INTRODUCTION — Acute lymphoblastic leukemia/lymphoma (ALL/LBL) is the most common form of cancer in children, comprising approximately 30 percent of all childhood malignancies [1]. Survival rates for ALL/LBL have improved dramatically since the 1980s, with current five-year overall survival rates >85 percent [1-4]. Five-year event-free survival rates are >93 percent for low-risk groups [5]. This improvement in survival is due to treatment of a large number of children on sequential standardized research protocols. Approximately 75 to 80 percent of children with newly diagnosed ALL/LBL participate in such trials, the goals of which are to improve clinical outcomes while minimizing acute toxicities and late-occurring adverse events.

The treatment of ALL/LBL in children and adolescents is reviewed here. The epidemiology, presentation, classification, risk group stratification, and outcome of childhood ALL/LBL are discussed separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Risk group stratification and prognosis for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents" and "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Although the majority of children with ALL/LBL will be cured, consultation with palliative care specialists may be considered at the time of diagnosis as with any life-threatening condition or for pain management. (See "Pediatric palliative care".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The 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. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

OVERVIEW OF TREATMENT — Successful treatment of children with ALL/LBL involves administration of a multidrug regimen that is divided into several phases (ie, induction, consolidation, and maintenance) and includes therapy directed to the central nervous system (CNS). Most treatment protocols take two to three years to complete, although the specific regimen varies depending upon immunophenotype and risk category (table 1). (See "Risk group stratification and prognosis for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)

At the time of diagnosis, patients with ALL/LBL commonly require transfusion support, treatment of suspected or proven infections with broad-spectrum antibiotics, and, for patients with a high tumor burden, correction of any metabolic imbalances such as hyperuricemia. A rare patient may require leukapheresis or exchange transfusion to control extreme leukocytosis. (See "Red blood cell transfusion in infants and children: Indications" and "Uric acid kidney diseases", section on 'Acute uric acid nephropathy' and "Hyperleukocytosis and leukostasis in hematologic malignancies".)

Despite improvements in supportive care, death resulting from treatment toxicity remains a challenge. In a review of over 1000 children with ALL/LBL treated at St. Jude Children's Research Hospital, the estimated 10-year cumulative incidence of treatment-related death was 2.9 percent [6]. Age was the only predictor of death; children in the age bracket from one to nine years had a significantly lower risk of treatment-related mortality than did either infants or older children. In a subsequent retrospective analysis of 8516 children ages 0 to 19 years of age with newly-diagnosed ALL/LBL treated at US institutions, induction mortality was 1.12 percent [7]. Induction mortality was not associated with race or socio-economic status, but was increased among children age <1 year (hazard ratio [HR] 3.34, 95% CI 1.22-9.13) and 10 to 19 years (HR 2.89, 95% CI 1.55-5.41) and among those with cardio-respiratory or other organ failure (HR 145.4, 95% CI 37.8-145.4).

INDUCTION THERAPY

Regimen — Induction therapy is the initial phase of treatment. The primary goal of induction is achievement of an initial complete remission (CR), defined as the eradication of ALL/LBL detectable leukemia cells (less than 5 percent blasts) from the bone marrow and blood and the restoration of normal hematopoiesis (>25 percent cellularity and normal peripheral blood counts). The induction therapy given differs depending upon whether a t(9;22) translocation (Philadelphia chromosome) is present. While t(9;22) translocation is uncommon in children, those with this translocation benefit from the addition of a tyrosine kinase inhibitor that targets the aberrant expression of BCR-ABL1.

t(9;22)/BCR-ABL1 negative ALL — More than 90 percent of children and adolescents with ALL/LBL enter CR at the end of induction therapy regardless of their initial risk grouping [8-17].

Induction therapy usually involves weekly administration of vincristine for three to four weeks, daily corticosteroids (prednisone, prednisolone, or dexamethasone), and asparaginase. Asparaginase is available as an Escherichia coli derivative, either in its native form (L-asparaginase) or in a pegylated form, which results in a longer period of asparagine depletion with comparable toxicity [18-20]. L-asparaginase is no longer available for use in the United States. For patients with E. coli asparaginase allergies, asparaginase is also available from Erwinia (Erwinase) [21]. A fourth agent such as an anthracycline (eg, doxorubicin or daunorubicin) may be added to the three-drug regimen, particularly for high-risk patients.

Response to therapy is often assessed by bone marrow examination during the induction phase of treatment. In addition to morphologic response, bone marrow aspirates are also assessed for the presence of measurable residual disease (MRD; also referred to as minimal residual disease). Assessments can be performed by either quantitative polymerase chain reaction (PCR) or by flow cytometry [22-24]. Both methods have shown that end-of induction and end-of consolidation bone marrow MRD strongly correlate with survival [5,25,26]. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in children'.)

Early clearance of lymphoblasts from peripheral blood during the first week of therapy, clearance of blasts from the bone marrow by the end of induction, and the presence or absence of MRD at the end of induction therapy are important indicators of outcome. Patients who respond rapidly to the induction regimen appear to have a more favorable outcome, whereas those who have a slow response or who fail induction therapy have a more guarded prognosis [5,22-26]. This is discussed in more detail separately. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in children'.)

t(9;22)/BCR-ABL1 positive ALL — The t(9;22) translocation (Philadelphia chromosome) is a rare mutation in children with ALL/LBL, with an incidence rate of <5 percent. Although the t(9;22)/BCR-ABL1 translocation was formerly associated with a very poor prognosis, outcome has significantly improved with the introduction of tyrosine kinase inhibitors (TKI), such as imatinib or dasatinib, to therapy regimens [27-32]. In a prospective clinical trial from the Children's Oncology Group (COG), 91 children (age 1 to 21 years) with Philadelphia chromosome-positive ALL/LBL were treated with intensive chemotherapy plus imatinib [31]. Those treated from induction until the completion of therapy with imatinib had the best outcome, with a five-year disease-free survival (DFS) of 70 percent. DFS was not statistically different between patients treated with chemotherapy plus imatinib (70±12 percent, n = 28) versus those who underwent sibling donor hematopoietic cell transplant (HCT) (65±11 percent, n = 21) or those receiving an unrelated donor HCT (59±15 percent, n = 13).

Patients with trisomy 21 — Patients with trisomy 21/Down syndrome (DS) who develop ALL/LBL are particularly susceptible to adverse events and treatment-related mortality. Intensive chemotherapy regimens with high-dose methotrexate frequently result in severe mucositis, and children with DS-ALL/LBL have an increased risk of severe infections [33]. An analysis of 653 children with DS-ALL/LBL demonstrated that these patients have both a high rate of relapse (26 percent eight-year cumulative relapse incidence) and an increased rate of two-year treatment-related mortality (7 versus 2 percent in non-DS-ALL/LBL) [34]. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Down syndrome'.)

Because of the increased incidence of infectious deaths in DS-ALL/LBL throughout all stages of chemotherapy treatment (induction, consolidation, and maintenance) [35], patients are often treated on protocols with reduced intensity chemotherapy, usually without evidence of inferior outcome [36]. In general, many patients can be cured without the use of HCT, which has been associated with high treatment mortality.

Although cytogenetic changes other than trisomy 21 are uncommon with DS-ALL/LBL, those with concurrent low-risk cytogenetics (ETV-RUNX1) comprise a risk group with an exceptionally good prognosis (eight-year event-free survival 95±4 percent). This group, although uncommon, can be treated with less intense chemotherapy [34]. Those with high-risk features can be successfully treated with reduced-intensity conditioning followed by HCT. Outcomes, however, remain poor with three-year EFS of only 24 percent [37].

Asparaginase inactivation and therapeutic drug monitoring — Between 2 to 8 percent of patients receiving E. coli asparaginase develop silent inactivation due to the production of neutralizing anti-asparaginase antibodies [38,39]. Therapeutic drug monitoring of asparaginase activity can accurately determine if a patient has neutralizing antibodies that are inactivating the target enzymatic activity of asparaginase [39]. Those with neutralizing antibodies have asparaginase activity well below the therapeutic threshold and can often be treated with Erwinia asparaginase as an effective alternative since there is only approximately 10 percent antibody cross-reactivity between E. coli and Erwinia asparaginase preparations [40]. (See "Infusion reactions to systemic chemotherapy".)

A retrospective study of 763 pediatric patients with ALL/LBL examined therapeutic drug monitoring and suggested that lower doses of PEG-asparaginase can be used to maintain asparagine depletion [41]; these results will need to be confirmed in prospective clinical trials. It is currently unknown if decreasing the asparaginase dose will result in fewer thrombotic or hemorrhagic complications. (See 'Thrombosis' below.)

Adverse effects — Some children with ALL/LBL experience significant adverse effects during induction chemotherapy. Toxicity can result from the chemotherapeutic agents or from the rapid elimination of a large tumor burden (ie, tumor lysis syndrome). Life-threatening adverse effects of induction therapy include tumor lysis syndrome, thrombosis, bleeding, and infection. Other acute side effects include mucositis, pancreatitis, and hyperglycemia. Late effects of chemotherapy are discussed separately. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Late effects'.)

Tumor lysis syndrome — Acute tumor lysis syndrome is the term applied to a group of metabolic complications that may occur after the treatment of neoplastic disorders. The findings that may be seen include hyperphosphatemia, hypocalcemia (caused by precipitation of calcium phosphate), hyperuricemia, hyperkalemia, and acute renal failure. Rapid leukemic cell lysis after chemotherapy can cause over-production and over-excretion of uric acid. The precipitation of uric acid in the tubules can lead to oliguric or anuric renal failure known as uric acid nephropathy [42]. (See "Tumor lysis syndrome: Definition, pathogenesis, clinical manifestations, etiology and risk factors" and "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)

In a study of 328 children with ALL/LBL, the following four factors were identified as independent predictors of tumor lysis syndrome on multivariate analysis [43]:

●Age >10 years

●Splenomegaly

●Mediastinal mass

●Initial white blood cell count >20,000/microL

Absence of all four of these risk factors indicated a low risk for development of tumor lysis syndrome, with a negative predictive value of 98 percent and a sensitivity of 96 percent.

Prophylactic regimens to prevent acute uric acid nephropathy in children with ALL/LBL include the administration of medications to reduce the production of uric acid (allopurinol or rasburicase, a recombinant uricase that catalyzes oxidation of uric acid to the much more soluble compound allantoin), and aggressive intravenous hydration [44]. Hemodialysis may be necessary to remove excess circulating uric acid and phosphate in patients who develop acute renal failure and in whom adequate diuresis cannot be achieved. These issues are discussed in detail separately. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)

Adverse effects of rasburicase include allergic reactions, including anaphylaxis, hemolysis, hemoglobinuria, methemoglobinemia, and interference with uric acid measurements [45]. This agent is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency because it can cause severe hemolysis [45].

Thrombosis — Thrombotic events, including intracranial dural sinus thrombosis with hemorrhage, deep vein thrombosis, and pulmonary embolism, have been reported with induction chemotherapy regimens for ALL/LBL that include all forms of asparaginase [46]. Thrombosis is a major complication that may be life-threatening and impact future therapy. In contemporary treatment protocols, the incidence of thrombotic complications among children with ALL/LBL receiving asparaginase has varied among studies from as low as 1.8 percent to as high as 15 percent in children with prothrombotic risk factors [47]. Increased risk of thrombosis occurs with increased age and the presence of a central venous catheter [48-50].

In a prospective trial of children and adolescents with ALL/LBL, thrombosis occurred in 63 of 1038 (6 percent) and was most common among those age 15 years and older (21 percent) [49]. Most thromboses were in the setting of asparaginase administration. Nine children died within 30 days of thrombosis with four deaths directly attributable to the thrombosis. In addition, approximately half of patients alive after thrombosis had delays or dose modifications of further asparaginase therapy.

A 2006 meta-analysis of 1752 children with ALL/LBL reported that 5.2 percent of patients developed a thrombosis at some time during treatment (ie, from the start of induction through the end of maintenance) [51]. Most (83 percent) of these events occurred during induction therapy. The following four risk factors for thrombosis were identified in this population:

●Treatment with asparaginase

●Concomitant use of steroids

●Thrombophilic genetic abnormalities

●Presence of central venous lines

In a European study, these risk factors were used to develop a predictive model for identifying children with ALL/LBL at the highest risk of thrombosis during induction with asparaginase-based therapy [52]. While the 2006 meta-analysis did not evaluate the impact of ABO blood group on the risk of thrombosis, a subsequent large retrospective analysis reported an association between non-O blood group and age and an increased risk of thrombosis [53]. Non-O blood type is a known risk factor for VTE in adults. (See "Overview of the causes of venous thrombosis", section on 'Non-O blood type'.)

A retrospective analysis of 336 consecutively recruited children with ALL/LBL treated on different Berlin-Frankfurt-Munster (BFM) study protocols found a lower incidence of thromboembolism when asparaginase was used in conjunction with dexamethasone rather than prednisone (1.8 versus 10.4 percent) [54]. The results of this study, limited by the small number of patients (n = 56) in the dexamethasone treatment group, bear further scrutiny in prospective trials with larger numbers of patients.

Asparaginase depletes plasma asparagine, thereby inhibiting protein synthesis in leukemic cells and the synthesis of several plasma proteins. The latter effect causes deficiencies of albumin, thyroxine-binding globulin, and various coagulation proteins, including prothrombin, factors V, VII, VIII, IX, X, XI, fibrinogen, antithrombin, protein C, protein S, and plasminogen [55,56]. These deficiencies result in prolongation of the prothrombin time, activated partial thromboplastin time (aPTT), thrombin time, and hypofibrinogenemia, with fibrinogen levels often less than 100 mg/dL. E. coli-asparaginase and Erwinia-asparaginase appear to have equivalent risk of severe thrombosis, including central nervous system hemorrhage. (See "Drug-induced thrombosis in patients with malignancy", section on 'L-asparaginase' and "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)

Bleeding — Hemorrhage in children with ALL/LBL usually is caused by thrombocytopenia. Patients who have platelet counts <10,000/microL are at greatest risk. Children with thrombocytopenia typically have bleeding from the skin or mucus membranes; significant visceral bleeding is unusual. Intracranial hemorrhages are rare but life-threatening events. Treatment or prevention of such bleeding is provided by transfusion of platelets. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HCT'.)

Patients who require prolonged antibiotic therapy may develop bleeding secondary to a vitamin K dependent coagulopathy. Patients with an elevated prothrombin time (PT) are treated with oral or intravenous vitamin K (2.5 to 5.0 mg orally per day; or if bleeding, 1 to 2 mg intravenously as a single dose). (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Hematologic reactions'.)

Infection — Children with newly diagnosed ALL/LBL are functionally neutropenic and lymphopenic at the time of diagnosis and may develop further myelosuppression following chemotherapy. These children are more susceptible to development of systemic bacterial, fungal, and viral infections (eg, varicella-zoster, herpes simplex virus). Infections account for the majority of treatment-related mortality in this population.

As an example, in a retrospective review of 425 children who received induction therapy for ALL/LBL at a single tertiary Canadian center, 20 percent of all patients experienced at least one documented infection [57]. Neutropenia was almost twice as common in those who developed infections compared with those without infection. Patients with pre-existing conditions (ie, Down syndrome, congenital heart disease, pre-existing immunodeficiency syndromes) were at highest risk of infections. The 85 infections included 65 bacterial, 15 viral, and 5 fungal infections. Infectious mortality was minimal (3 out of 425, or 1 percent) and included deaths from both fungal (Candida albicans) and bacterial (Bacillus cereus) infections.

Details regarding infection-related deaths are also available from the prospective UKALL 2003 trial, which reported 75 septic deaths among 3126 children (2.4 percent) with newly diagnosed ALL/LBL, accounting for 64 percent of treatment-related mortality [35]:

●Although infection-related mortality was most common during induction therapy (48 percent), it also occurred during consolidation (9 percent), delayed intensification (23 percent), and maintenance therapy (20 percent). Underlying Down syndrome was associated with a significantly increased risk of death due to sepsis (odds ratio 12) during all treatment periods. (See 'Patients with trisomy 21' above.)

●Most deaths occurred in neutropenic patients and within 48 hours of presentation with sepsis.

●Most septic deaths with an identified pathogen were due to bacteria (68 percent), with fungal (20 percent) and viral (12 percent) pathogens being less common. The most commonly identified bacteria were Pseudomonas, E. coli, and Enterococcus.

Because these infections are potentially life-threatening in any phase of therapy, fever in children who are receiving chemotherapy must be evaluated and aggressively treated. The use of prophylactic antimicrobial therapy is recommended, but the specific therapy varies by circumstance and institution. For example, the use of an antimicrobial (sulfamethoxazole-trimethoprim, dapsone, or pentamidine) for Pneumocystis pneumonia prophylaxis is almost universal in the management of patients receiving chemotherapy, while the administration of antifungals and antiviral agents is more individualized. (See "Fever in children with chemotherapy-induced neutropenia".)

The role of colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte macrophage colony-stimulating factor [GM-CSF]) to prevent or manage infectious complications during ALL/LBL induction has not been well studied. In one randomized, crossover study in 287 children with high-risk ALL/LBL, prophylactic use of G-CSF shortened periods of neutropenia, but did not reduce rates of febrile neutropenia, serious infections, or the need for hospitalization; overall survival at six years was not affected [58]. A systematic review has come to similar conclusions [59].

Neuropathy — Virtually all patients receiving vincristine have some degree of neuropathy and approximately 25 to 30 percent of children treated for ALL/LBL will develop clinically significant peripheral neuropathy requiring dose reduction or treatment discontinuation. The rate may be significantly higher in patients with a genetic predisposition (eg, single nucleotide polymorphism in the promoter region of CEP72) [60]. The neuropathy involves both sensory and motor fibers and can manifest as paresthesias, loss of reflexes, weakness, and autonomic neuropathies, including vocal cord paralysis. Patients with mild neuropathy can usually continue to receive full doses of vincristine, but when symptoms increase in severity and interfere with activities of daily living, dose reduction or discontinuation of the drug may be necessary. Vincristine neuropathy is usually reversible but improvement is gradual and may take up to several months. This is described in more detail separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vincristine'.)

Anaphylaxis — Some chemotherapy and supportive medications, such as asparaginase, the epipodophyllotoxins (etoposide and etopophosphamide), and uricase, can cause significant allergic reactions, including anaphylaxis. Medications used to treat anaphylaxis should be readily available when these drugs are administered. Anaphylactic reactions to PEG-asparaginase can be delayed by several hours. Because of this delay, a period of observation following administration of PEG-asparaginase has become common practice at many institutions. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

HPA axis suppression — The administration of daily corticosteroids during induction therapy results in suppression of the hypothalamic-pituitary-adrenal (HPA) axis in most patients [61]. A study of 64 patients showed that over 80 percent of children had significant suppression of cortisol release by adrenocorticotropic hormone (ACTH) stimulation [62]. In this study, all patients had recovered normal adrenal function by 10 weeks following induction chemotherapy. Because nearly all patients experienced adrenal insufficiency during the first days after cessation of glucocorticoid treatment, it is recommended that children with infections, trauma, or surgery occurring during or shortly after induction be treated with glucocorticoid replacement. While the majority recovers HPA axis function within a few weeks after corticosteroid cessation [62], HPA axis suppression lasted up to 34 weeks in one analysis [63]. For this reason, glucocorticoid replacement following trauma, infection, or surgery should be considered on a case-by-case basis for children with ALL/LBL following induction. (See "Glucocorticoid withdrawal", section on 'Hypothalamic-pituitary-adrenal axis suppression' and "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

Induction failure — Induction failure, which occurs in fewer than 5 percent of cases, is defined by the persistence of leukemic blasts in the blood, bone marrow, or any extramedullary site after four to six weeks of induction therapy. Induction failure has historically been considered a particularly ominous sign and an indication for allogeneic HCT [64]. Due to the rarity of induction failure, information regarding this population has been limited to small numbers of patients enrolled on prospective clinical trials [65-67].

An international retrospective analysis from 14 cooperative study groups identified 44,017 children (≤18 years) with previously untreated ALL/LBL diagnosed from 1985 to 2000 [68], of which 1041 (2.4 percent) had induction failure. In this cohort, patients with induction failure were more likely to have had at least one of the following unfavorable features at presentation: male sex, older age (>6 years), high leukocyte count (>100,000 cells/microL), T cell leukemia, central nervous system (CNS) involvement, or the 11q23 chromosomal rearrangement (associated with abnormalities of KMT2A [previously called MLL]). These same unfavorable features, except for male sex and CNS involvement, were also associated with reduced survival after induction failure. At a median follow-up of 8.3 years, the estimated overall survival (OS) at 10 years for patients with induction failure who did not demonstrate t(9;22)(BCR-ABL1) was 32 percent. For the 624 patients with genetic data available, patients could be stratified by karyotype with the following estimated 10-year OS:

●High hyperdiploid cytogenetics (n = 55) – 72 percent

●Normal karyotype (n = 159) – 36 percent

●Other chromosomal aberration (n = 250) – 30 percent

●11q23/KMT2A abnormality (n = 50) – 16 percent

These data highlight the heterogeneity of the induction-failure population and the need for individualized treatment decisions. Although the estimated OS rate was similar among the 198 patients who underwent HCT (43 percent) and the 427 patients who received chemotherapy alone (41 percent), the effect of HCT on survival appeared to differ greatly according to karyotype risk subgroup. As an example, children younger than six years with precursor B cell ALL/LBL without KMT2A rearrangement (ie, low-risk factors) appeared to have higher survival rates when treated with chemotherapy alone rather than HCT (73 versus 59 percent). In contrast, older children and those with elevated white blood cells, T cell ALL/LBL, and additional cytogenetic risk factors had higher survival rates with a matched related donor HCT rather than chemotherapy alone (59 versus 35 percent). A similar study in Europe showed that adolescents and young adults with T cell ALL/LBL also did better with allogeneic HCT compared with chemotherapy alone (67 versus 42 percent) [69].

A subset analysis of induction failures in a large prospective clinical trial suggested that OS for patients with induction failure had improved somewhat with aggressive chemotherapy, with a four-year OS of 60 percent [70].

In another study of 774 children with ALL/LBL (including T cell ALL/LBL) from the United States, 23 had persistent leukemia after completion of induction therapy and were treated with additional induction chemotherapy. Although 21 patients eventually achieved CR, their five-year event-free survival (EFS) was only 16 percent (95% CI 0-31 percent) regardless of management regimen, compared with 82 percent (95% CI 79-86 percent) in the group that achieved remission within one month and 79 percent (95% CI 70-87 percent) in those who had protracted hypoplasia [66].

In a French study of 1395 children with ALL/LBL, a multivariate analysis identified three groups based upon their risk for induction failure [67]. The intermediate- and high-risk groups had a 7- and 28-fold increase risk of induction failure compared with the low-risk group. The low-risk group (n = 1080) had precursor B cell ALL/LBL without the Philadelphia translocation, t(9;22). The intermediate-risk group had T cell ALL/LBL with mediastinal involvement and the high-risk group had either the Philadelphia translocation or T cell ALL/LBL without mediastinal involvement. The groups were treated based on Berlin-Frankfurt-Munster study (BFM) protocols. Overall, 53 patients failed induction therapy. With salvage therapy, 43 patients entered complete remission, 39 after one second-line course of chemotherapy and four who required more than one course. Both the OS rate and the EFS for the 53 patients who failed induction therapy compared with those who responded to therapy were markedly lower (30 and 27 percent versus 85 and 75 percent, respectively).

A subset of patients with Philadelphia chromosome negative (BCR/ABL1 negative) ALL/LBL have a gene expression signature profile similar to that seen with BCR/ABL1 positive disease. This BCR/ABL1-like B cell ALL/LBL is clinically more aggressive than other BCR/ABL1 negative ALL and resistant to standard chemotherapy. Detailed genomic analysis identified alternative mechanisms of activated kinase signaling in the majority of BCR/ABL1-like B cell ALL/LBL that may be targeted with novel agents in the future. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

CNS PREVENTIVE THERAPY — Leukemic involvement of the central nervous system (CNS) at the time of diagnosis is an uncommon finding, occurring in fewer than 5 percent of patients [71,72]. However, before the use of preventive CNS therapy, up to 80 percent of children with ALL/LBL who were in complete bone marrow remission relapsed with leukemic meningitis [73].

The routine use of preventive CNS therapy is a major therapeutic advance in the treatment of childhood ALL/LBL. CNS treatment usually begins during the induction phase and continues throughout the remainder of the treatment regimen. Craniospinal radiotherapy has been replaced by intrathecal chemotherapy in several CNS preventive therapy protocols. Current protocols contain either no CNS radiotherapy, or have a significantly reduced dose of 12 to 18 Gy. Outcome data from these protocols have demonstrated that replacement of craniospinal radiotherapy with frequent administrations of intrathecal therapy does not compromise event-free survival (EFS) or overall survival (OS) [4,74-80].

Craniospinal radiotherapy or cranial radiotherapy, once considered the standard of care, was effective in preventing CNS leukemia but was associated with significant toxicity, such as cognitive impairment and decreases in white matter volume [81,82]. Approximately 50 percent of children treated with 24 Gy craniospinal radiation developed CNS changes detected by magnetic resonance imaging (MRI) (atrophy, leukoencephalopathy, calcifications, or grey matter abnormalities), secondary brain tumors, and had decreased performance on neuropsychological testing [83,84]. As an example, a cancer survivorship study of 102 adult survivors of ALL/LBL who received radiotherapy suggested that there is a progressive decline in attention and verbal functioning that persists into adulthood [85]. The long-term toxicities of cranial radiation are discussed in more detail separately. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS and cognition' and "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Brain tumors' and "Delayed complications of cranial irradiation".)

The efficacy of intrathecal prophylaxis was illustrated in a randomized trial from the Dana-Farber Cancer Institute ALL Consortium, in which children with standard-risk ALL/LBL were assigned to receive either intensive triple intrathecal chemotherapy (cytarabine/methotrexate/hydrocortisone) or 1800 cGy cranial radiation with less frequent intrathecal therapy [74]. There was no difference between the two groups in five-year EFS (83 versus 86 percent) or the rate of CNS relapse (6 percent in each group). A subsequent analysis of the neuropsychological outcomes found that cognitive function was in the average range in both groups [75]. However, children who received 18 Gy or more of cranial radiotherapy had less fluent language output and were less effective at modulating their behavior according to their parents.  

A subsequent study evaluated the efficacy of regimens without cranial irradiation in 498 consecutive children (age range 1 to 18 years) with ALL/LBL who were treated with triple intrathecal therapy and intensified systemic chemotherapy based upon disease risk stratification after remission induction [4]. Intrathecal cytarabine was initially administered on day 1 of remission induction and followed by subsequent triple intrathecal chemotherapy (cytarabine/methotrexate/hydrocortisone). The number of intrathecal treatments ranged from 13 to 25 and was based upon disease risk stratification and patient characteristics, including CNS status of disease.

The following findings were noted:

●The five-year EFS and OS rates were 86 and 94 percent, respectively.

●The five-year cumulative risk was 3.9 percent for any CNS relapse (isolated, and combined CNS and hematologic relapse) and 2.7 percent for isolated CNS relapse.

●The five-year remission rate was significantly higher in the 71 patients who would have previously received prophylactic cranial irradiation than 56 historical controls who received cranial irradiation (91 versus 73 percent).

A similar study of 156 children from Taiwan indicated that triple intrathecal therapy could be used to replace radiotherapy, suggesting that replacement of radiotherapy with more intense intrathecal therapy can be generalized to a wide variety of ALL/LBL protocols [79].

The results of these studies demonstrate that intrathecal therapy provides similar EFS and OS in a cohort of children with ALL/LBL. However, all recommendations for CNS preventive therapies should be evaluated in the context of the related systemic therapy regimens and should not be applied to other treatments without more evidence. Some current protocols continue to incorporate lower dose cranial radiation (<1800 cGy) for patients where CNS leukemia is felt to be a significant risk factor.

Although the incidence of neurotoxicity is reduced by intrathecal therapy, it is not eliminated and remains a significant risk. Intrathecal chemotherapy (with either methotrexate alone, or methotrexate combined with cytarabine and prednisone) is associated with acute neurotoxicity [86], including seizures and leukoencephalopathy [86].

There is also an increasing body of evidence that CNS-directed therapy can impact attention and cognitive function. These effects appear to be more significant in girls and children who are radiated at a younger age. Because of the impact of these changes on functioning into adulthood, broad strategies for educational and pharmacologic interventions have been developed to remediate established cognitive dysfunction following childhood ALL/LBL [87].

POST-REMISSION THERAPY — Consolidation or intensification therapy is the second phase of ALL/LBL treatment and is initiated soon after attainment of complete remission (CR). Ongoing treatment is required because small numbers of leukemic lymphoblasts remain in the bone marrow despite histologic and molecular evidence of CR after induction therapy. In such cases, relapse occurs quickly if therapy is not continued. The goal of post-induction chemotherapy is to prevent leukemic regrowth, reduce residual tumor burden, and prevent the emergence of drug-resistance in the remaining leukemic cells.

There is evidence that leukemias undergo a process known as clonal evolution [88]. During induction, the vast numbers of leukemia cells originating from the dominant subclone are eliminated. However, leukemia-initiating cells are often from a heterogeneous population at diagnosis, with individual patients having multiple genetic subclones with leukemia-initiating potential [89]. These subclones are present within a complex clonal architecture at diagnosis, and often potentially chemoresistant leukemia-initiation cells are present but are undetectable by measurable residual disease (MRD; also referred to as minimal residual disease) assays. Post-induction therapies can help prevent the emergence of a drug resistance by eliminating these subdominant clones that were resistant to induction therapy. (See "Detection of measurable residual disease in acute lymphoblastic leukemia" and "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia".)

Consolidation — Consolidation therapy usually lasts from four to eight months. It commonly involves the use of several different drug combinations and drugs with mechanisms of action that differ from those used during the induction phase. Regimens often include the following drugs administered according to a variety of schedules to maximize drug synergy and minimize the development of drug resistance [90,91]:

●Cytarabine

●Methotrexate

●Anthracyclines (daunorubicin, doxorubicin)

●Alkylating agents (cyclophosphamide, ifosfamide)

●Epipodophyllotoxins (etoposide, etopophosphamide)

Intensification of therapeutic regimens is based upon the patient's risk group classification [92]. This has allowed a reduction of intensification therapy for patients with good prognosis while providing more intensive treatment for those in the high-risk groups. End of induction MRD, as well as cytogenetics and molecular abnormalities, are the most important predictors of disease-free and overall survival [5,24,93]. Patients with detectable MRD have an increased risk of relapse following conventional chemotherapy.

Ongoing trials are evaluating the escalation of consolidation therapy intensity for patients who are MRD positive following induction, and the reduction of therapy intensity in MRD-negative cases. As an example, in one trial (UKALL 2003), 533 patients clinically identified as having standard-risk or intermediate-risk ALL/LBL at diagnosis and MRD positivity (leukemia cells >0.01 percent) in the bone marrow at the end of induction therapy were randomly assigned to receive either standard or augmented post-remission therapy [94]. The augmented therapy included additional doses of asparaginase, vincristine, and methotrexate. Augmented therapy was associated with more adverse events including hypersensitivity, pancreatitis, and mucositis/stomatitis. After a median follow-up of 70 months, augmented therapy resulted in superior five-year event-free survival (90 versus 83 percent; p = 0.04). However, overall survival was not statistically different between the standard and augmented therapy groups (93 versus 89 percent, p = 0.16). Similar strategies of therapy intensification for patients that are MRD positive after induction are underway in Europe and the United States. (See "Clinical use of measurable residual disease detection in acute lymphoblastic leukemia", section on 'MRD in children' and "Risk group stratification and prognosis for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Measurable residual disease'.)

Delayed intensification — Improved survival also has been gained with the addition of more intensive therapy following consolidation, an approach known as delayed intensification [95-97]. Delayed intensification involves the administration of a five- to eight-week "pulse" of intensive, multi-agent chemotherapy similar to that administered during induction and consolidation. Delayed intensification pulses were given either once [95,96] or twice [98,99] during the first six months of post-remission therapy. Although the benefit of two pulses of delayed intensification has not been demonstrated [5,100], the addition of a single delayed intensification pulse has improved survival for both standard-risk and high-risk patients [99,101].

The intensity of delayed intensification therapy is commensurate with the patient's risk grouping. As a general rule, the higher the risk for treatment failure, the more aggressive intensification therapy is required. This was demonstrated in a Children's Oncology Group trial of 1299 patients with higher risk ALL/LBL that had rapid marrow response to induction therapy [102]. This study demonstrated that a more intensive delayed intensification regimen resulted in improved event-free survival and overall survival at five years compared with either standard therapy or longer duration of therapy.

During the delayed intensification phase of chemotherapy, most patients still have significant myelosuppression and immunosuppression. They remain at risk for bacterial, viral, and fungal infections during periods of neutropenia, and fevers should be aggressively treated. Patients can also experience many of the same complications (eg, infection) seen during induction therapy, although these are usually less common. (See 'Adverse effects' above.)

More aggressive treatment regimens involving multiple chemotherapeutic agents place high-risk patients at risk for additional complications. High-risk ALL/LBL patients have an increased risk of secondary cancers (associated with epipodophyllotoxins or radiation) and decreased fertility (a risk for adolescents receiving alkylating agents). (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Late effects'.)

Allogeneic hematopoietic cell transplantation — Allogeneic hematopoietic cell transplantation (HCT) is an acceptable option for some patients with higher-risk ALL/LBL. Patterns of use of allogeneic HCT vary between institutions and there is no consensus regarding patient selection, timing of transplantation, and other aspects of the procedure. However, some subsets of patients with higher-risk ALL/LBL do not appear to benefit from allogeneic transplantation, and we suggest that children <1 year of age should not undergo myeloablative allogeneic HCT because of increased transplant-related mortality.

No randomized trials have directly compared allogeneic HCT with other post-remission therapy for patients with higher-risk ALL/LBL, and the impact of transplantation on particular subsets of higher-risk ALL/LBL is not well defined. However, retrospective studies suggest that patients with induction failure or T cell ALL/LBL appear to have superior outcomes with allogeneic HCT [68,69,102,103]. In contrast, a retrospective review of hypodiploid ALL/LBL reported that, compared with 52 patients who did not undergo transplantation, 61 patients who underwent allogeneic HCT in first complete remission did not achieve superior five-year overall survival or event-free survival [104]. It is uncertain if patients with 11q23 rearrangements benefit from transplantation [68,69].

Selected patients with high-risk disease have an increased incidence of relapse during delayed intensification chemotherapy [69,105,106]. This includes patients with severe hypodiploid ALL/LBL (less than 46 chromosomes), those with KMT2A rearrangements, and infants with ALL/LBL. With the exception of patients <1 year of age, patients with these cytogenetic and molecular abnormalities are candidates for allogeneic HCT during first remission. There is evidence that HCT offers a survival advantage to those >10 years of age with severe hypodiploidy (and without Li-Fraumeni syndrome), high-risk T cell ALL/LBL [102], induction failure, and patients >1 year of age with 11q23 rearrangements [68,69].

An HLA-matched sibling donor is usually preferred and evidence shows that transplants with an HLA-matched sibling donor are associated with fewer severe infections and pulmonary complications [103]. A matched unrelated donor, however, is an acceptable alternative when a sibling donor is not available and appears to result in similar clinical outcomes (event-free survival, overall survival, non-relapse mortality, and relapse rates) [103]. A partially matched family member donor or umbilical cord blood is a reasonable option for patients who do not have an HLA-identical matched donor. (See "Donor selection for hematopoietic cell transplantation".)

In contrast, HCT has been associated with increased mortality in infants [107]. There is some evidence that HCT has been more successful in infants using reduced intensity conditioning [108]. Further study is needed to determine if HCT can improve outcomes in infants, particularly for those infants with KMT2A rearrangements [68,69,102].

MAINTENANCE THERAPY — The overall treatment duration for most children with ALL/LBL is 30 to 42 months. After completion of the consolidation or intensification phase of therapy, patients often receive a less intensive continuation regimen (eg, maintenance chemotherapy) using daily oral 6-mercaptopurine (6-MP) [109], weekly methotrexate with periodic vincristine, prednisone, and intrathecal therapy. 6-MP can be administered as a tablet or as an oral suspension.

Children and families must be educated regarding the importance of maintenance therapy. The importance of compliance with 6-MP was illustrated in a cohort study that demonstrated an association between decreased adherence rates and an increased risk of relapse [110]. Better medication adherence is associated with a consistent daily routine for 6-MP ingestion that integrates with the family's lifestyle (ie, selecting either morning or evening dosing) and removing commonly practiced restrictions regarding coadministration of 6-MP with food or milk products [111]. Self-reporting frequently overestimates the true intake of 6-MP, particularly in nonadherent patients [112].

Although it is unclear whether all patients with ALL/LBL benefit from maintenance therapy that includes a combination of pulse therapy vincristine and steroids in addition to a daily regimen of 6-MP and weekly methotrexate, patients with standard-risk ALL/LBL who receive this combination appear to have a more favorable long-term outcome than those treated with only 6-MP and methotrexate [113]. The optimal time interval for vincristine plus steroid pulses is also unclear; this question is currently being studied in a large prospective COG trial. Patients with high-risk ALL/LBL, such as infants with ALL/LBL, may require a more aggressive continuation regimen with additional drug combinations.

During maintenance therapy, patients remain at risk for infection. Fever in children who are receiving chemotherapy must be evaluated and treated aggressively, especially if the patient is either neutropenic or has a central venous access device. Trimethoprim-sulfamethoxazole, dapsone, pentamidine, or atovaquone prophylaxis is continued to prevent Pneumocystis pneumonia [114,115]. Therapy to prevent Pneumocystis infection should be given during therapy and for at least three to six months following the completion of treatment. Children and their household contacts should not be given live-virus immunizations while the patient is receiving chemotherapy. (See 'Immunizations' below.)

PRIMARY CARE CONSIDERATIONS — For practical reasons, most patients with ALL/LBL remain under the primary care of their oncologists during the induction and consolidation portions of their chemotherapy. Once a patient enters the less intensive maintenance therapy, however, the primary care provider (PCP) can often provide routine medical care with scheduled visits to the oncologist for chemotherapy, particularly if the family lives some distance from the oncology treatment center. When ALL/LBL therapy is complete, the PCP resumes primary care for the patient, including visits for health maintenance and acute illnesses.

During chemotherapy, the oncologist usually coordinates physical examinations, procedures, and imaging studies. The PCP, however, plays an important role in encouraging patients to return to their oncologist for scheduled visits and follow-up studies. Encouragement to maintain regularly scheduled follow-up visits with their oncologist is particularly important after the completion of chemotherapy treatment. Communication between the PCP and the oncologist is critical throughout the treatment process.

The purpose of frequent follow-up visits after the cessation of chemotherapy is to examine ALL survivors for disease recurrence and to screen them for the long-term side effects. Patients are closely followed for several years after completion of chemotherapy. Although there is no standard follow-up frequency, patients are typically seen by their oncologist monthly for the first year after therapy completion and then at less frequent 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. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Late effects'.)

Immunizations — Experience with vaccine administration in children undergoing cancer treatment is limited and there are few published data regarding response to specific vaccines in patients receiving immunosuppressive chemotherapy. Data from HIV-infected infants indicate that the risk of adverse events after immunization is low [116].

Patients with ALL/LBL should receive only inactive immunizations during chemotherapy [116]. Live-virus vaccines, such as MMR and oral poliovirus, are contraindicated. After completion of chemotherapy, the patient should receive any missed vaccinations, including MMR and varicella.

Cancer patients have a variable response to the immunizations received while immunosuppressed. In addition, children with ALL/LBL whose immunizations were up-to-date at the time of diagnosis may fail to maintain protective antibody titers after completion of chemotherapy [117,118]. For this reason, it is recommended that antibody titers be checked three to six months after the completion of chemotherapy, and that children be revaccinated if they have low antibody titers [116,119]. (See "Immunizations in adults with cancer".)

Patients whose therapy included hematopoietic cell transplantation often repeat their immunization series beginning approximately one year after transplantation. Testing of immune function may provide evidence for safe immunization timing in these patients [116]. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Varicella vaccine — Given the variability of chemotherapy regimens and the current decreasing incidence of varicella, the American Academy of Pediatrics does not recommend routine varicella vaccination for children actively receiving chemotherapy. If varicella vaccination is performed in a child in remission without evidence of immunity, it should be undertaken with expert guidance and with the availability of antiviral therapy should complications occur [120]. After the completion of therapy, varicella titers should be checked and, in the absence the varicella titers, the varicella vaccine should be readministered.

Influenza vaccine — The annual influenza vaccine is recommended for children with ALL/LBL receiving chemotherapy. It is also recommended that household contacts receive the flu vaccine to prevent patient exposure during periods of neutropenia when the patient is severely immunocompromised. Family members should not receive the nasal vaccine due to concerns that this live virus could spread to the child with leukemia and result in severe systemic disease in the immunocompromised host.

Monitoring for relapse — The signs and symptoms of ALL/LBL relapse typically are similar to those of initial presentation. They include fever, malaise, bleeding, and bone pain. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

ALL/LBL relapse most commonly occurs in the bone marrow and usually presents with persistent peripheral blood cytopenias. Healthcare providers should pay close attention to persistent abnormal blood counts in the ALL/LBL survivor. Monitoring for the presence of measurable residual disease (MRD; also referred to as minimal residual disease) is also common practice in patients who have had a stem cell transplant as part of their treatment regimen. Prompt referral for bone marrow examination is warranted if there is suppression of more than one cell line (white cells, red cells, platelets) or unexplained suppression of one cell line that persists for longer than three to four weeks. Prompt bone marrow examination is also warranted for patients with a history of a stem cell transplant that have persistently positive MRD or recurrence of the cytogenetic abnormality associated with their initial leukemia clone [121].

The second most common site of ALL/LBL relapse is the central nervous system (CNS). However, the frequency of CNS relapse has diminished with the advent of initial prophylactic intrathecal therapy. CNS relapse may manifest with symptoms of increased intracranial pressure (headache, morning vomiting), nuchal rigidity, focal neurologic findings (particularly cranial nerve palsies), or papilledema.

Testicular relapse is uncommon (<5 percent) with current treatment regimens. Testicular relapse often presents as unilateral, painless testicular enlargement [122]. Diagnosis is made by testicular biopsy. Bilateral biopsies are indicated if testicular relapse is suspected, since leukemic cells are frequently found in the contralateral testis [122]. Leukemic infiltrates rarely recur in other extramedullary sites, including the ovary, kidney, skin, and eye.

RELAPSED DISEASE — Approximately 10 to 15 percent of children fail initial treatment of ALL/LBL, but relapse rates are substantially higher (25 to 30 percent) in certain high-risk subgroups [123].

Factors associated with an increased risk for relapse of ALL/LBL are discussed separately. (See "Risk group stratification and prognosis for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)

Management — Patients with relapsed ALL/LBL require aggressive reinduction therapy and intensification, often using agents not administered in the original treatment protocol [124]. Patients with high-risk ALL/LBL, such as those with high initial white blood cell counts or children >10 years old, often do not respond well to treatment with additional chemotherapy alone [125,126]. Patients who have central nervous system (CNS) or testicular relapse require radiation therapy at some point during the rescue therapy program [127].

There is no consensus regarding optimal management of relapsed ALL/LBL, and we suggest participation in a clinical trial whenever possible.

Various chemotherapy and immunotherapy approaches show promise in this setting, but there are no prospective, randomized trials that have directly compared them. Retrospective studies of relapsed ALL/LBL are difficult to compare because of heterogeneous populations of patients.

Selection of therapy is influenced by characteristics of the relapsed leukemia (eg, immunophenotype), available agents, and institutional and/or physician expertise. As examples, some immunotherapeutic agents are available only in institutions with the resources and expertise for their administration and management of treatment-related complications.

The following agents have been used for the treatment of relapsed ALL/LBL (see "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Remission induction'):

T cell ALL — Treatment with activity for relapsed T cell ALL/LBL includes:

●Nelarabine, a prodrug converted in vivo to ara-GTP, has shown efficacy as a single agent for the treatment of relapsed or resistant T cell ALL/LBL in children and adults, and is undergoing study for newly diagnosed T cell ALL/LBL by the Children’s Oncology Group (COG). Indications for nelarabine treatment and toxicity are provided separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Nelarabine'.)

●Bortezomib is a proteasome inhibitor that prevents degradation of misfolded proteins, and was shown to synergize with steroids in preclinical studies [128,129]. Bortezomib has shown promise in the treatment of both pre-B ALL/LBL [130] and T cell ALL/LBL, and is currently being tested in clinical trials for newly diagnosed T cell ALL/LBL by the COG. Response rates of 68 to 73 percent were reported in very early relapse of B-ALL/LBL and in T-ALL/LBL when combined with chemotherapy [130,131].

B cell ALL — Treatment options for relapsed B cell ALL/LBL include:

●Blinatumomab is a bispecific T cell engager (BiTE) monoclonal antibody directed at both CD19 on precursor B cell ALL/LBL tumor cells and CD3 on cytotoxic T cells. It is approved by the US Food and Drug Administration (FDA) for children with relapsed B-ALL/LBL. Its efficacy in relapsed ALL/LBL in children is not well defined but, in a phase 3 trial in adults with relapsed or refractory B-ALL/LBL, blinatumomab was superior to chemotherapy in regard to overall survival (OS), event-free survival (EFS), and complete remission (CR) rate [132]. Blinatumomab is also effective in eradicating measurable residual disease (MRD; also referred to as minimal residual disease) in adults with relapsed pre-B ALL/LBL [133,134]. In children with relapsed lymphoma, blinatumomab was associated with grade 3 neurologic toxicity (22 percent), cytopenias and capillary leak syndrome [135]. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Blinatumomab'.)

●Chimeric antigen receptor T (CAR-T) cells are a form of genetically modified autologous immunotherapy that can be directed at B cell precursor ALL. This is a customized treatment in which the individual's own T lymphocytes are genetically modified (transduced) with a gene that encodes a chimeric antigen receptor to direct the patient's T cells against the leukemic cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient.

CAR-T therapy is associated with neurological events and cytokine release syndrome, which is a systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to the activation and proliferation of CAR-T cells. Facilities that dispense these agents require special certification, staff must be trained to recognize and manage its adverse events, and tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor) must be available for immediate administration.

Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy that is approved by the FDA for treatment of patients ≤25 years of age with B cell precursor ALL/LBL that is refractory or in second or later relapse [136]. Tisagenlecleucel is only available in the United States through a risk evaluation and mitigation strategy (REMS), and its label carries a boxed warning for neurological events and for cytokine release syndrome. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T'.)

Studies of tisagenlecleucel for relapsed or refractory B cell precursor ALL/LBL in children include:

•In a single center study, a single infusion of tisagenlecleucel achieved 81 percent CR, and all patients who had a response were found to be negative for MRD by flow cytometry [137]. At six months, EFS and OS were 73 and 90 percent, respectively, and the corresponding rates at 12 months were 50 and 76 percent. Severe adverse events (grade 3/4) occurred in 73 percent.

•A multicenter trial of 63 pediatric and young adult patients reported an 83 percent overall remission rate (including 63 percent CR and 19 percent CR with incomplete hematologic recovery); all responding patients were negative for MRD by flow cytometry [138].

Axicabtagene ciloleucel (axi-cel) is a CD19-directed CAR-T immunotherapy that has been approved by the FDA for treatment of relapsed or refractory diffuse large B cell lymphoma.

●Clofarabine is a deoxyadenosine analog that is approved by the FDA for treatment of pediatric patients (ages 1 to 21 years) with relapsed or refractory ALL/LBL who have experienced treatment failure with two prior regimens. Studies of clofarabine in adults with relapsed/refractory ALL/LBL are discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Clofarabine'.)

Informative studies of clofarabine in children with relapsed/refractory ALL/LBL include:

•In a multicenter study, 61 heavily pretreated children (median age, 12 years; range 1 to 20) received a median of three cycles of clofarabine and achieved an overall response rate of 30 percent (seven CR, five CR without platelet recovery, six partial remissions) [139]. The most common severe adverse events (grade ≥3) were febrile neutropenia, anorexia, hypotension, and nausea.

•A retrospective multicenter study reported 61 percent overall response rate (52 percent CR) among children treated with clofarabine alone or combined with other agents; half of the children were able to proceed to allogeneic HCT [140].

Clofarabine has been combined with other cytotoxic chemotherapy, including etoposide, cyclophosphamide, and cytarabine, but such regimens have resulted in a high rate of infections and other adverse events [141,142].

Patients who relapse after salvage chemotherapy or immunotherapy are candidates for allogeneic HCT once they have attained second remission [143,144].

Survival after relapse — The outcome for patients with relapsed ALL/LBL is guarded when compared with those without recurrence. Relapse following ALL/LBL therapy remains the second most common cause of cancer-related death in children. The vast majority of relapses occur within 2.5 years from diagnosis.

The survival rate of patients who relapse is dependent on a variety of risk factors. This was illustrated in a retrospective review of 1961 patients with a relapse from a cohort of 9585 enrolled children with ALL/LBL in the COG clinical trials [145]. The following findings were noted:

●The strongest predictor of survival was the time of relapse from initial diagnosis. Patients who relapsed less than 18 months after diagnosis had a poor outcome, with a five-year survival rate of approximately 21 percent.

●Five-year survival rates were higher in patients with isolated CNS relapse compared with isolated or concurrent bone marrow relapse (59, 24, and 39 percent, respectively). A similar study determined that patients with a late CNS relapse (greater than 18 months from diagnosis) fared better than those with a relapse prior to 18 months from diagnosis (83 versus 46 percent) [146].

●Patients with high-risk disease had a lower survival rate than those with lower risk disease. The lowest survival rate was in patients with high-risk disease who relapsed before 18 months after diagnosis (15 percent).

●After adjusting for site and time of relapse, multivariate analysis of 1391 patients demonstrated that older age (>10 years), presence of CNS disease at diagnosis, male gender, and T cell disease were associated with lower survival rates.

As noted above, important predictors of survival include the site and timing of relapse and the prior treatment regimen. These findings have been confirmed in other prospective clinical trials [125,147,148].

●Genetic features – As with newly diagnosed disease, findings on routine cytogenetics and fluorescence in situ hybridization (FISH) studies may help to stratify children with relapsed disease into prognostic groups. As an example, in one study, the outcome of children with clinically standard-risk relapsed B cell precursor ALL/LBL who had high-risk cytogenetic findings at relapse was similar to that of children with clinically high-risk relapsed disease [149].

●Site of relapse – The long-term survival in ALL/LBL patients with bone marrow relapse varies from 5 to 60 percent and depends on the additional treatment for relapse, standard versus high-risk initial disease status, and time to relapse [125,147]. Children who have isolated CNS relapse fare better than those who have bone marrow relapse, with 5- to 10-year EFS rates of approximately 54 percent [145]. However, those with early CNS relapse (<36 months from diagnosis) tend to do less well, with survival rates of only 38 percent [150].

●Time to relapse – The longer the duration between relapse and the time of diagnosis, the better the survival rate [125,145]. Patients who relapse after completion of chemotherapy fare better than those who relapse while still on therapy. Patients with high-risk disease often relapse while still receiving chemotherapy. For these patients, survival rates improve with increased duration of first remission. Patients with low-risk disease tend to relapse after the completion of chemotherapy, often after a prolonged time in remission.

Response to a second therapy regimen correlates directly with the length of first remission [151,152]. As an example, in the experience of the COG, rates of survival after isolated bone marrow relapse were 21 percent for those relapsing prior to 18 months from diagnosis versus 50 percent for those relapsing >36 months from diagnosis [145]. Although HCT appears to be more successful than chemotherapy for patients who relapse early (ie, <36 months), its role in the management of late failures is less well defined [143,153].

●Phase of treatment – Patients in the maintenance portion of their chemotherapy who are receiving methotrexate and 6-mercaptopurine can be successfully treated with more aggressive chemotherapy regimens. Patients who relapse while receiving induction or consolidation chemotherapy, however, usually respond poorly to additional chemotherapy. Following reinduction, these patients are often considered for HCT.

●Treatment regimen – Outcome also varies by the treatment regimen used at relapse. As an example, a multicenter phase III randomized trial compared idarubicin with mitoxantrone in 216 children with relapsed ALL/LBL [154]. Consolidation after this second induction was stratified based on risk. Although mitoxantrone did not result in an increase in CR rate after induction, mitoxantrone resulted in significantly higher rates of progression-free survival (65 versus 36 percent), and OS (69 versus 45 percent) at three years.

The prognosis at the time of relapse, however, does not appear to be related to the intensity of the initial therapy regimen used in current treatment protocols, or the age at transplantation (ie, patients <14 years versus 14 to 18 years) [155,156]. As an example, a report from the COG included 256 evaluable children with relapsed ALL/LBL whose initial treatment was randomly assigned to include either a standard intensity post-induction regimen or an augmented intensity post-induction regimen [155]. Three-year survival rates after relapse were similar in the two treatment groups (36 versus 39 percent).

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

●Most children with newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL/LBL) are treated on research protocols with risk stratification based on prognostic indicators available at the time of presentation (table 1). Such research protocols have helped to standardize treatment, improve survival rates, and reduce the long-term complications of therapy.

●Although cure rates are >85 percent in many studies, significant challenges remain, particularly for children with adverse prognostic factors. (See "Risk group stratification and prognosis for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)

●Novel therapies for these patients and the implementation of new techniques to further refine risk stratification should further improve survival rates in childhood ALL/LBL. (See 'Induction therapy' above.)

●Because they are at risk for long-term complications, it is crucial that survivors of childhood ALL/LBL continue regular follow-up with their oncologists after the cessation of chemotherapy. Long-term complications are related to the type and intensity of the treatment regimen. Patients with high-risk ALL/LBL receive more aggressive chemotherapy and are at greater risk for acute and chronic adverse effects. (See "Overview of the outcome of acute lymphoblastic leukemia/lymphoma in children and adolescents".)