Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents

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 the same disease, distinguished only by the primary location of the disease and level of bone marrow involvement.

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 toxicity. Optimizing outcomes for pediatric ALL/LBL, while simultaneously limiting toxicities, 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 "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)

PRETREATMENT — 

The 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 – 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 syndrome (eg, dysphagia, dyspnea, and swelling of face, neck, or upper extremities).

•Physical examination – The child is evaluated for hepatosplenomegaly and lymphadenopathy. The neurologic examination should include an 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'.)

Children with somatic findings consistent with Down syndrome or inherited/germline genetic conditions warrant special consideration that may influence the treatment of ALL/LBL, as discussed below. (See 'Down syndrome' below.)

●Laboratory

•Hematology – Complete blood count 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 and uric acid.

•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 varies among institutions.

•Pregnancy testing – As appropriate.

●Bone marrow – The bone marrow specimen is evaluated by flow cytometry for immunophenotype (ie, B cell versus T cell) and cytogenetic/molecular techniques to determine the ALL/LBL subtype, as described separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

●Central nervous system evaluation – All patients should have a diagnostic lumbar puncture (LP) to evaluate central nervous system (CNS) involvement, including cytology for leukemic cells in the cerebral spinal fluid. If the diagnosis of ALL is established before the diagnostic LP, it is customary to administer the first intrathecal chemotherapy with the first LP.

Imaging is performed as clinically indicated by neurologic findings. Some protocols require imaging in every case.

CNS evaluation is described below. (See 'Central nervous system evaluation' below.)

●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 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 suspicious lymphadenopathy or superior vena cava syndrome.

-Positron emission tomography (PET) – If lymphomatous involvement is suspected (eg, lymphadenopathy, mediastinal mass, or bone lesions).

-Brain and/or spine CT or magnetic resonance imaging (MRI) if neurologic abnormalities are present. (See 'Central nervous system evaluation' below.)

-Scrotal ultrasound – For suspected testicular involvement.

•Pretreatment management

-Placement of a central venous access device.

-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 and to initiate a donor search, if indicated.

OVERVIEW — 

Treatment of pediatric ALL/LBL is intensive, complex, and prolonged. The management should be overseen by clinicians experienced with the disease and its treatment and complications. Optimal outcomes are associated with strict adherence to a contemporary research protocol.

ALL/LBL subtype — The management of pediatric ALL/LBL varies according to the leukemia subtype.

Most cases are B cell immunophenotype, while approximately 15 percent are T cell immunophenotype. The frequency of Philadelphia chromosome (Ph)-positive ALL is <5 percent in children, but the incidence increases in adolescents and young adults.

●(See 'B cell ALL/LBL' below.)

●(See 'T cell ALL/LBL' below.)

●(See 'Philadelphia chromosome-positive' below.)

Features and classification of ALL/LBL subtypes are discussed separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

Risk stratification — Management of ALL/LBL is guided by the risk for relapse, which is determined by clinical presentation, immunophenotype, cytogenetic features of the leukemic cells, and response to initial therapy (table 1) [1]. Risk stratification affects all phases of treatment.

●Standard risk

•Clinical features – White blood cell (WBC) count <50,000/microL, age ≥1 year to <10 years.

•Cytogenetic features – Hyperdiploid karyotype (>50 chromosomes [in particular with trisomy of chromosomes 4 and 10, according to some groups]), ETV6::RUNX1-fusion.

●High risk

•Clinical features – WBC ≥50,000/microL, age <1 year or ≥10 years.

Treatment of children <1 year is discussed below. (See 'Infant ALL/LBL' below.)

•Genetic features – Hypodiploid karyotype (<44 chromosomes), Ph positivity, Ph-like phenotype, KMT2A-rearrangement, iAMP21, or t(17;19).

Risk-stratified therapy provides excellent outcomes with lower treatment intensity and less toxicity for most children with ALL/LBL. Children with high-risk features receive intensified therapy that may cause more adverse effects (AEs).

Risk factors are defined differently by some cooperative groups/consortia. Risk stratification should be according to the criteria used in the chosen treatment protocol.

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".)

Phases of treatment — Details of drugs, doses, timing, and other aspects of management vary among clinical trial groups, and no approach has been proven to be superior. Treatment should adhere to the chosen protocol; it is not advisable to "mix and match" components of care from different treatment protocols.

Broadly speaking, management of ALL/LBL can be grouped into:

●Remission induction – Remission induction reduces the initial burden of disease and seeks to achieve complete remission (CR). Remission induction therapy is guided by the clinical and pathologic features (ie, immunophenotype and cytogenetic findings) at presentation.

●Consolidation/late intensification – Consolidation/late intensification is guided by the disease subtype and the response to induction therapy.

●Maintenance – Maintenance phase is prolonged (≥2 years) lower-intensity chemotherapy that may vary by leukemic subtype.

●Central nervous system management – All patients require evaluation and management for central nervous system (CNS) involvement, as discussed below. (See 'Central nervous system evaluation and management' below.)

Certain patient populations require distinctive management, as discussed below. (See 'Special populations' below.)

Outcomes — Treatment outcomes have improved with the development of more effective therapy, the use of measurable residual disease (MRD) to assess treatment response, proactive CNS management, better supportive care, and increased attention to preventing long-term AEs.

Contemporary pediatric regimens are associated with 98 percent CR, 90 percent 5-year overall survival, 1 percent mortality during induction therapy, and <3 percent cumulative 10-year treatment-related mortality (TRM) [2-10]. Late AEs can impair quality of life, neurocognition, adult function, and long-term survival in survivors of childhood ALL/LBL [9,10].

Details of outcomes are presented separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)

Emergencies/complications — ALL/LBL and its treatment may be associated with life-threatening complications, including:

●Tumor lysis syndrome – Tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis and the 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, and acute kidney failure.

ALL/LBL is associated with an intermediate to high risk for TLS [11]. (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 for those with elevated uric acid [12]. Rasburicase-associated AEs 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 [13].

In rare cases, hemodialysis may be needed to remove excess circulating uric acid and phosphate in patients who develop acute kidney failure. (See "Tumor lysis syndrome: Prevention and treatment", section on 'TLS prophylaxis'.)

•Incidence and risk factors – The incidence of TLS varies among studies.

In one study, TLS was reported in nearly one-quarter of children during treatment of ALL/LBL [14]. Age >10 years, splenomegaly, mediastinal mass, and presenting WBC count ≥20,000/microL were associated with an increased risk.

●Infections – Infections are the most common cause of TRM in pediatric ALL/LBL.

Patients are susceptible to 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 jirovecii (eg, using sulfamethoxazole-trimethoprim, pentamidine, dapsone, or atovaquone) is routinely given, while administration of other antibiotic, antifungal, and antiviral agents varies among institutions.

Growth factors, such as granulocyte colony-stimulating factor (G-CSF), have not been shown to improve survival 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 [15]. 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, need for hospitalization, or survival at six years [16]. (See "Fever in children with chemotherapy-induced neutropenia".)

•Sepsis/infections – Deaths due to sepsis were reported in 2.4 percent of 3126 children in the prospective UKALL 2003 trial; these deaths accounted for two-thirds of TRM [17]. Infection-related mortality occurred during induction therapy (48 percent), 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, Escherichia coli, Enterococcus spp), fungi (20 percent; eg, Aspergillus spp, Candida spp), and viruses (12 percent).

A retrospective review reported infection in one-fifth of 425 children undergoing induction therapy, and it was especially common in children who were neutropenic or had an underlying condition (eg, Down syndrome, congenital heart disease, pre-existing immunodeficiency syndromes) [18]. 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, with platelet counts <10,000/microL presenting the 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 vitamin K, as discussed separately. (See "Overview of vitamin K", section on 'Vitamin K-deficient bleeding in newborns and young infants'.)

●Cytopenias – Cytopenias at presentation are compounded by prolonged treatment with cytotoxic agents. Transfusion support for infants and children is discussed separately. (See "Red blood cell transfusion in infants and children: Selection of blood products".)

●Thrombosis – There is an increased risk for venous thromboses, including the inferior vena cava, superior sagittal sinus, and other deep veins, with or without pulmonary embolism.

Most thromboembolic events are associated with asparaginase-containing regimens, but the underlying malignancy, a central venous catheter, and administration of other prothrombotic medications (eg, glucocorticoids) may also contribute. Asparaginase-related thrombosis is discussed below. (See 'Asparaginase' below.)

●Hypothalamic-pituitary-adrenal axis suppression – Daily administration of glucocorticoids during induction therapy suppresses the hypothalamic-pituitary-adrenal (HPA) axis in most patients [19]. Stress-dose steroids should be administered as needed during infections, trauma, or surgery. (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 ACTH (adrenocorticotropic hormone) stimulation, but all patients recovered normal adrenal function within 10 weeks of induction therapy [20]. However, another study reported that HPA axis suppression can last for up to 34 weeks [21].

B CELL ALL/LBL — 

Approximately 85 percent of cases of pediatric ALL/LBL are B cell lineage.

Induction therapy — Remission induction therapy for B cell ALL/LBL is stratified according to the risk of relapse, based on clinical and pathologic features at presentation, as described above. (See 'Risk stratification' above.)

Remission induction therapy for B cell ALL/LBL includes a glucocorticoid, vincristine, and pegylated asparaginase. Some protocols incorporate an anthracycline into remission induction therapy for all patients, while others include an anthracycline only for some high-risk subgroups. Drug doses and schedules vary with the risk category and the chosen protocol. The components of induction therapy are discussed in the sections that follow.

Examples of treatment protocols for B cell ALL/LBL by the Children's Oncology Group (COG) include:

●Standard risk – Induction therapy with a glucocorticoid, vincristine, and pegasparaginase and central nervous system (CNS) prophylaxis, as in COG AALL0932 [22] and COG AALL0331 [23].

●High risk – Inclusion of an anthracycline, more intensive glucocorticoid treatment, and CNS prophylaxis, as in COG AALL1131 [24,25].

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.

Dexamethasone has a longer half-life and better CNS penetration than prednisone, but it is associated with more frequent adverse effects (AEs), including infections, fractures, osteonecrosis, mood/behavior problems, and myopathy [26]. Adolescents have a higher risk of osteonecrosis with dexamethasone [24].

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 neuropsychologic AEs) [27-30].

Studies that compared dexamethasone versus prednisone reported mixed results:

●A meta-analysis that compared dexamethasone with prednisone in nearly 9000 children with ALL/LBL in 8 randomized trials reported no difference in overall survival (OS) or AEs, including osteonecrosis, sepsis, fungal infection, diabetes, or pancreatitis [26].

●The phase 3 ALL0232 trial of 2154 patients with high-risk B cell ALL/LBL reported that dexamethasone improved outcomes for patients aged <10 years, but it was associated with a higher risk of osteonecrosis in patients ≥10 years [24].

●The phase 3 AIEOP-BFM ALL 2000 trial of 3720 children reported no difference in OS with dexamethasone versus prednisone [31]. Dexamethasone was associated with a lower five-year relapse rate (11 versus 16 percent) but more induction-related deaths (2.5 versus 0.9 percent). The benefit of dexamethasone was mostly in patients with T cell ALL/LBL.

Vincristine — Vincristine is a component of induction therapy, and its use continues throughout the course of treatment, including during maintenance therapy (although some protocols do not include vincristine in maintenance therapy).

The dose of vincristine 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 manifest as paresthesias, loss of reflexes, weakness, and autonomic neuropathies (including vocal cord paralysis).

Virtually all patients have some degree of peripheral neuropathy with vincristine; while it is usually reversible, 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 [32].

Asparaginase — Asparaginase is associated with superior outcomes in pediatric ALL/LBL but has substantial toxicity.

Pegylated asparaginase (conjugation with polyethylene glycol [PEG], which slows clearance of asparaginase) is the preferred preparation because it provides equal or greater efficacy than other formulations while being less immunogenic [33-37]. Patients who receive pegylated asparaginase are less likely to develop antibodies that increase the clearance of asparaginase from circulation [38-45].

●Administration

•Pegylated asparaginase – The dose and schedule for pegaspargase (pegylated Escherichia coli asparaginase) are defined by the treatment protocol. The US Food and Drug Administration (FDA) label lists 2500 units/m² no more frequently than every 14 days for patients ≤21 years.

Calaspargase pegol is a formulation that enables a longer interval between doses (eg, 2500 units/m² intravenously every three weeks). Calaspargase pegol is approved by the FDA for treatment of ALL in patients 1 month to 21 years [46].

•Nonpegylated preparations – Nonpegylated asparaginase preparations are more immunogenic and require more frequent administration.

Nonpegylated products include:

-Native E. coli asparaginase – This formulation is not available in the United States. The half-life is approximately one day. The dose and schedule of administration varies according to the protocol.

-Erwinia asparaginase – This preparation is not available in the United States. The half-life is approximately 8 hours when given intravenously and 16 hours when given intramuscularly. A typical regimen is 25,000 units/m² administered three times weekly.

-Recombinant Erwinia asparaginase – This product is approved by the FDA for patients with hypersensitivity to E. coli asparaginase, including PEG-asparaginase. The half-life is approximately 14 hours. Dosing regimens include 25 mg/m² administered every 48 hours or 25 mg/m² on Monday and Wednesday and 50 mg/m² on Friday.

●Toxicity – Asparaginase can cause allergic reactions, coagulopathies, acute pancreatitis, and hepatic toxicity [47].

Because of the relatively high incidence of infusion reactions, asparaginase should only be administered in settings where anaphylaxis can be appropriately managed. A period of observation following administration of pegylated asparaginase is common practice at many institutions because anaphylaxis may be delayed.

•Anaphylaxis – The incidence of anaphylaxis may vary with the route of administration.

Medications should be readily available to treat anaphylaxis. Premedication with acetaminophen, diphenhydramine, and an H2-blocker may decrease the incidence of allergic reactions, but the benefit is uncertain [25,48-50]. Premedication, however, may mask an allergic reaction that might herald the 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 [51]. Switching to a nonpegylated formulation or an Erwinia source is indicated for patients who experience PEG allergy or persistent anti-PEG antibodies; drug desensitization can also be successful [52,53]. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase' and "Anaphylaxis: Emergency treatment".)

In a study of 16,534 patients enrolled on COG clinical trials, grade ≥3 allergic reactions were more frequent with subcutaneous or intramuscular administration, than with intravenous treatment [54]. After the second or third treatment, allergic reactions occurred in 10 percent of patients receiving it subcutaneously or intramuscularly, compared with 5 percent with intravenous administration. Another trial also reported that intravenous treatment caused fewer allergic reactions but more anxiety [55]. Patients who develop an anaphylactic reaction to one preparation may be considered for treatment with another preparation, as discussed separately. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

•Thrombosis – Asparaginase can induce a hypercoagulable state and catastrophic thrombosis of the inferior vena cava or the superior sagittal sinus, in addition to deep vein thromboses with or without pulmonary embolism. The risk of thromboembolic events in children increases with age, the presence of a central venous catheter, and treatment with an asparaginase-containing regimen [56-61].

Consistent asparaginase activity levels >50 to 100 international units completely deplete serum asparagine (thereby inhibiting protein synthesis in leukemic cells) [62] but also reduce the synthesis of coagulation-associated plasma proteins [63,64]. This can cause prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, and hypofibrinogenemia, with fibrinogen levels often <100 mg/dL.

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) [65], and a prospective study of >1000 children (ages 1 to 18 years) reported thrombosis in 6 percent [57]. 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 [66]. E. coli asparaginase and nonpegylated forms of asparaginase appear to have equivalent risks for severe thrombosis.

Management of asparaginase-associated thrombosis, including anticoagulation and use of antithrombin, is discussed separately. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)

•Neutralizing antibodies – Neutralizing antibodies against E. coli asparaginase develop in 2 to 8 percent of children treated for ALL/LBL [62,67]. Neutralizing antibodies are generally associated with symptoms of hypersensitivity, but some patients with inactivating antibodies have silent inactivation without allergic manifestations. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

Children who develop neutralizing antibodies can often be treated successfully with Erwinia-based asparaginase since there is only approximately 10 percent antibody cross-reactivity between E. coli and Erwinia preparations [68].

●Monitoring asparaginase activity – Monitoring asparaginase levels can help to detect enzyme-inactivating antibodies.

Monitoring of asparaginase antibody levels is not universal. Some clinicians monitor antibodies only if there has been an allergic reaction or there is concern that antibodies may inactivate the drug. Expert recommendations for monitoring asparaginase have been published [69].

Serum drug levels are minimal or nondetectable in many patients who develop antibodies to asparaginase. If asparaginase levels are nondetectable with one preparation, an alternative preparation may be more effective. The best time to measure asparaginase activity depends on the formulation, dosing, and schedule of asparaginase used. We consider ≥0.1 international units/mL 14 days post-administration a desirable level of activity for patients receiving pegylated asparaginase [69].

Response assessment — Bone marrow is examined at the end of induction phase to determine if the patient achieved a morphologic remission and to assess the level of measurable residual disease (MRD).

Clinical/morphologic response criteria include [70]:

●Complete remission (CR)

•Blast clearance

-Bone marrow blasts <5 percent

-No circulating blasts or extramedullary disease

•Blood count recovery

-Absolute neutrophil count >1000/microL

-Platelets >100,000/microL

•No relapse – No evidence of recurrence for ≥4 weeks.

●Less than CR – Failure to achieve any of the criteria above.

There is no consensus approach for monitoring MRD. Many clinical settings use flow cytometry, which is generally sensitive to the level of 10^-4 (1 leukemic cell per 10,000 nucleated cells). Others use more sensitive molecular techniques to assess MRD. As an example, rearrangement of immunoglobulin loci or mutation testing can provide 10^-6 sensitivity. Methods and thresholds for detecting MRD are described separately. (See "Detection of measurable residual disease in acute lymphoblastic leukemia/lymphoblastic lymphoma".)

Consolidation/intensification therapy — Consolidation/late intensification therapy for B cell ALL/LBL is evolving with the availability of effective immunotherapy and the widespread use of MRD for response assessment.

Treatment is generally stratified according to the MRD response to induction therapy. Consolidation/late intensification includes multiagent chemotherapy, with or without blinatumomab (CD19 x CD3 bispecific T cell enhancer).

●Chemotherapy – This generally includes a glucocorticoid, cyclophosphamide, cytarabine, vincristine, pegylated asparaginase, and 6-mercaptopurine (6-MP). No regimen has proven superior, and studies that compared the intensity of chemotherapy have reported varying results.

Some trials reported that augmented chemotherapy achieved better outcomes (eg, UKALL 2003 [71], CCG 1961 [72]), while others reported no clear benefit beyond previously proven intensification approaches (eg, COG AALL0331 [23], COG AALL1131 [25,73], NOPHO ALL 2008 [74]). The intensification of therapy for high-risk patients that was reported by CCG 1961 [72] continues in contemporary protocols.

●Blinatumomab – Blinatumomab improves outcomes for some patients when it is added to consolidation chemotherapy, but the method and threshold for assessing MRD and the timing and number of cycles of blinatumomab should be guided by the chosen protocol.

The phase 3 AALL1731 trial was stopped early when a planned interim analysis found that blinatumomab plus chemotherapy achieved better outcomes than chemotherapy alone [75].

However, the results may not be broadly generalizable because the method for detecting MRD (high-throughput sequencing of immunoglobulin loci) is more sensitive than flow cytometry, which is more often used clinically. At three years, there was no difference in OS, but blinatumomab plus chemotherapy achieved better disease-free survival (96.0 versus 87.9 percent) and fewer relapses (3.3 versus 11.8 percent) than chemotherapy alone. However, the incidence of grade ≥3 nonfatal sepsis and catheter-related infections was higher among patients with average relapse risk who received blinatumomab.

Maintenance chemotherapy — Maintenance phase is lower-intensity multiagent chemotherapy that is generally given for at least two years.

Maintenance therapy generally includes daily 6-MP, weekly methotrexate, and periodic intrathecal (IT) therapy, with or without pulses of vincristine and a glucocorticoid [76-78]. Drug doses, schedules, and duration of maintenance therapy vary among clinical trial groups. Some protocols vary the intensity and/or duration of maintenance therapy for selected patients.

●Importance of treatment adherence – 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 [79].

A consistent daily routine (ie, either morning or evening dosing) improves treatment adherence and outcomes. Self-reporting frequently overestimates the true intake of 6-MP, particularly in poorly adherent patients [80]. A cohort study reported that the rate of relapse was increased in patients with <90 percent adherence to 6-MP administration [81].

●Duration – Maintenance phase usually lasts for two years, but this may vary in different protocols.

One study reported that <1 year of maintenance therapy was associated with a higher rate of relapse (39 percent at 12 years), but it still cured more than one-half of the children with ALL/LBL [82]. However, shortened maintenance therapy was associated with excellent outcomes for some ALL/LBL subtypes (eg, TCF3::PBX1 and ETV6::RUNX1 rearrangements).

●Antimetabolite – 6-MP, which is metabolized to the bioactive compound 6-thioguanine, is the preferred antimetabolite for maintenance therapy.

Drug and metabolite concentrations vary widely; age, sex, and genetic polymorphisms affect the bioavailability of 6-MP [83-87]. To optimize dosing, we determine the genotype of TPMT (thiopurine S-methyltransferase) and NUDT15 (nudix hydrolase 15) enzymes. TPMT heterozygosity (5 to 10 percent of patients, but the frequency varies among certain populations) is associated with increased toxicity [88-90]. NUDT15 deficiency is also associated with 6-MP intolerance.

Compared with 6-MP, 6-thioguanine caused excess toxicity without an apparent benefit in a phase 3 trial of nearly 1500 children [91]. With six-year follow-up, there was no difference in OS or event-free survival (EFS) between trial arms. 6-thioguanine was associated with fewer isolated CNS relapses (odds ratio [OR] 0.53 [95% CI 0.30-0.92]), but this was offset by an 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 noncirrhotic portal hypertension due to liver fibrosis or nodular regenerative hyperplasia [92,93]. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in children".)

●Vincristine/steroid pulses – The use and schedule of vincristine/steroid pulses varies among protocols. Studies that tested the role of vincristine/steroid pulses in maintenance therapy have reported mixed results.

•A meta-analysis that included 1700 patients in 11 randomized trials reported that adding vincristine/steroid pulses to maintenance therapy was associated with improved five-year EFS (OR 0.71 [95% CI 0.61-0.84]) but did not affect OS [94].

•Adding pulses of vincristine and prednisone to maintenance therapy achieved better EFS than maintenance with 6-MP and methotrexate alone in a phase 3 trial [95]. However, the addition of one-week pulses of dexamethasone with two doses of vincristine did not improve outcomes in another randomized trial [96].

•In the AALL0932 phase 3 trial of 2364 children with average-risk ALL/LBL, neither decreasing the frequency of vincristine/dexamethasone pulses (from every 4 weeks to every 12 weeks) nor increasing the weekly dose of methotrexate (from 20 mg/m² to 40 mg/m²) in maintenance therapy significantly impacted outcomes [22].

T CELL ALL/LBL — 

T cell ALL/LBL was historically associated with a poor prognosis, but outcomes have improved with the intensification of treatment. We encourage participation in a clinical trial when possible.

T cell ALL/LBL most commonly affects adolescent/young adult patients, and they are more likely than others to have a mediastinal mass (60 percent) and/or central nervous system (CNS) involvement (10 percent) [2,97]. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma".)

Although T cell lineage was historically associated with inferior outcomes, the use of intensified treatment now achieves outcomes that are similar to B cell ALL/LBL [98-100]. A subset of patients has early T cell progenitor (ETP) ALL/LBL, which is characterized by the absence of CD1a and CD8, weak CD5 expression, and expression of one or more myeloid or stem cell markers [101]; ETP ALL/LBL is treated like other T cell ALL/LBL [99].

Distinctive features of T cell ALL/LBL management include:

●Induction therapy – All cooperative groups include an anthracycline and/or nelarabine along with a glucocorticoid, vincristine, and pegylated asparaginase [99].

•Anthracycline – The addition of an anthracycline to induction therapy is more effective than three-drug regimens for T cell ALL/LBL, based on randomized trials [102-104].

•Dexamethasone – Dexamethasone is generally used because it is more potent and has increased CNS penetration compared with prednisone, but it is associated with more infections [98].

UKALL2003, which used dexamethasone, was associated with improved overall survival (OS) and low rates of infections and avascular necrosis, compared with earlier studies [71,105]. AIEOP-BFM 2000 reported that, compared with prednisone, dexamethasone achieved a lower rate of five-year relapse (11 versus 16 percent) but more toxicity and increased treatment-related mortality (TRM; 3 versus 1 percent) [106]. DFCI ALL 00-01 suggested that dexamethasone was associated with improved five-year event-free survival [103].

●Response monitoring – T cell ALL/LBL can respond more slowly than B cell disease. As a result, the level of measurable residual disease (MRD) at the end of consolidation phase is the most important prognostic factor.

Outcomes were favorable with MRD <10^-4 at the end of consolidation phase, regardless of MRD status at the end of induction therapy in the AIEOP-BFM 2000 trial [106]. Other groups reported similar findings [71,107,108]. The prognostic importance of MRD at the end of consolidation is even more striking for ETP ALL/LBL [109]. Unlike B cell disease, no other clinical or genetic features are independently associated with outcomes in T cell ALL/LBL [98,100,110-112].

●Consolidation/late intensification – Randomized trials (CCG 1882 and CCG 1961) demonstrated the benefit of an intensive consolidation phase for T cell ALL/LBL [113,114].

Nelarabine, a deoxyguanosine analog that inhibits deoxyribonucleic acid (DNA) synthesis, is associated with better outcomes for some children with T cell ALL/LBL, but it can cause substantial neurologic and other toxicity. The optimal dose for children is nelarabine 650 mg/m²/day for five days [115]. Adverse effects (AEs) include neuropathy, dizziness, confusion, ataxia, seizures, mood alterations, and cytopenias [116].

Addition of nelarabine achieved superior five-year disease-free survival (88 versus 82 percent) and fewer CNS relapses (1 versus 7 percent) compared with no nelarabine in the phase 3 COG AALL0434 trial for children with intermediate- and high-risk T cell ALL/LBL [117]. Nelarabine was well tolerated, and AEs were similar in both trial arms [118]. Other studies also reported that nelarabine was associated with improved outcomes in children with T cell ALL/LBL [119-121], but it is uncertain if there is benefit with T cell LBL [122]. In the AALL1231 trial, the addition of bortezomib was associated with improved outcomes in T cell LBL [123].

Children with detectable MRD at the end of consolidation are generally offered allogeneic hematopoietic cell transplantation [99].

●Maintenance therapy – Like that for B cell ALL/LBL. (See 'Maintenance chemotherapy' above.)

●CNS management – Some groups use cranial radiation therapy as prophylaxis because of the increased risk for CNS relapse with T cell ALL/LBL. However, we restrict cranial radiation therapy to patients with overt CNS disease (CNS3) at diagnosis to reduce AEs, as used in the COG AALL1231 trial [124].

CNS evaluation and management are discussed below. (See 'Central nervous system evaluation and management' below.)

PHILADELPHIA CHROMOSOME-POSITIVE — 

Philadelphia chromosome (Ph)-positive ALL/LBL accounts for <5 percent of children with ALL/LBL, but the incidence is higher in adolescents.

A BCR::ABL1 tyrosine kinase inhibitor (TKI) is incorporated into all phases of treatment (ie, remission induction, consolidation, and maintenance phases) of Ph-positive ALL/LBL. Cases of Ph-like ALL/LBL may resemble Ph-positive ALL/LBL, but BCR::ABL1 is not detected; some experts treat Ph-like ALL/LBL with a Ph-positive protocol (ie, inclusion of a TKI).

Distinctive aspects of management of Ph-positive ALL/LBL include:

●Remission induction – Induction therapy includes a TKI plus either chemotherapy or a glucocorticoid [125-131]. The TKI generally begins on day 15 of induction therapy.

There is no preferred TKI, and no randomized trials have directly compared individual TKIs in this setting. Long-term outcomes are better with dasatinib-based therapy than imatinib (86 versus 70 to 72 percent five-year overall survival [OS]) [129-131]. A retrospective study reported that ponatinib was associated with better OS and event-free survival than dasatinib, but these data should be confirmed with prospective studies [132].

●Consolidation – Post-remission management varies according to the treatment response at the end of induction.

•Standard risk – For children in complete remission (CR) with low measurable residual disease (MRD) at the end of induction, treatment includes a TKI plus consolidation chemotherapy.

Consolidation therapy has not been directly compared with allogeneic hematopoietic cell transplantation (HCT) for standard-risk Ph-positive ALL/LBL.

•High risk – For patients with a poor disease response, options include consolidation therapy (ie, a TKI plus either chemotherapy, blinatumomab, or tisagenlecleucel [chimeric antigen receptor T cell therapy]), followed by allogeneic HCT.

Allogeneic HCT is associated with better long-term outcomes than consolidation chemotherapy in this setting [133-135], but these approaches have not been directly compared in prospective studies.

●Maintenance – Like that for B cell ALL/LBL, but the TKI is continued indefinitely. (See 'Maintenance chemotherapy' above.)

CENTRAL NERVOUS SYSTEM EVALUATION AND MANAGEMENT — 

Central nervous system (CNS) management is an essential aspect of care and has contributed importantly to improved outcomes for children with ALL/LBL.

Prior to the routine use of CNS prophylaxis, more than one-half of children with ALL/LBL who achieved complete remission (CR) relapsed with leukemic meningitis [136].

Central nervous system evaluation — All children with ALL/LBL should have a diagnostic lumbar puncture (LP) to determine if there is CNS involvement, whether there are neurologic findings.

If neurologic abnormalities are present, brain and/or spine CT or MRI should be performed.

●Diagnostic LP – An experienced clinician should perform the LP, often with the patient under moderate sedation or general anesthesia. The diagnostic LP is generally coupled with the first intrathecal (IT) chemotherapy treatment.

The first diagnostic LP is usually performed prior to systemic chemotherapy, without regard for the level of circulating blasts. Some institutions briefly delay the LP 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). A traumatic LP 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) [137].

Platelets should be transfused before the LP if the patient is bleeding or has significant thrombocytopenia. The threshold for platelet transfusion 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.

●CSF analysis – 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.

●Classification of CNS status – Findings from the initial LP are used to classify CSF status [138], 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.

•Traumatic lumbar puncture (TLP)-positive – TLP (ie, red blood cell [RBC] count ≥10/microL) with blasts but not meeting criteria for CNS3.

Risk factors — Increased risk for CNS relapse is associated with:

●Leukemic cells detected by initial LP (ie, CNS2, CNS3, or TLP)

●Hyperleukocytosis at presentation (>50,000 leukocytes/microL)

●T cell immunophenotype

●High-risk genetic abnormalities (eg, Philadelphia chromosome (Ph)-positive, Ph-like)

Patients with none of these findings are considered standard risk.

Central nervous system prophylaxis — CNS prophylaxis is guided by risk factors and the chosen treatment protocol (algorithm 1).

●Standard risk – For standard-risk disease, we suggest prophylaxis using IT methotrexate or "triple IT therapy" (IT methotrexate, cytarabine, and hydrocortisone), rather than cranial radiation therapy (RT), to reduce adverse effects (AEs).

Prophylaxis using either IT methotrexate or triple IT therapy is associated with CNS relapse in <5 percent and grade ≥3 AEs in <10 percent [139,140]. Cranial RT is not more efficacious than IT therapy, but it is associated with greater short-term and long-term AEs [76,136,141].

A cytospin of the CSF sample should be reviewed by a hematopathologist with every LP for potential relapse.

Outcomes are comparable with IT methotrexate and triple IT prophylaxis.

•Compared with IT methotrexate, triple IT therapy reduced CNS relapses (3.4 versus 5.9 percent), but it did not affect six-year overall survival (OS) or event-free survival in the phase 3 CCG 1952 trial of 2027 children with standard-risk ALL/LBL [142].

•In AALL1131, accrual was stopped when analysis revealed no difference between IT methotrexate and triple IT therapy for relapses (isolated CNS, bone marrow only, or combined), toxicity, five-year OS, or five-year disease-free survival [143].

●Higher risk – Prophylaxis for children with higher risk generally includes IT therapy plus systemic treatment (eg, dexamethasone, high-dose methotrexate with leucovorin rescue, and/or intensive asparaginase) and/or cranial RT.

The 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) [123]; some institutions have eliminated CNS RT entirely. A meta-analysis that pooled data on 16,623 patients with childhood ALL/LBL in 10 trials found that cranial RT reduced CNS relapse only in patients with CNS3; however, even for that subgroup, cranial RT was not associated with improved OS [144].

Patients with CNS2 disease may not require the same level of intensive therapy as the other higher-risk criteria. One approach is the administration of IT cytarabine twice-weekly until one to three successive LPs reveal no blasts [145]. However, analysis of AALL0932 and AALL1131 reported that twice-weekly LPs did not improve survival or relapse risk [146].

Central nervous system involvement — CNS involvement (ie, CNS3 disease) is treated with IT therapy, enhanced systemic treatment, and/or cranial RT according to the chosen protocol.

Enhanced systemic therapy may include dexamethasone (rather than other glucocorticoids), high-dose methotrexate with leucovorin rescue, and/or intensive asparaginase. In some phase 3 trials, dexamethasone was associated with lower rates of CNS relapse than prednisone, but this was offset by increased toxicity [24,147,148].

The use of RT has declined because of substantial long-term neurocognitive deficits, endocrinopathies, growth impairment, and CNS secondary malignancies, especially when treating younger children [149,150]. Contemporary cranial RT generally uses ≤18 gray (Gy) to limit AEs.

A meta-analysis of data from 16,623 patients with childhood ALL/LBL in 10 trials found that cranial RT reduced CNS relapse only in patients with CNS3 disease; however, even for that subgroup, cranial RT was not associated with improved OS [144]. Cranial RT did not reduce CNS relapse compared with IT treatment in phase 3 trials [151,152].

Further discussion of the long-term effects of cranial RT is presented separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Central nervous system, mental health, and cognition' and "Delayed complications of cranial irradiation".)

FOLLOW-UP — 

Patients are monitored for relapse and screened for long-term adverse effects (AEs) of treatment.

Most children with ALL/LBL are under the care of a pediatric oncologist while they are receiving chemotherapy and for several years after completing therapy. Follow-up can transition to a long-term cancer survivor program, where available. A primary care provider generally assumes health maintenance and other medical needs after treatment is completed.

●Monitoring for relapse – 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.

Blood counts and clinical evaluation for possible relapse are performed regularly, as specified by the chosen treatment protocol.

Clinical manifestations of relapse are like 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/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 to patients with a history of 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 an evaluation of cerebrospinal fluid (CSF) in association with lumbar puncture (LP) for intrathecal (IT) chemotherapy administration. This is usually reserved for patients with CNS symptoms.

•Other sites – Testicular relapse is uncommon (<5 percent) with contemporary treatments, but it may present as unilateral, painless testicular enlargement [153]. Diagnosis of relapse is made by testicular biopsy; bilateral biopsies should be performed because leukemic cells are frequently found in the contralateral testis [153].

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 an 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 the late effects of pediatric ALL/LBL treatment are presented separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment 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.

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 while patients are receiving chemotherapy, in part because the effectiveness of vaccination in an immunocompromised patient is unclear [154]. Live-virus vaccines, such as varicella, measles-mumps-rubella (MMR), and oral poliovirus, are contraindicated. Approximately 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 [155,156]. For this reason, some centers routinely check antibody titers three to six months after completing chemotherapy; children with low antibody titers are generally revaccinated [154,157]. (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 [154]. (See "Immunizations in hematopoietic cell transplant candidates, recipients, and donors".)

SPECIAL POPULATIONS — 

Treatment of ALL/LBL is modified for certain populations of children.

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, Philadelphia chromosome [Ph]-positive, 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 [158,159].

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 [149], NOPHO ALL2008 [160], DFCI ALL 00-01 [103], and C10403 [161].

●Superiority of pediatric regimens may be related to greater treatment intensity (eg, more cumulative asparaginase, vincristine, steroids; incorporation of delayed intensification, more intensive central nervous system [CNS] prophylaxis) and lower cumulative doses of alkylators, anthracyclines, and cytarabine (thereby reducing long-term adverse effects [AEs], especially infertility) [161-163]. However, asparaginase therapy carries a higher risk of hepatic, pancreatic, and thrombotic complications; the risk increases in older or obese individuals [160,161,164-166].

●As an example, AYA patients in COG AALL0232 achieved 77 percent five-year overall survival (OS) and 65 percent five-year event-free survival [167]. Other studies reported that compared with adult-like regimens, outcomes with pediatric regimens were superior [161]. However, a single-institution study found that hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) was associated with outcomes that were comparable with pediatric-like therapy [168].

●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 [163]. One study reported that only one-third of AYAs who were treated by adult oncologists received pediatric-type regimens [169].

Infant ALL/LBL — Most infants with ALL/LBL present with adverse prognostic features (eg, high white blood cell count, CNS involvement, leukemia cutis, KMT2A rearrangement). Infant ALL/LBL is associated with a 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 hematopoietic cell transplantation (HCT) in this setting.

●Molecular features – 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 [170]. Blasts in infant ALL/LBL frequently coexpress lymphoid and myeloid markers.

●Management – Infants with ALL/LBL should be enrolled in a clinical trial whenever possible. Treatment generally involves a seven-day prophase of prednisone therapy followed by a complex protocol of induction, consolidation, and maintenance phases [171,172].

Adding blinatumomab (CD19 x CD3 bispecific T cell engager) to chemotherapy was associated with improved survival and deep responses in 30 infants with KMT2A-rearranged ALL/LBL [173], compared with the same chemotherapy regimen alone in an earlier trial (Interfant-06) [172]. The addition of one post-induction course of blinatumomab (15 microg/m²/day in a 28-day continuous infusion) to the Interfant-06 protocol was associated with 93 percent two-year OS (compared with 66 percent in Interfant-06) and 82 percent two-year disease-free survival (compared with 49 percent in Interfant-06). After blinatumomab infusion, measurable residual disease (MRD) was negative in 16 patients and <5 x 10^-4 in 12 additional patients; all patients who continued chemotherapy became MRD-negative during further treatment. There were 10 serious AEs (ie, infections, fever, hypertension, vomiting), but none were attributed to blinatumomab treatment.

Blinatumomab is approved by the US Food and Drug Administration (FDA) for the treatment of CD19-positive B cell ALL/LBL in children ≥1 month old.

Down syndrome — Patients with trisomy 21/Down syndrome (DS) who develop ALL/LBL are particularly susceptible to treatment-related mortality (TRM) and AEs. Management should take place in a center with experience treating DS-associated leukemias, if possible.

Patients with DS-associated cancers are typically treated with reduced-intensity chemotherapy, but DS-associated ALL/LBL requires intensive chemotherapy (ie, no reduced intensity) [174]. Because of an increase in infection-related TRM, some experts increase infection prophylaxis with antibiotics and/or intravenous immunoglobulins in children with DS-associated ALL/LBL.

Many patients with DS-related ALL/LBL are cured without transplantation, which has been associated with high TRM in children with DS [17,175]. These children have an increased risk of infections, and intensive chemotherapy regimens frequently cause severe mucositis [176]. Analysis of 653 children with DS ALL/LBL reported both a high rate of relapse (26 percent eight-year cumulative relapse) and an increased two-year TRM (7 versus 2 percent in non-DS ALL/LBL) [177]. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)

Patients ≥10 years with DS may have a higher risk of seizures with blinatumomab [178]. The FDA label for blinatumomab states that seizure prophylaxis should be considered for children with DS receiving blinatumomab.

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 [177]. Those with high-risk features can be treated with reduced-intensity conditioning followed by HCT, but outcomes remain poor [179].

PROGNOSIS — 

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) [2-7].

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 [2,180]. Details of outcomes with treatment for pediatric ALL/LBL are presented separately. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment 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 TRM [8]. Long-term adverse effects can have a significant impact on quality of life, school performance, neurocognition, adult function, and long-term survival [9,10].

Outcomes are associated with age, white blood cell count at presentation, immunophenotype, and cytogenetic/molecular features (table 1). Patients who respond rapidly and robustly to induction and consolidation phases have more favorable outcomes than those with a slow response or incomplete remission [181-186]. (See 'Risk stratification' above.)

Details of the 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".)

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 5^th to 6^th 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 10^th to 12^th 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

●Description – Acute lymphoblastic leukemia/lymphoma (ALL/LBL) is the most common childhood cancer.

●Pretreatment – Clinical evaluation, screening laboratory studies, bone marrow examination, and lumbar puncture (LP) are performed. A central venous access device is inserted. (See 'Pretreatment' above.)

All children should have an LP to evaluate the risk for central nervous system (CNS) involvement, as discussed above. (See 'Central nervous system evaluation' above.)

●Overview – Treatment is intensive, complex, and prolonged and should be overseen by clinicians experienced with the disease and its complications. Optimal outcomes are associated with strict adherence to a contemporary research protocol. (See 'Overview' above.)

Management is guided by immunophenotype (ie, B cell versus T cell lineage), clinical presentation (age, leukocyte count at presentation), cytogenetic/molecular features, and treatment response (table 1).

●Emergencies – Tumor lysis syndrome, cytopenias, infections, thrombosis, and/or bleeding at presentation or during treatment can be life-threatening. Evaluation and management are discussed above. (See 'Emergencies/complications' above.)

●B cell – The most common subtype of ALL/LBL. Treatment includes:

•Induction therapy – Treatment is stratified by risk for relapse (defined by the chosen protocol) and includes a glucocorticoid, vincristine, and asparaginase; some protocols include an anthracycline. (See 'Induction therapy' above.)

•Response – Treatment response is based on the evaluation of bone marrow/other involved sites and the level of measurable residual disease (MRD) at the end of induction. (See 'Response assessment' above.)

•Consolidation – Multiagent chemotherapy with the components and intensity stratified by risk factors and MRD response. Some protocols add blinatumomab (CD19 x CD3 bispecific T cell enhancer) following consolidation. (See 'Consolidation/intensification therapy' above.)

•Maintenance therapy – Lower-intensity treatment with 6-mercaptopurine and methotrexate, with or without vincristine/glucocorticoid pulses, which is given for two years and guided by the chosen protocol. (See 'Maintenance chemotherapy' above.)

●T cell – Induction therapy generally adds an anthracycline to glucocorticoid, vincristine, and asparaginase. Consolidation therapy and CNS prophylaxis are usually intensified. (See 'T cell ALL/LBL' above.)

MRD at the end of consolidation therapy is the most important prognostic factor for T cell ALL/LBL.

●Philadelphia chromosome-positive – A BCR::ABL1 tyrosine kinase inhibitor (TKI) is given through all treatment phases, but the choices of TKI, induction regimen, and consolidation therapy vary by protocol. (See 'Philadelphia chromosome-positive' above.)

●CNS management

•Evaluation – All patients have a diagnostic LP to assess CNS involvement. CNS imaging is performed as needed. (See 'Central nervous system evaluation' above.)

The diagnostic LP is usually coupled with the first intrathecal (IT) treatment.

•CNS prophylaxis – All children receive CNS prophylaxis guided by the cerebrospinal fluid analysis, other risk factors, and the chosen protocol. CNS prophylaxis continues through all phases of treatment. (See 'Central nervous system prophylaxis' above.)

-Standard risk – We suggest either IT methotrexate or triple IT therapy (methotrexate, cytarabine, and hydrocortisone), rather than cranial radiation therapy (RT) (Grade 2B).

-Higher risk – IT therapy plus intensified systemic treatment (eg, dexamethasone, high-dose methotrexate/leucovorin rescue, and/or intensive asparaginase) and/or cranial RT, as guided by the chosen protocol.

•CNS involvement – Treated with IT therapy, enhanced systemic treatment, and/or cranial RT, according to the chosen protocol. (See 'Central nervous system involvement' above.)

●Follow-up – Monitor for relapse by clinical and laboratory evaluation, and screen for long-term adverse effects. (See 'Follow-up' above.)

●Special populations – ALL/LBL in adolescents, infants, and children with Down syndrome requires special aspects of care. (See 'Special populations' above.)