. Children with Ph+ ALL/LBL should receive a TKI through all phases of treatment (ie, remission induction, consolidation, and maintenance) .
Treatment for Ph+ ALL/LBL is stratified according to the response to initial therapy and presence of additional chromosomal abnormalities.
●Remission induction – Induction therapy for Ph+ ALL/LBL includes a TKI (usually started on day 15 of induction) plus either chemotherapy or a glucocorticoid, the choice of which varies among cooperative groups [150-155].
●Post-remission management – Post-remission management varies according to the response at end-of-induction (ie, complete remission [CR] versus less than CR and the level of MRD).
•Standard risk – For children who have standard-risk Ph+ ALL/LBL (ie, CR with low MRD at end-of-induction), post-remission treatment includes consolidation chemotherapy followed by maintenance therapy. Some experts favor indefinite treatment with the TKI, while others favor allogeneic HCT, but these approaches have not been compared in a randomized trial.
•High risk – For patients with a poor disease response, options include consolidation therapy (ie, TKI plus either chemotherapy, blinatumomab, or tisagenlecleucel), followed by allogeneic HCT.
Noteworthy findings from studies of Ph+ ALL/LBL include:
●TKI – The randomized EsPhALL trial demonstrated similar AEs and a trend toward improved four-year EFS among children with standard-risk Ph+ ALL/LBL who received a TKI plus chemotherapy, compared with chemotherapy alone (75 versus 56 percent) . In another study, addition of imatinib on day 15 of induction therapy was associated with 97 percent CR, 72 percent five-year OS, and 57 percent five-year EFS . Studies that compared a TKI plus chemotherapy versus chemotherapy alone (from the pre-TKI era) demonstrated the benefit of dasatinib (69 versus 32 percent five-year EFS) .
No prospective studies have directly compared individual TKIs for pediatric Ph+ ALL/LBL, but long-term outcomes after dasatinib-based treatment (eg, 86 percent five-year OS) are generally superior to imatinib (70 to 72 percent five-year OS) [154-156]. Two retrospective studies reported higher OS and EFS with front-line ponatinib compared with dasatinib, but these data should be confirmed with prospective studies .
●Transplantation – Allogeneic HCT is no longer required in first complete remission (CR1) for all patients with Ph+ ALL/LBL.
COG AALL0031 reported similar three-year EFS among very high-risk patients who underwent HCT in CR1 versus children who received continuous imatinib (ie, starting early in treatment and continuing through maintenance chemotherapy) without HCT [154,159,160].
A retrospective analysis reported that HCT in CR1 was associated with improved five-year OS and DFS in children and adolescents with Ph+ ALL/LBL, compared with chemotherapy alone . Benefits were seen with matched sibling donor (MSD), matched unrelated donor (MUD), mismatched related donor allogeneic HCT, and autologous HCT . Other studies also demonstrated a benefit for transplantation using a matched donor . OS and EFS were superior with allogeneic HCT (MSD or MUD) compared with chemotherapy alone. The incidence of TRM was 27 percent with MSD grafts and 39 percent with MUD grafts, but there was no significant difference in five-year OS.
Adolescents/young adults — Adolescents (age ≥15 years) with ALL/LBL generally have inferior outcomes compared with younger children and require special considerations for treatment.
Adolescents and young adults (AYA) are more likely to have adverse features (eg, Ph+, Ph-like, KMT2A rearrangement, iAMP21) and are less likely to have favorable features (eg, hyperdiploidy, ETV6::RUNX1), compared with younger children. As an example, more than one-quarter of AYA ALL/LBL is Ph-like, a category associated with inferior survival [163,164].
For AYA patients, we favor pediatric-based therapy, rather than adult-type regimens, because they are associated with improved outcomes. Examples of suitable protocols include COG AALL0232 , NOPHO ALL2008 , DFCI ALL 00-01 , and C10403 .
●Superiority of pediatric regimens may be related to greater treatment intensity (eg, more cumulative asparaginase, vincristine, steroids; incorporation of delayed intensification, more intensive CNS prophylaxis) and lower cumulative doses of alkylators, anthracyclines, and cytarabine (thereby reducing long-term AEs, especially infertility) [54,166,167]. However, asparaginase therapy carries a higher risk of hepatic, pancreatic, and thrombotic complications, and the risk increases in older patients or patients with obesity [54,165,168-170].
●As an example, AYA patients in COG AALL0232 achieved 77 percent five-year OS and 65 percent five-year EFS . Other studies reported that, compared with adult-like regimens, outcomes with pediatric regimens were superior . However, a single-institution study found that hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) achieved similar OS (60 percent) compared with a pediatric-like regimen .
●The complexity of pediatric regimens may be challenging to administer outside of a center with a large volume of patients and a support staff familiar with the largely outpatient administration of therapy . One study reported that only one-third of AYAs who were treated by adult oncologists received pediatric-type regimens .
Infant ALL/LBL — Most infants with ALL/LBL present with adverse features (eg, high white blood cell [WBC] count, CNS involvement, leukemia cutis, KMT2A rearrangement). Infant ALL/LBL is associated with very poor prognosis and treatment requires distinctive and intensive therapy that combines elements of treatments for lymphoid and myeloid leukemias. Infants are especially vulnerable to treatment-related toxicity and there is no proven benefit for allogeneic HCT in this setting.
More than 80 percent of infant ALL/LBL involves rearrangement of KMT2A (previously known as MLL), which is associated with a mixed lineage phenotype (ie, elements of both lymphoid and myeloid leukemia); KMT2A mutations are associated with a very low incidence of co-occurring mutations. In addition to KMT2A rearrangement, a few infants also have mutations involving the PI3K-RAS signaling pathway . Blasts in infant ALL/LBL frequently co-express lymphoid and myeloid markers.
Treatment generally involves a seven-day prophase of prednisone therapy, followed by a hybrid induction regimen (ie, conventional ALL/LBL therapy plus elements of treatment for acute myeloid leukemia [AML]) . Infants who are MRD-positive at end-of-induction should receive intensified consolidation. Infants age <3 months, WBC ≥300,000/microL, or detectable MRD after intensive consolidation therapy receive either maintenance therapy or undergo allogeneic HCT; infants without these adverse features receive maintenance therapy.
●Interfant 99 – Outcomes of infants who received this hybrid therapy (47 percent four-year EFS) were superior to previous reports . High WBC count, age <6 months, poor response to prophase therapy, and KMT2A rearrangements were all independently associated with inferior outcomes.
●Interfant 06 – The Interfant-06 trial reported 58 percent six-year OS and 46 percent six-year DFS . For patients with KMT2A rearrangement, there was no difference in six-year DFS between those who received lymphoid versus myeloid consolidation therapy.
●Addition of blinatumomab to Interfant 06 – Preliminary results (presented in abstract form) from a phase 2 study of 28 infants reported that addition of blinatumomab to the Interfant 06 backbone was well-tolerated and associated with 89 percent MRD-negative CR . Longer-term follow-up is awaited.
Down syndrome — Patients with trisomy 21/Down syndrome (DS) who develop ALL/LBL are particularly susceptible to treatment-related AEs and mortality. Management should take place in a center with experience treating DS-associated leukemias, if possible.
Patients with DS-associated ALL/LBL are typically treated with reduced-intensity chemotherapy. Many patients are cured without transplantation, which has been associated with high TRM in children with DS [11,178]. These children have increased risk of infections and intensive chemotherapy regimens frequently cause severe mucositis . Analysis of 653 children with DS-ALL/LBL reported both a high rate of relapse (26 percent eight-year cumulative relapse) and increased two-year treatment-related mortality (7 versus 2 percent in non-DS-ALL/LBL) . (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Down syndrome'.)
Although cytogenetic changes other than trisomy 21 are uncommon with DS-ALL/LBL, patients with concurrent low-risk cytogenetics (ETV::RUNX1) have an exceptionally good prognosis . Those with high-risk features can be treated with reduced-intensity conditioning followed by HCT, but outcomes remain poor .
OUTCOMES — Contemporary treatment of pediatric ALL/LBL is associated with 98 percent complete remission (CR), 90 percent five-year overall survival (OS), 1 percent induction mortality, and <3 percent 10-year cumulative incidence of treatment-related mortality (TRM) [131,182-186].
No regimen has been proven to be superior. Improved outcomes are the result of risk-stratified treatment, improved central nervous system prophylaxis, better supportive care, and high rates of enrollment in well-designed cooperative group trials [131,187]. Details of outcomes with treatment for pediatric ALL/LBL are presented separately. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
TRM remains a challenge. Acute infectious and noninfectious toxicities are common during therapy and can be associated with significant morbidity and 3 to 5 percent mortality . Long-term toxicities are also a substantial burden to survivors of ALL and can have a significant impact on quality of life, neurocognition, adult function, and long-term survival [189,190].
Outcomes are associated with age, presenting white blood cell count, immunophenotype, and cytogenetic/molecular features (table 2). Patients who respond rapidly and robustly to induction and consolidation phases have more favorable outcomes than those with a slow response or incomplete remission [56,111,191-194].
Details of prognosis for ALL/LBL in children and adolescents are presented separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Leukemia in children (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Principles of treatment – Optimal outcomes with acute lymphoblastic leukemia/lymphoma (ALL/LBL) are associated with adherence to a contemporary research protocol and treatment at a site with substantial experience in managing pediatric ALL/LBL (or in close consultation with an experienced pediatric oncologist). (See 'Treatment principles' above.)
●Pretreatment evaluation – In addition to clinical and laboratory evaluation and bone marrow examination, all patients require (see 'Clinical and laboratory evaluation' above):
•Lumbar puncture (LP) – Initial diagnostic LP should be coupled with the first treatment with intrathecal (IT) chemotherapy. (See 'Lumbar puncture' above.)
•Pretreatment risk stratification – Treatment is guided by the leukemic immunophenotype, genetic/molecular features, age, presenting white blood cell (WBC) count (table 2) and response to therapy. (See 'Risk stratification' above.)
●Complications – Life-threatening complications of ALL/LBL or its treatment include tumor lysis syndrome (TLS), cytopenias, infections, thrombosis, and bleeding. (See 'Complications of ALL/LBL and treatment' above.)
●Treatment – Therapy of pediatric ALL/LBL is intensive, complex, and prolonged. Treatment should adhere to the chosen protocol; it is not advisable to "mix and match" stratification schemes, CNS management, and treatment phases from different research groups/protocols.
Treatment is divided into phases:
•Central nervous system (CNS) management – Patients receive CNS-directed therapy throughout treatment, according to findings from the initial LP and clinical/genetic features (algorithm 1). (See 'CNS management' above.)
-Higher risk – Management generally includes IT therapy plus systemic treatment and/or cranial radiation therapy (RT).
-Lower risk – For patients with lower risk of CNS relapse, we suggest prophylaxis with IT methotrexate (MTX) or triple IT therapy, rather than cranial RT (Grade 2C).
•Remission induction – Intensive treatment using a glucocorticoid, vincristine, and asparaginase for four to six weeks; some protocols include an anthracycline or a targeted agent. (See 'Remission induction' above.)
•Response assessment – Bone marrow (BM) examination at end-of-induction is analyzed for morphologic response and measurable residual disease (MRD). (See 'Response assessment' above.)
Response criteria are evolving; historically, response was judged as:
-Complete remission (CR) – <5 percent BM blasts, clearance of extramedullary and circulating blasts, and recovery of blood counts.
-Less than CR – Children who do not achieve CR are treated for refractory ALL/LBL. (See "Relapsed or refractory acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
•Consolidation/intensification – For patients in CR, treatment is guided by findings from end-of-induction MRD examination and risk category. Consolidation may include:
-Chemotherapy – (See 'Chemotherapy' above.)
-Allogeneic hematopoietic cell transplantation (HCT) – (See 'Allogeneic HCT' above.)
-Immunotherapy – (See 'Immunotherapy' above.)
•Maintenance therapy – Lower-intensity treatment with vincristine, mercaptopurine, glucocorticoid pulses, and IT MTX that lasts up to two and one-half years. (See 'Maintenance therapy' above.)
●Follow-up – Patients are monitored for relapse, late complications of therapy, and growth/development. (See 'Follow-up' above.)
●Special scenarios – Special considerations are needed for certain disease categories and populations:
•T cell ALL/LBL – (See 'T cell ALL/LBL' above.)
•Philadelphia chromosome (Ph)-positive ALL/LBL – (See 'Ph+ B-ALL/LBL' above.)
•Infants – (See 'Infant ALL/LBL' above.)
•Adolescents/young adults – (See 'Adolescents/young adults' above.)
•Down syndrome – (See 'Down syndrome' above.)
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58 : Systemic Exposure to Thiopurines and Risk of Relapse in Children With Acute Lymphoblastic Leukemia: A Children's Oncology Group Study.
59 : Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.
60 : Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study.
61 : 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study.
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125 : Elective testicular biopsy during chemotherapy for childhood leukaemia is of no clinical value.
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127 : Immunodeficiency in children with acute lymphoblastic leukemia after completion of modern aggressive chemotherapeutic regimens.
128 : Current chemotherapy protocols for childhood acute lymphoblastic leukemia induce loss of humoral immunity to viral vaccination antigens.
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146 : JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias.
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150 : Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005.
151 : Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial.
152 : Imatinib mesylate in combination with chemotherapy in four children with de novo and advanced stage Philadelphia chromosome-positive acute lymphoblastic leukemia.
153 : Longer follow-up confirms major improvement in outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish Cooperative Study SHOP/ALL-2005.
154 : Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031.
155 : Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.
156 : Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study.
157 : Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): a prospective, intergroup, open-label, single-arm clinical trial.
158 : Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis.
159 : Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study.
160 : Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review.
161 : Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005.
162 : Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993.
165 : Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.
166 : Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.
167 : Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens.
168 : Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.
169 : Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial.
170 : Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen.
171 : Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children's Oncology Group Study AALL0232.
172 : Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper-CVAD regimen.
173 : Adoption of pediatric-inspired acute lymphoblastic leukemia regimens by adult oncologists treating adolescents and young adults: A population-based study.
175 : A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.
176 : Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study.
177 : A Phase 2 Study to Test the Feasibility, Safety and Efficacy of the Addition of Blinatumomab to the Interfant06 Backbone in Infants with Newly Diagnosed KMT2A-Rearranged Acute Lymphoblastic Leukemia. a Collaborative Study of the Interfant Network
178 : Improved Toxic Mortality Rates for Children with Down Syndrome Acute Lymphoblastic Leukemia (DS-ALL) Treated on Children's Oncology Group (COG) Trials for Standard Risk (SR; AALL0331) but not High Risk (HR; AALL0232) ALL
179 : Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol.
180 : Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group.
182 : Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century.
184 : Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group.
186 : Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience.
187 : Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances.
188 : Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.
189 : Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.
190 : Cognitive, behaviour, and academic functioning in adolescent and young adult survivors of childhood acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study.
191 : A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome.
192 : Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008.
193 : Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial.
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