INTRODUCTION — Acute lymphoblastic leukemia/lymphoma (ALL/LBL) is the most common malignancy in children. It is thought that ALL and LBL are overlapping clinical presentations of the same disease, and they should be referred to collectively as ALL/LBL [1].
The outcomes of ALL/LBL in children is 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".)
OUTCOMES
Event-free survival — Outcomes for ALL/LBL have steadily improved since the 1980s [2-5]. Five-year event-free survival (EFS) for childhood ALL/LBL currently approaches 90 percent in developed countries [6-8]. Five-year and estimated 10-year overall survival (OS) rates were reported as 90 and 85 to 88 percent, respectively [3,6,9].
In contrast, in the developing world, cure rates are <35 percent, in part because of abandonment of treatment and/or lack of dedicated, multidisciplinary pediatric oncology units [10-13]. When children in the developing world are treated on international protocols, rates of EFS and OS at five years are improved (74 and 82 percent, respectively), yet treatment-related mortality (TRM) remains higher than in the developed world (5 percent death in complete remission [CR]) [14,15]. TRM correlates with differences in available supportive care [16].
Individual prognosis varies according to risk group (table 1):
●Five-year EFS rates are highest (>90 percent) for patients with low- or standard-risk B-precursor ALL/LBL who have a good response to induction chemotherapy [6,17-24].
●Patients with high-risk features at presentation and a good early response to induction chemotherapy have a >80 percent five-year EFS with intensive chemotherapy [17-23,25].
●A subset of very high-risk patients, such as those with hypodiploid karyotype (<44 chromosomes, with or without TP53 mutations) or slow response to induction chemotherapy, have a poor prognosis, with <60 percent five-year EFS using current chemotherapy regimens [25-31].
●Children with T cell ALL/LBL have variable outcomes. Those children without high-risk features do relatively well, but most have high-risk features at presentation (eg, unfavorable age or high white blood cell [WBC] count) [32,33]. Nevertheless, five-year 85 percent EFS with T cell ALL/LBL now rivals outcomes for precursor B ALL/LBL. (84 percent five-year EFS in the COG AALL0434 clinical trial) [34,35]. The large AALL0434 study showed that dose escalation of low-dose methotrexate with vincristine resulted in an improved survival with fewer relapses over five years [35]. Recent data have shown that nelarabine may also improve EFS and many institutions have chosen to add nelarabine to all patients with T-ALL [36].
●Outcomes for children with mature B cell ALL/LBL have also improved. In one study, seven-year EFS for 151 patients with Burkitt-type lymphomas, including mature B cell ALL/LBL, was 81 percent. Patients with mature B cell ALL/LBL were treated using highly aggressive B cell lymphoma treatment protocols [37]. Patients with B cell ALL/LBL who relapse tend to have early recurrences. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
●The outcome for children with Philadelphia chromosome positive (Ph+) ALL/LBL has had a significant increase in EFS with the addition of tyrosine kinase inhibitors [38]. One study of 65 patients with Ph+ ALL/LBL reported that incorporating imatinib into an intensive chemotherapy increased three-year EFS from 35 to 80 percent.
●Ph-like ALL/LBL is a high-risk group in which the gene expression signature resembles that of Ph+ ALL/LBL, but the BCR::ABL1 fusion gene is not detected [39,40]. This type of leukemia is more common in young adults, males, and those of Hispanic ancestry [41]. In one report, Ph-like ALL/LBL accounted for 21 percent of ALL/LBL in adolescents; OS was approximately 40 percent and clinical outcomes inversely correlated with age [42].
There are several molecular lesions accounting for Ph-like ALL, which can be grouped into at least three categories [43]. One group includes tyrosine kinase fusion genes, including ABL1, CSF1R, and PDGFRB. These lesions are often responsive to tyrosine kinase inhibitors (TKI) and are treated using chemotherapy with dasatinib or another TKI.
The second group includes patients with CRLF2/JAK pathway mutations that are frequently co-associated with Ikaros (IKZF1) mutations. These patients are usually not responsive to TKI, but they can be responsive to JAK inhibitors, such as ruxolitinib. There is not yet a standard of care for this of this group. There are several research trials in progress to address this issue, both in adults and adolescents.
A third group of patients have mutations in other genes that recapitulate the gene expression pattern of BCR::ABL1, but do not have any of the mutations described above. These patients may be responsive to TKI. Although there is no standard of care for these patients currently, this is an area of active research [44].
●Survival in ALL/LBL is age-related, with adolescents and young adults (AYA) faring less well than younger children. Survival in AYAs is largely influenced by a lower percentage with favorable cytogenetics (ETV6-RUNX1) and a concurrent increase in adverse-risk cytogenetics (BCR-ABL1, hypodiploidy) [45]. While prognosis is improving with the development of AYA protocols, OS is approximately 48 percent at 20 years. Outcomes are influenced by cytogenetic features, with those having hypodiploid, Ph-like ALL/LBL, and IgH rearrangements doing less well than the group overall.
●The prognosis for infant ALL/LBL is poor, with an EFS of 10 to 30 percent [46-48]. Infants tend to have higher WBC counts, KMT2A translocations, and skin involvement [49]. Aggressive treatment protocols are associated with improved outcomes in some studies [50-53]. The outcome for infants <90 days at diagnosis who have the t(4;11) KMT2A (MLL) translocation with a high WBC count was substantially worse than for older infants without this translocation (9.4 versus 55 percent) [54,55]. Treatment intensity is often decreased in patients <90 days of age since this group is very sensitive to chemotherapy toxicities [56].
Several studies have evaluated the length of time from completion of therapy to recurrence [57,58]. A majority (60 to 75 percent) of patients who relapse after successful completion of an initial therapy regimen do so within the first year of completion [59]. The risk of relapse decreases by 7 to 10 percent per year in the second through fourth years after treatment cessation [59]. Recurrences after four years are rare [57,58]. Children at higher risk of relapse include those with persistent measurable residual disease (MRD) after induction chemotherapy and iAMP21 amplification treated on standard-risk protocols as well as mutations such as IKZF1 and KMT2A (MLL), which are associated with chemotherapy resistance [60].
As survival from childhood leukemia increases, there has also been an increase in the proportion of children who are "cured" from their disease, defined as the proportion of survivors for whom, as a group, there is no excess mortality compared with the general population. In one study, data on children diagnosed with leukemia during 1971 to 2000 in Great Britain demonstrated an increase in the cure rate from 25 to 68 percent [61].
In another study, the estimated cumulative risk of leukemic relapse 30 years after the induction of remission for those with 10 years of EFS was 0.6 percent [62]. For the subgroup of children not receiving radiation therapy, long-term survival (98.3 percent at 30 years) was similar to that of the general United States population matched for age, sex, and race.
Treatment-related mortality — While the vast majority of children with ALL/LBL enjoy long-term survival/cure, the serious nature of the disease, as well as the aggressiveness of the treatment programs employed in obtaining such results (eg, use of corticosteroids, central lines, antibiotics, chemotherapy, hematopoietic cell transplantation), have resulted in significant TRM.
Much of the TRM occurs during the first year of ALL/LBL treatment, often during induction or shortly thereafter. Estimates of overall TRM (ie, deaths during induction plus during first CR) have ranged from 2.6 to 5 percent [63-66]. As an example, in a study from the Nordic countries covering 1652 children with ALL/LBL diagnosed between 1992 through 2001, TRM during induction and TRM while in first CR were 1.2 and 2.2 percent, respectively, with infection being the most frequent cause of death (68 percent) [66]. The presence of Down syndrome (RR 4.5, 95% CI 2.0-10) significantly increases the risk for TRM [67,68]. (See 'Down syndrome' below.)
Rates of late mortality among survivors of childhood leukemia have improved over time. One analysis performed by the Childhood Cancer Survivor Study (CCSS) evaluated late mortality among over 34,000 survivors of childhood cancer treated from 1970 through 1999 with a median follow-up of 21 years, including a cohort of 8500 patients who had survived at least five years after a diagnosis of childhood ALL/LBL [69]. In the group as a whole, later decades demonstrated a significant decline in mortality rates, reflecting fewer deaths due to recurrence and long-term toxicities. Early cohorts had a TRM of 18 percent in the following 25 years. Long-term survival has increased in more recent studies, with a long-term survival of 88 percent [70]. The cause of death was evenly split between progression (2.0 percent) and long-term toxicities (2.1 percent). Childhood ALL/LBL was one of four diagnoses for which temporal reductions in 15-year rates of death followed temporal reductions in therapeutic exposure. Subsequent neoplasms were the most common cause of TRM (1.4 percent at 15 years).
Down syndrome — Children with trisomy 21 are at increased risk for development of several hematopoietic disorders, including transient myeloproliferative disease during the newborn period, acute myeloid leukemia (most commonly AML, not otherwise specified, acute megakaryoblastic leukemia in the WHO classification; formerly described as FAB M7 subtype) as toddlers, and both myeloid and lymphoid leukemias in childhood (table 2). (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)" and "Down syndrome: Clinical features and diagnosis".)
B-precursor ALL/LBL is the most common type of leukemia among patients with Down syndrome (DS) [71]. Children with DS who develop ALL/LBL are usually <10 years of age and often respond to chemotherapy as well children without DS. However, children with DS are more likely to experience severe toxicity with standard chemotherapy regimens, particularly those requiring methotrexate, and often require reduced doses of chemotherapy. Because children with DS have a higher incidence of treatment-related toxicity, their survival rate is generally inferior to that of children without DS, with a five-year EFS of 65 percent [67,72,73]. In addition, prognostic factors in DS-ALL/LBL differ markedly from non-DS-ALL/LBL. Factors associated with a good prognosis in DS-ALL/LBL include age <6 years, low WBC count (<10,000), and low-risk genetic mutations including the ETV6-RUNX1 translocation, or high hyperdiploidy [74].
In an international study of patients enrolled on prospective trials, the outcomes of 653 children with DS were compared with those of 4445 children with ALL/LBL who did not have DS [74]. DS-associated ALL/LBL was associated with the following:
●Greater TRM (7.7 versus 2.3 percent)
●A higher cumulative incidence of relapse at eight years (26 versus 15 percent)
●Lower EFS at eight years (64 versus 81 percent)
●Inferior OS at eight years (74 versus 89 percent)
TRM occurred during all phases of treatment, and the most common cause of death was infection [74]. Of the patients with DS-associated ALL/LBL, 18 died during induction (13 infectious, five noninfectious) and 32 died of treatment-related causes in CR (25 infectious, seven noninfectious). In another study, severe infections experienced by DS patients with ALL/LBL were often not associated with findings characteristic for other children with ALL/LBL-associated infections (ie, not associated with fever, prior anthracycline therapy, or neutropenia) [68]. These findings emphasize the need for providing aggressive supportive care for patients with DS and ALL/LBL [75].
In addition, the frequency of genetic abnormalities seen in DS-associated ALL/LBL is different from that of ALL/LBL in children without DS [74,76,77]. Approximately 40 percent will have a normal karyotype. While ETV6::RUNX1 (30 percent) and trisomies (30 percent) are the most common genetic abnormalities seen in common B cell precursor ALL/LBL in children without DS, these mutations were much less frequent in patients with DS (3 percent ETV6-RUNX1; 8 percent trisomies 4 and 10) [77]. However, when present, ETV-RUNX1 and high hyperdiploidy were associated with improved clinical outcomes [74]. The most common genetic abnormality seen in DS-associated ALL/LBL is overexpression of CRLF2 (62 percent). Fifty percent of DS patients with CRLF2 over-expression are associated with JAK2 mutations [77,78]. Although JAK2 mutations and CRLF2 overexpression have clearly been associated with poor prognosis in patients with non-DS ALL/LBL [79], the prognostic significance of these molecular changes in DS-ALL/LBL remains unclear [78-81].
To date very few clinical trials have been conducted that have allowed enrollment of children with DS-ALL. This population is more susceptible to treatment-related toxicities and TRM. While new approaches for treatment of relapsed and very high-risk ALL are in development for non-DS-ALL, including blinatumomab, inotuzumab and CAR-T cells, studies are limited to case reports in DS-associated ALL/LBL [82]. An exception is a large cooperative group trial run by the Children's Oncology Group (COG) is treating DS patients with blinatumomab (AALL1731 NCT03914625). Further research is needed to improve outcomes for DS-ALL [83].
LATE EFFECTS — As long-term survival in ALL/LBL improves, more children experience late adverse effects, including central nervous system (CNS) impairment, decreased linear growth, cardiotoxicity, infertility, cataracts, and an increased incidence of secondary cancers [84], as well as an overall decreased health status due to such factors as neurocognitive dysfunction, endocrinopathies, depression, fatigue, and anxiety [85-88]. A recent UK study of 3466 cancer survivors showed that cancer survivors were five to seven times more likely to have cardiovascular disease by the age of 45 than non-cancer siblings, and were more likely to have healthcare visits related to infections, and disorders of the immune system [89].
The occurrence of specific complications depends on the patient's age and the type and intensity of therapy with which they were treated. As an example, neurocognitive decline is more likely to occur in children younger than six years of age who received CNS radiotherapy [90], whereas decreased fertility is more common among adolescents who received alkylating agents, such as cyclophosphamide [91].
Neurologic effects
CNS, mental health, and cognition — The effects of leukemia treatment on CNS development are variable [92,93]. Decline in cognitive function in children treated for ALL/LBL has historically been a common finding, particularly in those who received cranial radiation or triple intrathecal chemotherapy [90,94-98]. As an example, in one report, Finnish patients with ALL/LBL who received cranial radiation at an early age were compared with matched controls and had lower ninth-grade school reports in all school subjects [99]. Current therapy regimens have reduced or eliminated cranial radiation from the CNS preventive therapy for the majority of patients with ALL/LBL in an attempt to minimize the incidence and severity of cognitive impairment [100-102]. Initial reports suggest that these measures have decreased, but not eliminated, the incidence and severity of cognitive impairment [96,103-105].
●A meta-analysis of 10 studies compared neurological outcomes of 509 pediatric ALL/LBL survivors in continuous first CR after initial treatment with intrathecal and systemic chemotherapy alone (no radiation) compared to 555 healthy controls [104]. Most studies excluded children with documented premorbid learning disabilities or developmental conditions. ALL/LBL survivors had lower intelligence quotient (IQ) test scores, which corresponded to an approximately 6 to 8 point decrease in IQ. They also had moderate impairments in working memory, information processing speed, and fine motor functioning.
●Children younger than six years of age who received high-dose cranial radiotherapy (≥24 Gy) in combination with intrathecal chemotherapy are at the greatest risk for incurring subsequent CNS impairment. In one study of long-term toxicity in 150 ALL/LBL survivors, 35 of whom had received cranial radiotherapy, intellectual performance was evaluated with standardized neuropsychological tests (age-adapted versions of the Wechsler test) for a median follow-up time of 10 years [94]. Eighty-three percent had minimal or no impairment, 14 percent had moderate deficiencies, and 3 percent had severe cognitive dysfunction. Median IQ scores for the ALL/LBL survivors as a group were comparable to those found in the general population.
●In another study, 22 patients with ALL/LBL were treated with chemotherapy alone (including high-dose methotrexate) and 11 treated with radiation plus chemotherapy. Those treated with radiotherapy had significant cognitive effects when compared to normal controls [106]. Those treated with either chemotherapy alone or chemotherapy plus 12 Gy radiotherapy had decreased volumes in the hippocampus and caudate nucleus by MRI. ALL survivors also had decreased long-term memory, recall and processing speed.
●Mental health – A recent meta-analysis indicated that, although most leukemia survivors are well adjusted, survivors are at risk for anxiety and depression [107]. The rate of suicidal ideation and post-traumatic stress (PTSD) symptoms are low; however, adult cancer survivors are at increased risk for both compared to healthy control [107].
In a second single institution study of 2208 survivors and 10,457 controls, survivors of AYA cancer had an increased rate of mental health visits (relative risk [RR] 1.3; 95% CI 1.1-1.5) and an increase in risk for severe psychologic event (suicide, emergency department visit, admission) (HR = 2, 95% CI 1.3-2.4) [108,109].
There is also a small but statistically significant increase in the mental health care needs in both mothers and siblings of childhood cancer survivors (mothers RR 1.4, siblings RR 1.1). Risks for increased need of social services include young maternal age, low socioeconomic status, rural residence and older sibling at age of patient diagnosis.
Together, these studies support limiting or eliminating cranial irradiation and suggest that all patients with ALL/LBL should be monitored for the development of both early attention deficits, late cognitive deficits, and mental health symptoms. CNS preventative therapy is discussed in more detail separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'CNS management'.)
Stroke — Survivors of childhood leukemia are also at increased risk for late-occurring stroke. This was illustrated in a report from the Childhood Cancer Survivor Study (CCSS) that demonstrated an increased incidence of stroke in ≥5-year survivors of childhood leukemia compared with their siblings (RR 6.4, 95% CI 3-13.8) [110]. The risk of developing stroke in patients who received chemotherapy only or low-dose radiation (<30 Gy) did not differ from age-matched siblings. However, patients who received cranial radiation greater than 30 Gy compared with those who only received chemotherapy were more likely to have late-occurring stroke. Most current regimens give substantially less radiation (eg, 12 to 18 Gy) than those in this study.
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 [111]; these neurologic findings were more likely to occur in patients who relapsed or had received intracranial radiation. Subtle behavioral and educational sequelae may also be noted in survivors of childhood ALL/LBL [112,113].
Neurologic follow-up care — Neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI) and periodic neurocognitive testing are recommended for children who have cognitive deficits or known lesions by CT/MRI, such as leukoencephalopathy. Particularly at risk are long-term survivors who have a history of high-dose central nervous radiation therapy coupled with intrathecal chemotherapy [114]. We recommend neurocognitive testing before beginning school, but there are no standard guidelines for the frequency of subsequent evaluations. More frequent testing is recommended if neurocognitive abnormalities are progressive.
Endocrinopathies — Endocrine dysfunction, including thyroid disorders, obesity, diabetes mellitus, and gonadal dysfunction, are among the most common late effects of treatment for childhood ALL/LBL. The cumulative risk steadily increases over time, and is more common in those who received high-dose irradiation of the head, neck, or pelvis, or after exposure to high doses of alkylating agents. In a large study of 14,290 childhood cancer survivors, 46 percent of survivors of treatment for childhood leukemia exhibited endocrine dysfunction at a median follow-up of 25 years [85]. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)
Impaired growth — Many, but not all, children with ALL/LBL experience "catch-up" growth after completion of chemotherapy. However, some children have permanent short stature, the cause of which is not entirely clear [88,115].
This was best illustrated in a study from the CCSS that determined adult height for 2434 ALL/LBL survivors and 3009 of their siblings [115]. Height comparisons for ALL/LBL survivors and their siblings were based on the patients' treatment exposure, which included chemotherapy alone, chemotherapy and cranial radiation, or chemotherapy and craniospinal radiation. The following findings were noted:
●Compared with their siblings, all three ALL/LBL treatment exposure groups had decreased adult height and an increased risk of adult short stature (height standard deviation scores less than –2), (OR 12.5, 95% 8.1-19.2).
●Patients treated only with chemotherapy had a threefold increased risk of short stature compared with their siblings (OR 3.4, 95% CI 1.9-6). No specific chemotherapy agent was identified as increasing the risk of short stature.
●Identified risk factors for short stature included diagnosis of ALL/LBL before puberty, higher-dose cranial radiotherapy (≥20 Gy versus <20 Gy), any radiotherapy to the spine, and female sex.
Some patients with ALL/LBL may have low growth hormone (GH) levels possibly due to abnormal hypothalamic-pituitary function from cranial radiation [88,115,116]. In contrast, GH levels at the end of treatment do not appear to correlate with height in adulthood among children treated with regimens that omit cranial irradiation [117]. Other patients may have undiagnosed mild primary or central hypothyroidism.
In addition, children with ALL/LBL are at increased risk for developing osteoporosis, which can result in vertebral compression fractures and loss of height [88,118,119]. A more general discussion of growth failure and bone problems in childhood cancer patients 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 — Long-term survivors of childhood ALL/LBL may have an increased incidence of obesity and other cardiovascular risk factors [120-127]. This was illustrated in a meta-analysis of 47 studies that included data from 1742 survivors of childhood ALL/LBL [126]. The mean body mass index (BMI) z score was 0.83 (95% CI 0.60-1.06), which corresponds to the 80th BMI percentile and is higher than that seen in a healthy population (expected mean BMI z score between 0.4 and 0.6). This increased incidence in obesity was seen in all patient subgroups, regardless of gender, age at diagnosis, or history of cranial irradiation.
Other reports have suggested association with pretreatment characteristics or treatment variables. For example, in a meta-analysis [122] there was an age- and race-adjusted increased risk for being obese (BMI >30 kg/m2) in survivors treated with cranial radiation doses ≥20 Gy, a dose not used in most current pediatric treatment regimens.
Another study from the CCSS suggested that leptin receptor (LEPR) gene polymorphism, which is associated with leptin insensitivity, was more commonly found among female survivors of childhood ALL, particularly those who were treated with cranial irradiation [123]. In this analysis of 273 young adults from a single center, cranial radiation increased the risk of adiposity, insulin resistance, dyslipidemia, and higher leptin levels. In contrast, in a different multivariate analysis, increasing BMI was associated with higher level of corticosteroid exposure but not exposure to cranial radiotherapy [125]. Further research is needed to determine if cranial radiation at current doses will also lead to obesity and insulin resistance. (See 'Glucose metabolism' below.)
A prospective study from a single center of 456 children who were treated under a single protocol found that the prevalence of obesity in the 248 ALL/LBL survivors who attained adult height was comparable to that of the general population [128]. The following findings were noted:
●Risk factors for obesity in ALL/LBL survivors included a young age (younger than six years of age) and being overweight or obese at the time of diagnosis.
●There was no difference in the rate of obesity between patients treated with radiation and those who did not receive radiation. In addition, the dose of cranial radiation (18 versus 24 Gy) did not affect the rate of obesity.
Importantly, survivors who are obese compared to those who are not obese may have a greater risk of relapse. This was illustrated in a report that analyzed data from the Children's Cancer Group from 1995 to 1998 [129]. Patients who were obese compared to nonobese survivors had a lower five-year EFS rate (72 versus 77 percent) and a higher risk of relapse (26 versus 20 percent).
Glucose metabolism — Pancreatic beta cell function and glucose metabolism may be altered during the acute phase of ALL/LBL therapy by L-asparaginase, prednisone, or the leukemic process [130,131]. A retrospective study of 167 children with ALL/LBL reported that hyperglycemia during induction was associated with an increase in mortality and relapse [132]. Prospective studies are needed to confirm this observation, and if there is an association between hyperglycemia during induction and outcome, further investigations will be needed to see if treatment of hyperglycemia improves outcome.
In some patients, abnormal glucose metabolism may persist after completion of therapy [133]. Glucose metabolism was studied in 32 children with ALL/LBL who were off of therapy for at least one year [134]. Among these children, 22 (69 percent) had an impaired insulin response, nine had impaired glucose tolerance, and one had overt diabetes [121].
The incidence of insulin resistance is increased among survivors of allogeneic hematopoietic cell transplantation (HCT). In a retrospective analysis of 91 survivors of childhood ALL/LBL or non-Hodgkin lymphoma followed for a median of 15 years, the prevalence of insulin resistance was higher among those treated with HCT (88 versus 9 to 16 percent) [135]. Insulin resistance was associated with decreased lean body mass and increased central obesity.
Reproductive health — The reproductive capacity and sexual function of ALL/LBL survivors are affected by age at time of therapy and treatment regimen. Postpubescent males with ALL/LBL can have treatment-related declines in reproductive function, particularly if they were treated with high-dose alkylating agents [91]. The gonadal function and fertility of prepubescent ALL/LBL patients, however, are relatively unaffected by current treatment regimens [136].
Both males and females are more likely to have decreased fertility if treated with high-dose (≥24 Gy) cranial radiotherapy [137]. Women are more likely to have decreased fertility if they received cranial radiotherapy around the time of menarche [137]. Women are also at risk for premature ovarian insufficiency [85].
Congenital abnormalities are no more common among the offspring of ALL/LBL survivors than the general population [137,138].
Thyroid dysfunction — Survivors of childhood ALL/LBL are at increased risk of thyroid disorders, including underactive or overactive thyroid, thyroid nodules, and thyroid cancers [85]. The risk of thyroid disorders is greatest in those who underwent irradiation, but the risk is increased at least twofold even in those who did not undergo irradiation or high-dose alkylator therapy.
Cardiotoxicity — Treatment with anthracyclines (eg, daunorubicin, doxorubicin) may cause cardiovascular complications, including irreversible and fatal cardiomyopathy [139]. However, with the doses of anthracyclines used in current regimens (≤200 mg/m2 cumulative dose), cardiotoxicity is an infrequent occurrence. Strategies for preventing 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 single institution retrospective study, 2204 childhood leukemia survivors were matched with 11,020 age-matched controls [140]. Compared with controls, the rate of infections in leukemia survivors was elevated 1.8-fold at <1 year, 1.7-fold between 1 to 5 years, and 1.3-fold ≥5 years after completion of treatment. Since this study was based on registry data, it was not possible to correlate infectious events with risk factors such as presence of central venous lines or graft-versus-host disease. The study also covered several decades of treatment and infectious-related complications could be different in patients treated on contemporary protocols.
Second neoplasms — Approximately 2 to 3 percent of childhood ALL/LBL survivors develop a second malignancy [69,141-143]. The risk is greatest among patients who received cranial radiotherapy [136,144] or intensive therapy for relapse [145]. Brain tumors and hematologic malignancies, such as acute myeloid leukemia, are the most common secondary malignancies [141,144,146].
In a study of 856 patients with childhood ALL/LBL who had at least 10 years of EFS, 44 developed second malignancies, 41 of which were radiation related. The estimated rates for second malignancy 30 years after remission induction were 20.9 and 0.95 percent for those receiving or not receiving radiation therapy, respectively [62]. Virtually all of the tumors in the former group were located in the field of irradiation, and most were either benign or low-grade. The most common tumors in the radiated group were basal cell carcinomas (10), meningiomas (10), malignant brain tumors (5), and thyroid carcinoma (4). It is unclear that patients receiving current doses of prophylactic radiation (12 Gy) would have similar secondary neoplasm rates.
Brain tumors — In one review of almost 10,000 children treated for ALL/LBL, the risk of developing a primary brain tumor, particularly an astrocytoma, was increased by 22-fold [147]. This corresponds to a 10- to 20-year cumulative incidence of 1 to 2 percent. Brain tumors were seen only in children who had previously undergone cranial irradiation. Similar findings were noted in another, smaller series of children with ALL/LBL [148]. Children treated with cranial irradiation for ALL also may develop glioblastoma multiforme. In one series of 37 such children, three of these tumors were multifocal, an unusual finding [149].
The combination of prophylactic cranial irradiation and orally administered 6-mercaptopurine (6MP) has resulted in a much higher than expected incidence of brain tumors in survivors of ALL/LBL who have genetic defects in 6MP metabolism [148].
Adult survivors of childhood ALL/LBL who received cranial radiation are also at high-risk of developing subsequent meningiomas. In a case series of 49 cranially irradiated adult survivors, 11 (22 percent) developed meningiomas at a mean follow-up of 25 years (range 14 to 34 years) [150]. No other brain tumors were detected. Meningiomas occurred only in patients who received cranial irradiation doses ≥21 Gy. The incidence of meningioma was higher in patients (47 percent) treated by 1980 (>20-year follow-up) who received irradiation doses between 21 and 25 Gy. Although no meningioma had been detected in patients treated with lower radiation dose (18 Gy) after 1980, it remains unknown whether these patients will develop a meningioma over time as the latency period was shorter for these patients. These results suggest periodic brain imaging in cranially irradiated adult survivors of ALL/LBL, particularly if they are symptomatic.
Hematologic malignancies — Survivors of childhood ALL/LBL are at risk for the development of a secondary hematologic malignancy. One study evaluated the risk of developing acute myeloid leukemia (AML) during initial remission in 733 children with ALL/LBL who were treated with intensive chemotherapy [151]. At six years of follow-up, the cumulative risk of development of secondary AML was 5 percent (95% CI 2-10 percent). The risk was greater among patients with T cell ALL/LBL (cumulative risk at six years of follow-up: 19 percent, 95% CI 6-47 percent).
Long-term follow-up — ALL/LBL survivors should have comprehensive follow-up care with attention to nutritional assessments and education, growth monitoring, mental health and social functioning, and education to prevent high-risk behaviors. Since the risk of malignancy recurrence is highest during the period immediately following the completion of chemotherapy, an intensive follow-up schedule is recommended and is often specified as part of protocols.
The nature and schedule of screening for secondary malignancies is influenced by the treatment received. Care should ideally transition to either a clinic dedicated to childhood cancer long-term survivors, or to a physician (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) additional follow-up and imaging may be necessary.
Specific long-term follow-up guidelines after treatment of childhood cancer have been published by the Children's Oncology Group, and are available at www.survivorshipguidelines.org. Those undergoing hematopoietic stem cell transplant 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
●Outcomes – Treatment of childhood acute lymphoblastic leukemia/lymphoma (ALL/LBL) is associated with long-term overall survival and event-free survival that approach 90 percent in economically-advanced nations. (See 'Outcomes' above.)
•Prognostic factors – Outcomes are less favorable for infants and adolescent/young adults, and for children with hypodiploid karyotype, slow response to induction therapy, T cell ALL/LBL, and Philadelphia chromosome (Ph)-positive or Ph-like ALL/LBL. (See 'Outcomes' above.)
•Down syndrome (DS) – ALL/LBL in children with DS (trisomy 21) is associated with increased toxicity and treatment-related mortality. (See 'Down syndrome' above.)
●Late effects of treatment – Long-term complications are related to the type and intensity of treatment. Patients with high-risk ALL/LBL receive more aggressive chemotherapy and are at greater risk for acute and chronic adverse effects. (See 'Late effects' above.)
Late effects include:
•Neurologic – Impaired cognition, stroke, neurodevelopmental delay. (See 'Neurologic effects' above.)
•Endocrine – Growth retardation, obesity, abnormal glucose metabolism, reduced fertility, thyroid dysfunction. (See 'Endocrinopathies' above.)
•Cardiac – Cardiomyopathy – (See 'Cardiotoxicity' above.)
•Infections – (See 'Infections' above.)
•Second cancers – Cutaneous malignancies, brain tumors, hematologic malignancies, 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 review.
