Version May 2024
INTRODUCTION — Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) is the most common malignancy in children, accounting for one-quarter of all pediatric cancer diagnoses. ALL/LBL refers to malignancies of undifferentiated lymphoid precursors that involve bone marrow, blood, and/or extramedullary sites. There is a large body of literature that considers ALL and LBL the same entity, distinguished only by the primary location of the disease.
ALL/LBL is categorized according to immunophenotype as:
●T cell (T lymphoblastic) ALL/LBL
●B cell (B lymphoblastic or B precursor) ALL/LBL
In addition, there are distinct subtypes of B cell ALL/LBL, which are defined by molecular features such as Philadelphia chromosome (Ph)-positive ALL/LBL and Ph-like ALL/LBL.
Leukemia with features of B cells or T cells plus myeloid characteristics is described as mixed phenotype acute leukemia, which is discussed separately. (See "Mixed phenotype acute leukemia".)
Outcomes and late effects of treatment of ALL/LBL in children are reviewed in this topic.
Clinical presentation, classification, risk group stratification, and treatment of childhood ALL are discussed separately.
●(See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
ALL/LBL in the setting of Down syndrome/trisomy 21 or various inherited conditions may require distinctive treatment, experience specific toxicities, and have different prognoses compared with ALL/LBL in children without these underlying conditions. ALL/LBL in these settings are discussed separately.
●(See "Down syndrome: Clinical features and diagnosis".)
●(See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
OUTCOMES
Survival — Survival for children with ALL/LBL has steadily improved since the 1980s, with an increasing proportion of children who are cured [1-5]. Treatment outcomes are influenced by the disease category (eg, B cell, T cell), clinical risk factors (eg, age, extranodal involvement), and genetic features (chromosomal and molecular abnormalities).
Children with ALL/LBL in developed nations have approximately 90 percent five-year overall survival (OS) and event-free survival (EFS); the 10-year OS in this setting is estimated to be 85 to 88 percent [2,6-9]. Treatment for pediatric ALL/LBL is stratified, so that higher-risk disease is treated with more aggressive therapy, while lower-risk disease is treated with less intensive therapy to reduce toxicity while maintaining favorable outcomes. Among other advances, standardized treatment at specialized centers and routine prophylaxis to prevent relapse in the central nervous system (CNS) and other extranodal sites have contributed to improved outcomes.
By contrast, the rate of cure is <35 percent for children in the developing world, in part because of abandonment of treatment and/or lack of dedicated, multidisciplinary pediatric oncology units [10-13]. When children in the developing world were treated on international protocols, five-year rates of OS and EFS improved (82 and 74 percent, respectively), yet treatment-related mortality (TRM) remained elevated (eg, 5 percent death in complete remission [CR]) [14,15]. TRM correlates with differences in available supportive care [16].
Clinical characteristics (eg, age) and pathologic features of the leukemic blasts (eg, immunophenotype, genetic findings) contribute importantly to outcomes in pediatric ALL/LBL.
Effect of age — Survival is related to the age at diagnosis, with adolescents and young adults (AYAs) faring less well than younger children, while ALL/LBL in infants has a grim prognosis.
●Adolescents and young adults ALL/LBL – Survival in AYAs is influenced by a lower percentage of cases with favorable cytogenetics (eg, ETV6::RUNX1) and a concurrent increase in adverse-risk cytogenetics (eg, BCR::ABL1, hypodiploidy) [17]. While prognosis is improving with the development of AYA protocols, OS at 20 years is approximately 48 percent.
●Infant ALL/LBL – The prognosis for infant ALL/LBL is poor, with an EFS of 10 to 30 percent [18-20].
Infants tend to have higher white blood cell (WBC) counts at presentation, KMT2A (formerly called MLL) translocations, and skin involvement [21]. Aggressive treatment protocols are associated with improved outcomes in some studies [22-25]. The outcome for infants <90 days at diagnosis who have the t(4;11) KMT2A translocation with a high WBC count was substantially worse than for older infants without this translocation [26,27]. Treatment intensity is often decreased for infants <90 days of age, since this group is very sensitive to adverse effects of chemotherapy [28].
Classification — Diagnosis, treatment stratification, and prognosis varies according to the ALL/LBL disease category.
ALL/LBL should be classified using either the International Consensus Classification [29] or the 5th edition of the World Health Organization classification of lymphoid neoplasms [30]. Both systems use cytogenetic and molecular features to classify ALL/LBL, and the use of either is acceptable.
Classification of ALL/LBL is discussed separately. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)
B cell ALL/LBL — B cell ALL/LBL (B precursor ALL/LBL) is the largest category of ALL/LBL, and it includes many genetic subtypes that are distinguished by chromosomal abnormalities (eg, aneuploidy or translocations), which deregulate hematopoietic transcription factors, epigenetic modifiers, cytokine receptors, or tyrosine kinases [31-33].
Outcomes are strongly associated with genetic features, clinical characteristics (eg, age, WBC count at presentation), response to induction therapy, and persistence of measurable residual disease (MRD) at specified time points during treatment. Details of prognostic features and risk group stratification are presented separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
Following are examples of outcomes stratified according to the B cell ALL/LBL risk group:
●Low or standard risk – For children with low- or standard-risk B cell ALL/LBL, five-year EFS is >90 percent in children who have a good response to induction chemotherapy [6,34-41].
●High risk – For patients with high-risk features at presentation and a good early response to induction chemotherapy, five-year EFS with intensive chemotherapy is >80 percent [34-40,42].
●Very high risk – For children with hypodiploid karyotype (<44 chromosomes) or a slow response to early phases of chemotherapy, five-year EFS is <60 percent [42-49].
Management of B cell ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
T cell ALL/LBL — T cell ALL/LBL represents approximately 15 percent of pediatric ALL/LBL [31-33]. It arises from a multistep process of accumulated mutations that alter growth, differentiation, proliferation, and cell survival during thymopoiesis. The genetics of T cell ALL/LBL are highly heterogeneous, and chromosomal abnormalities are found in almost all patients; altered expression of T lineage transcription factors, NOTCH1/MYC signaling, and cell-cycle control are affected in most cases of T cell ALL/LBL. Despite the numerous mutations associated with T cell ALL, most do not contribute to risk stratification. T cell ALL/LBL has a higher incidence in males than in females and in patients with African ancestry; high WBC count and a mediastinal mass at presentation are more common in this subtype of ALL/LBL [50,51].
Although most children with T cell ALL/LBL have high-risk features at presentation (eg, unfavorable age or high WBC count), outcomes now rival those with B-precursor ALL/LBL [52,53]. The COG AALL0434 trial of T cell ALL/LBL reported 84 percent five-year EFS; this trial compared two different methods of methotrexate delivery during the interim maintenance phase and also randomized patients to add nelarabine or not [54,55]. Outcomes for the AALL1231 clinical trial, which decreased radiation for almost all patients, were similar [55].
Management of T cell ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'T cell ALL/LBL'.)
Philadelphia chromosome positive/BCR::ABL1 positive — BCR::ABL1 positive ALL/LBL accounts for approximately 2 to 3 percent of pediatric ALL/LBL [56]. It was associated with a dismal prognosis until the routine incorporation of a tyrosine kinase inhibitor (TKI) into multiagent chemotherapy regimens.
Among 91 children with Philadelphia chromosome-positive (Ph+) ALL/LBL treated with imatinib plus intensive chemotherapy in Children’s Oncology Group (COG) trial AALL0031, five-year EFS was 70 percent [57]. Treatment that included the second generation TKI, dasatinib, achieved similar or better outcomes compared with imatinib [58,59].
Management of BCR::ABL1 positive ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Ph+ B-ALL/LBL'.)
Philadelphia chromosome-like ALL/LBL — Ph-like ALL/LBL is a disease subtype that has a pattern of gene expression similar to Ph+ ALL/LBL, but the BCR::ABL1 fusion gene is not detected [32,60,61]. The genetics are heterogeneous, but most cases involve activating mutations of CRLF2/Janus kinase (JAK) pathway signaling, ABL1-class tyrosine kinase fusions, or alterations of other kinases or signaling molecules.
The incidence of pediatric Ph-like ALL/LBL increases with age, from 10 percent in younger children to 25 to 30 percent in AYAs [62]; it is also more common in males and individuals of Hispanic ancestry [63]. In one report, OS was approximately 40 percent, and clinical outcomes correlated inversely with age [64].
Treatment of Ph-like ALL/LBL with TKIs and JAK inhibitors (eg, ruxolitinib) is being evaluated. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
Relapse — Most relapses of ALL/LBL in children occur within the first year after completing therapy. Certain clinical and pathologic features are associated with increased risk for relapse.
The risk of relapse is highest in the first year and decreases by 7 to 10 percent per year in the second through fourth years after treatment cessation [65]; recurrences after four years are rare [66,67]. For children who experienced 10 years of EFS after achieving CR, the 30-year risk for leukemic relapse was 0.6 percent [68]. For children who did not receive radiation therapy, the 30-year OS was 98.3 percent, which was comparable to that of the general United States population matched for age, sex, and race.
Clinical, biological, and response-based features are associated with relapse in childhood ALL/LBL [69]. Persistence of MRD after induction chemotherapy is the strongest predictor of relapse, but one-half of relapses occur in patients with an excellent response to therapy during induction [69]. Other factors associated with increased risk for relapse are age <1 year or ≥10 years, CNS involvement, elevated WBC at diagnosis, and pathologic features, such as T cell immunophenotype, hypodiploid karyotype (<44 chromosomes), and molecular features (eg, Ph-like subtype, iAMP21, mutated IKZF1 or KMT2A).
Treatment-related mortality — Despite improvements in long-term survival, children with ALL/LBL remain at risk for late toxicity and TRM. Most TRM occurs in the first year of ALL/LBL treatment (ie, during induction therapy or shortly thereafter).
Many factors contribute to TRM, including the aggressiveness of the treatment protocol and adverse events associated with high-dose corticosteroids, antibiotics, chemotherapy, and hematopoietic cell transplantation. Estimates of overall TRM (ie, deaths during induction or while in CR) range from 2.6 to 5 percent [70-73]. As an example, in a study of 1652 children with ALL/LBL (1992 through 2001), TRM during induction phase of therapy was 1.2 percent, and TRM while in first CR was 2.2 percent; infection was the most frequent cause of death during induction (68 percent) [73].
Long-term survival with pediatric ALL/LBL approaches 90 percent, and late mortality due to relapse, long-term toxicities, and second cancers has decreased among survivors of childhood leukemia [74]. The Childhood Cancer Survivor Study (CCSS) evaluated late mortality from 1970 through 1999 among 8500 patients who survived ≥5 years after diagnosis of childhood ALL/LBL [75]; mortality in the 25 years after completing treatment was 18 percent in earlier decades of the study but declined to 6 percent by 1990.
Children with Down syndrome are at an increased risk for treatment-related complications and TRM, as discussed separately. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)
LATE EFFECTS — Long-term survivors of pediatric ALL/LBL may experience late adverse effects (AEs) of treatment. The incidence of specific complications is influenced by the type and intensity of treatment and age.
Prominent late AEs associated with treatment of ALL/LBL in children include neurocognitive dysfunction and other central nervous system (CNS) complications, endocrinopathies, cardiotoxicity, infections, and second cancers; other late effects include decreased linear growth, depression, fatigue, and anxiety [76-80].
By age 35 years, the cumulative burden of late effects of cancer treatment was higher for leukemias than for treatment of lymphomas or solid tumors [81]. The greatest burden of late effects of chemotherapy and/or radiation therapy (RT) by age 45 years involved cardiovascular conditions, followed by endocrine, gastrointestinal, hematologic, and immunologic/infectious complications.
The likelihood of specific complications is influenced by the age at treatment and the type and intensity of therapy. As examples, neurocognitive decline is more likely to occur in children treated with RT at <6 years [82], while impaired fertility is more common in adolescents who received cyclophosphamide or other alkylating agents [83].
Neurologic effects
Central nervous system, mental health, and cognition — Late neurologic AEs vary with the method and intensity of CNS prophylaxis/treatment.
Effects of CNS prophylaxis and treatment on neurologic development are variable [84,85]. Impaired cognitive function has been reported in children treated for ALL/LBL, particularly in those who received cranial RT or triple intrathecal (IT) chemotherapy [82,86-90].
Contemporary treatment protocols have reduced or eliminated cranial RT as CNS prophylaxis for most children with ALL/LBL to minimize the incidence and severity of cognitive impairment [91-93]. Treatment protocols now use substantially lower RT doses (eg, 12 to 18 grey [Gy]) compared with earlier treatments; this appears to have decreased, but not eliminated, the incidence and severity of cognitive impairment [88,94-96]. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS management'.)
CNS management in children with ALL/LBL is associated with various neurologic effects, including attention disorders, late cognitive deficits, and mental health symptoms.
●Neurologic impairment – Neurologic sequelae vary with inclusion of RT in prophylaxis and treatment.
•Radiation therapy administered – Younger children (eg, <6 years) who received high-dose cranial RT (≥24 Gy) in combination with IT chemotherapy are at the greatest risk for subsequent CNS impairment [97].
-A study of 150 survivors of childhood ALL/LBL (35 of whom had received cranial RT) reported that, with a 10-year median follow-up, 83 percent had minimal or no impairment, 14 percent had moderate deficiencies, and 3 percent had severe cognitive dysfunction, as evaluated with standardized neuropsychologic tests (age-adapted versions of the Wechsler test) [86]. However, median intelligence quotient (IQ) scores for the ALL/LBL survivors were comparable to those in the general population.
-In another study, 22 patients with ALL/LBL were treated with chemotherapy alone (including high-dose methotrexate), and 11 were treated with RT plus chemotherapy. Those treated with RT had significant cognitive effects compared with normal controls [98]. Children treated with either chemotherapy alone or chemotherapy plus 12 Gy RT had decreased long-term memory, recall, and processing speed, along with abnormalities of the hippocampus and caudate nucleus by magnetic resonance imaging (MRI).
-Compared with matched controls, children who received cranial RT at an early age had inferior ninth-grade school grade reports in all school subjects [99].
•No radiation therapy administered – A meta-analysis of 10 studies reported neurologic impairment in 509 pediatric ALL/LBL survivors in continuous first complete remission (CR) who received IT and systemic chemotherapy without RT, compared with 555 healthy controls [95]. ALL/LBL survivors had a six- to eight-point decrease in IQ test scores and moderate impairments in working memory, information processing speed, and fine motor functioning.
●Mental health
•A meta-analysis reported that while most pediatric ALL/LBL survivors are well adjusted, there is an increase in anxiety and depression [100]. Adult survivors of childhood cancer are at an increased risk for both suicidal ideation and symptoms of post-traumatic stress disorder (PTSD) compared with healthy controls [100].
•A study of 2208 survivors and 10,457 controls reported that survivors of adolescent and young adult cancer had an increased rate of mental health visits (relative risk [RR] 1.3 [95% CI 1.1-1.5]) and increased risk for a severe psychologic event (ie, suicide, emergency department visit, admission; hazard ratio [HR] 2.0 [95% CI 1.3-2.4]) [101,102].
Stroke — Survivors of childhood leukemia are at an increased risk for late-occurring stroke.
The Childhood Cancer Survivor Study (CCSS) reported that, compared with their siblings, children who survived childhood leukemia for ≥5 years had an increased risk for stroke (RR 6.4 [95% CI 3-13.8]) [103]. Compared with age-matched siblings, patients who received >30 Gy cranial RT were more likely to have late-occurring stroke; however, the stroke risk was not elevated for patients who received chemotherapy only or RT ≤30 Gy.
Other neurologic sequelae — Adult survivors of childhood leukemia are at risk for late-onset auditory-vestibular-visual sensory deficits, coordination and motor problems, seizures, and headaches [104]. These neurologic findings were more likely to occur in patients who relapsed or had received intracranial RT. Subtle behavioral and educational sequelae may also be noted in survivors of childhood ALL/LBL [105,106].
Endocrinopathies — Endocrine dysfunction, including thyroid disorders, obesity, diabetes mellitus, and gonadal dysfunction, are among the most common late treatment-related AEs after childhood ALL/LBL. The cumulative risk steadily increases over time and is more common in those who received high-dose RT to the head, neck, or pelvis, or after exposure to high doses of alkylating agents.
In a study of 14,290 childhood cancer survivors with a median follow-up of 25 years, 46 percent of childhood leukemia survivors exhibited endocrine dysfunction, including hypo- or hyperthyroidism, thyroid cancer, growth hormone deficiency, obesity, and diabetes mellitus [77]. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)
Impaired growth — Many children with ALL/LBL experience "catch-up" growth after completion of chemotherapy, but some have permanent short stature. The cause of short stature may be multifactorial, as no single aspect of treatment has been implicated.
A study from the CCSS reported shorter adult height for 2434 ALL/LBL survivors compared with 3009 of their siblings [107]. Across all treatments, ALL/LBL survivors had decreased adult height and increased risk of adult short stature (ie, height standard deviation scores less than -2; overall risk [OR] 12.5 [95% CI 8.1-19.2]). Those treated with chemotherapy only had a higher risk of adult short stature compared with their siblings (OR 3.4 [95% CI 1.9-6]); no specific chemotherapy agent was implicated. Risk factors for short stature included diagnosis of ALL/LBL before puberty, higher-dose cranial RT (≥20 Gy versus <20 Gy), RT to the spine, and female sex.
Some patients have low growth hormone (GH) levels due to abnormal hypothalamic-pituitary function from cranial RT [80,107,108]. However, GH levels at the end of treatment do not correlate with adult height for children treated with regimens that did not include cranial RT [109]. Other patients may have undiagnosed mild, primary, or central hypothyroidism. Childhood ALL/LBL survivors are also at an increased risk for developing osteoporosis, which can result in vertebral compression fractures and loss of height [80,110,111].
Further discussion of growth failure and bone problems in childhood cancer survivors is presented separately. (See "Bone problems in childhood cancer patients", section on 'Reduced bone mineral density' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Disordered growth'.)
Obesity — The incidence of obesity is increased in long-term survivors of childhood ALL/LBL. Cranial RT is associated with obesity, but other risk factors are less well defined.
●A meta-analysis of 47 studies, which included data from 1742 childhood ALL/LBL survivors, reported an increased incidence in obesity in all patient subgroups, regardless of sex, age at diagnosis, or history of cranial RT [112]. The mean body mass index (BMI) Z-score was 0.83, which corresponds to the 80th BMI percentile and is higher than that in a healthy population (expected mean BMI Z-score between 0.4 and 0.6).
●Another meta-analysis reported an age- and race-adjusted increased risk for obesity (BMI >30 kg/m2) in survivors treated with cranial RT ≥20 Gy [113]. This is a higher RT dose than most current pediatric treatment regimens, and it is uncertain if current RT doses will be associated with obesity.
●A prospective study of 456 children who were treated using a single protocol reported that the prevalence of obesity in the 248 ALL/LBL survivors who attained adult height was comparable to that of the general population [114]. Risk factors for obesity in ALL/LBL survivors included a young age (<6 years) and being overweight or obese at the time of diagnosis. There was no effect of RT or RT dose on the rate of obesity.
●A study from the CCSS reported that adiposity, insulin resistance, dyslipidemia, and higher leptin levels were increased in 273 young adults who received cranial RT [115]. However, in another study, increased BMI was associated with higher levels of corticosteroid exposure but not exposure to cranial RT, according to multivariate analysis [116].
●Obese survivors of childhood ALL/LBL had a greater risk of relapse compared with those who are not obese, according to data from the Children's Cancer Group (1995 to 1998) [117]. Compared with 3971 nonobese survivors, 343 obese survivors had a lower five-year event-free survival (EFS; 72 versus 77 percent; HR 1.36 [95% CI 1.04-1.77]) and higher risk of relapse (26 versus 20 percent; HR 1.29 [95% CI 1.02-1.56]). These effects were more prominent in 1003 patients ≥10 years old at diagnosis and were confirmed with a separate cohort of 1160 survivors.
Other studies also reported an increased incidence of obesity and other cardiovascular risk factors [113,115,116,118-121].
Glucose metabolism — Abnormal glucose metabolism may occur during induction therapy and can persist after treatment is complete.
Glucose metabolism and pancreatic beta cell function may be affected during treatment of ALL/LBL by L-asparaginase, prednisone, or the leukemic process [122,123]. Abnormal glucose metabolism may persist after completion of therapy in some patients [124]. Among 32 children with ALL/LBL who were off of therapy for ≥1 year, 22 had an impaired insulin response, 9 had impaired glucose tolerance, and 1 had overt diabetes [119,125].
In a retrospective analysis of 91 survivors of childhood ALL/LBL or non-Hodgkin lymphoma, the prevalence of insulin resistance was higher among those who underwent allogeneic hematopoietic cell transplantation/total body irradiation (88 percent), compared with patients who were not transplanted and received either chemotherapy only (9 percent) or chemotherapy plus cranial RT (16 percent) [126]. A retrospective study of 167 children with ALL/LBL reported that hyperglycemia during induction was associated with increased rates of mortality and relapse [127]; however, these findings await confirmation in other studies, and it is uncertain if glycemic control would improve these outcomes.
Reproductive health — Reproductive capacity and sexual function of ALL/LBL survivors are affected by age at the time of treatment and by the components of therapy.
Postpubescent males with ALL/LBL can have treatment-related declines in reproductive function, particularly after treatment with high-dose alkylating agents [83], while gonadal function and fertility of prepubescent ALL/LBL patients are relatively unaffected [128].
Both males and females are more likely to have decreased fertility if treated with high-dose (≥24 Gy) cranial RT [129]. Females are more likely to have decreased fertility if they received cranial RT around the time of menarche [129] and are at risk for premature ovarian insufficiency [77].
Congenital abnormalities are no more common among the offspring of ALL/LBL survivors than the general population [129,130].
Thyroid dysfunction — Survivors of childhood ALL/LBL are at an increased risk of thyroid disorders, including underactive or overactive thyroid, thyroid nodules, and thyroid cancers [77]. The risk is greatest for those who underwent RT, but the risk is increased at least twofold even in patients who did not receive RT or high-dose alkylator therapy.
Cardiotoxicity — Cardiovascular disease is more common in survivors of childhood ALL/LBL.
One study reported that cardiovascular disease by age 45 years was at least fivefold higher among 3466 childhood cancer survivors compared with their siblings without cancer [81]. Treatment with anthracyclines (eg, daunorubicin, doxorubicin) may cause cardiovascular complications, including irreversible and fatal cardiomyopathy [131]. However, doses of anthracyclines used in current regimens and/or the use of dexrazoxane as a cardioprotectant are associated with less cardiotoxicity [132,133].
Management of anthracycline cardiotoxicity and monitoring children for acute and late manifestations of cardiotoxicity are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
Infections — Infections are a frequent complication after treatment for ALL/LBL.
In a retrospective, single-institution study, 2204 childhood leukemia survivors were matched with 11,020 age-matched controls [134]. Compared with controls, the rate of infections in leukemia survivors was elevated 1.8-fold at <1 year, 1.7-fold between one to five years, and 1.3-fold ≥5 years after the completion of treatment. As a registry study, it was not possible to correlate infectious events with specific risk factors (eg, central venous lines or graft-versus-host disease), and it is uncertain if contemporary treatment protocols are associated with such risks for infections.
Survivors of ALL/LBL were more likely than their siblings to have health care visits related to infections and disorders of the immune system [81]
Second neoplasms — Approximately 2 to 3 percent of childhood ALL/LBL survivors develop a second malignancy [75,135-137].
Brain tumors and hematologic malignancies (eg, acute myeloid leukemia [AML]) are the most common secondary malignancies [135,138,139]. The risk of a second cancer is greatest among patients who received cranial RT [128,138] or intensive therapy for relapse [140].
Among 856 survivors of ALL/LBL with >10 years EFS, 44 developed second malignancies, 41 of which were radiation related [68]. The estimated rates for a second malignancy 30 years after remission induction were 20.9 and 0.95 percent for those receiving RT or not receiving RT, respectively. Virtually all tumors in children who received RT arose in the field of irradiation, and most were either benign or low grade; the most common tumors were basal cell carcinomas (10), meningiomas (10), malignant brain tumors (5), and thyroid carcinoma (4). It is unclear if patients receiving current doses of prophylactic radiation (eg, 12 Gy) will have similar rates of secondary neoplasms.
Brain tumors — In a review of almost 10,000 children treated for ALL/LBL, the risk of developing a primary brain tumor, particularly an astrocytoma, was increased 22-fold, which corresponds to a 1 to 2 percent cumulative incidence over 10 to 20 years [141]. Brain tumors were seen only in children who had previously undergone cranial RT. Similar findings were noted in another series of children with ALL/LBL [142]. Children treated with cranial RT for ALL/LBL may also develop glioblastoma multiforme; in one series of 37 such children, three experienced multifocal tumors [143].
The combination of prophylactic cranial RT with orally administered 6-mercaptopurine (6MP) was associated with a higher-than-expected incidence of brain tumors in survivors of ALL/LBL who have genetic defects in 6MP metabolism [142].
Adult survivors of childhood ALL/LBL who received cranial RT are also at high risk of developing subsequent meningiomas. With a median follow-up of 25 years, 22 percent of 49 adult survivors who received cranial RT developed meningiomas; no other brain tumors were reported [144]. Meningiomas occurred only in patients who received cranial RT doses ≥21 Gy. The incidence of meningioma was higher in patients treated by 1980 (47 percent), but it is uncertain if this is related to longer follow-up or to higher RT doses (eg, 21 to 25 Gy).
Hematologic malignancies — Survivors of childhood ALL/LBL are at risk for the development of a secondary hematologic malignancy.
A retrospective review of 2169 children with ALL/LBL treated at a single institution (1962 to 1998) reported secondary myeloid malignancies in 2.2 percent [145]. Most cases were AML, but there were also cases of myelodysplastic syndrome/neoplasms and chronic myeloid leukemia. The median follow-up was >18 years, and compared with the United States general population, the standardized incident ratio was 150.9 (95% CI 98.1-185.4).
LONG-TERM FOLLOW-UP — ALL/LBL survivors should have comprehensive follow-up care, with attention to nutritional assessments, education, growth monitoring, mental health and social functioning, and education to prevent high-risk behaviors.
Ideally, care should transition to either a clinic dedicated to childhood cancer long-term survivors or to a clinician (eg, pediatrician, family practice, or internal medicine) who has an association or contact with a long-term survivor clinic, if questions arise. For high-risk groups (eg, those who have received craniospinal, testicular, or other radiation therapy), additional follow-up and imaging may be necessary.
The nature and schedule of screening for secondary malignancies is influenced by the treatment received. Since the risk of malignancy recurrence is highest during the period immediately following the completion of chemotherapy, an intensive follow-up schedule is often specified as part of protocols.
Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group. Those undergoing hematopoietic stem cell transplantation have risks for additional long-term complications.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Leukemia in children (The Basics)")
SUMMARY
●Description – Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) is the most common cancer in children. Advances in treatment are associated with improved outcomes, with long-term overall survival and event-free survival that approach 90 percent in many settings. (See 'Outcomes' above.)
Children with ALL/LBL in the setting of Down syndrome/trisomy 21 or various inherited conditions may require distinctive treatment, experience specific toxicities, and have different prognoses compared with ALL/LBL in children with these underlying conditions. Outcomes and adverse effects with treatment are discussed separately. (See "Down syndrome: Clinical features and diagnosis" and "Familial disorders of acute leukemia and myelodysplastic syndromes".)
●Outcomes – Features associated with outcomes of treatment for ALL/LBL include:
•Age – Outcomes are less favorable for infants and adolescents/young adults. (See 'Effect of age' above.)
•Leukemia classification – Outcomes vary with the leukemic subtype:
-B cell ALL/LBL – This is generally the most favorable category, but outcomes vary with clinical and pathologic features. (See 'B cell ALL/LBL' above.)
-T cell ALL/LBL – Risk-stratified treatment has led to outcomes that approach those with B cell disease. (See 'T cell ALL/LBL' above.)
-Philadelphia chromosome-positive/BCR::ABL1 ALL/LBL – This category was traditionally associated with an adverse prognosis, but treatment that includes a tyrosine kinase inhibitor has greatly improved outcomes. (See 'Philadelphia chromosome positive/BCR::ABL1 positive' above.)
-Philadelphia chromosome-like ALL/LBL – This diverse category remains a challenging clinical problem, with newer approaches informed by molecular features. (See 'Philadelphia chromosome-like ALL/LBL' above.)
•Clinical/genetic features – Children with hypodiploid karyotype, certain mutations, and slow response to induction therapy are associated with inferior outcomes. (See 'Outcomes' above.)
●Late effects of treatment – Long-term complications of treatment are related to the type and intensity of treatment. (See 'Late effects' above.)
Late effects include:
•Neurologic – Impaired cognition, stroke, and neurodevelopmental delay. (See 'Neurologic effects' above.)
•Endocrine – Growth retardation, obesity, abnormal glucose metabolism, reduced fertility, and thyroid dysfunction. (See 'Endocrinopathies' above.)
•Cardiac – Cardiomyopathy. (See 'Cardiotoxicity' above.)
•Infections. (See 'Infections' above.)
•Second cancers – Other hematologic malignancies, brain tumors, and other cancers. (See 'Second neoplasms' above.)
●Importance of long-term follow-up – Survivors of childhood ALL/LBL must continue long-term oncology follow-up to detect and manage long-term complications. (See 'Long-term follow-up' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges C Philip Steuber, MD, who contributed to earlier versions of this topic.
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