Abstract

The improvement in overall survival in children with acute lymphoblastic leukemia (ALL) over the last 5 decades has been considerable, with around 90% now surviving long term. The risk of relapse has been reduced to such an extent that the risk of treatment-related mortality is now approaching that of mortality caused by relapse. Toxicities may also lead to the suboptimal delivery of chemotherapy (treatment delays, dose reductions, dose omissions), potentially increasing relapse risk, and short- and long-term morbidity, adding to the “burden of therapy” in an increasing number of survivors. Thus, the need to reduce toxicity in pediatric ALL is becoming increasingly important. This work focuses on the risk factors, pathogenesis, clinical features, and emergency management of the life-threatening complications of ALL at presentation and during subsequent chemotherapy, including leucostasis, tumor lysis syndrome, infection, methotrexate encephalopathy, thrombosis, and pancreatitis. Potential strategies to abrogate these toxicities in the future are also discussed.

Learning Objectives
  • To understand the importance of reducing toxicity if additional improvements in high-quality, long-term survival in pediatric acute lymphoblastic leukemia are to be achieved

  • To gain a greater understanding of the risk factors, presentation, and immediate management of the life-threatening complications of pediatric ALL chemotherapy and to also learn how these toxicities could be reduced in the future

Introduction

Since the first description of pediatric acute lymphoblastic leukemia (ALL) in the 1920s, outcomes have improved1,2  from an invariably fatal disease to one with event-free survival rates of 73% to 87% at 5 years (Table 1). Contemporary protocols allocate stratified chemotherapy of different intensities according to risk factors present at diagnosis (including age, white count, involvement of the cerebrospinal fluid, and cytogenetics) and response to early therapy (determined by minimal residual disease assessment after induction and sometimes, also after consolidation). The risk of relapse has considerably reduced over time1,2 ; current relapse rates are 8% to 19% at 5 years, of which around 23% to 67% are salvageable, leading to overall long-term survival rates of around 90% at 5 years (Table 1).

Table 1.

Outcomes of contemporary pediatric protocols

TrialNo. of patientsYears of recruitmentAge, yOverall survival, %Event-free survival, %ToxicityRelapse risk, %
Induction death, %Death in remission, %Proportion of patients with at least 1 serious adverse event, %
UKALL200315  3126 October 2003 to June 2011 1-24 89 at 5 y 87 at 5 y 1.5 2.3 37.2 (30.6 ages 1-9 y) 8.8 at 5 y 
IC-BFM 200242  5060 November 2002 to November 2007 1-17 82 at 5 y 74 at 5 y 2.8 5.3 — 19 at 5 y 
NOPHO ALL20084  1162 July 2008 to April 2013 1-45 — 88 ages 1-9 y, 79 ages 10-17 y, 73 ages 18-45 y at 5 y 1.1 3.3 49.8 (44.5 ages 1-9 y) 8.2 at median 4 y 
St. Jude’s Total Therapy XV43  498 June 2000 to October 2007 1-18 93 at 10 y 86 at 10 y — 2.3 — 11.6 at 10 y 
DFCI 05-00144  551 April 2005 to February 2010 1-18 91 at 5 y 85 at 5 y 2.0 — — 8.9 
DCOG 945  859 January 1997 to November 2004 1-18 86 at 5 y 81 at 5 y 1.0 2.7 — 15.8 
COG2  21626 January 1990 to December 2005 0-22 90 at 5 y — — 1.6 — Death after relapse 7.22 at 5 y 
TrialNo. of patientsYears of recruitmentAge, yOverall survival, %Event-free survival, %ToxicityRelapse risk, %
Induction death, %Death in remission, %Proportion of patients with at least 1 serious adverse event, %
UKALL200315  3126 October 2003 to June 2011 1-24 89 at 5 y 87 at 5 y 1.5 2.3 37.2 (30.6 ages 1-9 y) 8.8 at 5 y 
IC-BFM 200242  5060 November 2002 to November 2007 1-17 82 at 5 y 74 at 5 y 2.8 5.3 — 19 at 5 y 
NOPHO ALL20084  1162 July 2008 to April 2013 1-45 — 88 ages 1-9 y, 79 ages 10-17 y, 73 ages 18-45 y at 5 y 1.1 3.3 49.8 (44.5 ages 1-9 y) 8.2 at median 4 y 
St. Jude’s Total Therapy XV43  498 June 2000 to October 2007 1-18 93 at 10 y 86 at 10 y — 2.3 — 11.6 at 10 y 
DFCI 05-00144  551 April 2005 to February 2010 1-18 91 at 5 y 85 at 5 y 2.0 — — 8.9 
DCOG 945  859 January 1997 to November 2004 1-18 86 at 5 y 81 at 5 y 1.0 2.7 — 15.8 
COG2  21626 January 1990 to December 2005 0-22 90 at 5 y — — 1.6 — Death after relapse 7.22 at 5 y 

COG, Children's Oncology Group; DCOG, Dutch Childhood Oncology Group; DFCI, Dana-Farber Cancer Institute; IC-BFM, International Berlin-Frankfurt-Münster Study Group; NOPHO, Nordic Society of Paediatric Haematolgy and Oncology.

As a result of these advances, the risk of treatment-related mortality is now approaching that of the mortality associated with relapse,3  with induction death rates of 1.0% to 2.8% and death in complete remission rates of 2.3% to 5.3% (Table 1). Specific toxicities may also lead to subsequent delays,4  omissions, or dose reductions of different agents, thereby potentially compromising the efficacy (relapse prevention) of treatment. In addition, toxicities are a source of immediate and sometimes, ongoing morbidity, adding to the “burden of therapy” in an increasing number of long-term survivors of ALL.3  For these reasons, reduction in the toxicity of pediatric ALL protocols is becoming an increasingly pressing issue. This work focuses on the immediate management of the life-threatening complications of acute leukemia or its treatment. Although addressing nonlife-threatening and late treatment–related complications, such as avascular necrosis, neurocognitive effects, and secondary malignancies, is equally important, these will not be discussed in detail here because of space constraints.

What goes wrong?

The risk of an individual patient experiencing a specific toxicity is determined by genetic and acquired risk factors (Table 2). There are a number of rare syndromes that predispose to both the development of ALL and also, overall treatment–related mortality or particular side effects when exposed to ALL therapy5 ; these include Down syndrome, Li Fraumeni syndrome, and ataxia telangiectasia (Tables 2 and 3). Specific polymorphisms and acquired risk factors may also predispose to individual toxicities.

Table 2.

Risk factors for toxicity

Etiology and risk factors
Inherent 
 Syndromes5  
  Down syndrome (increased risk of gastrointestinal toxicity and infections) 
  Li Fraumeni (increased risk of induction death, death in remission, and second malignancies) 
  Ataxia telangiectasia (increased risk of toxic death, cyclophosphamide-induced cystitis, and second malignancies) 
 Polymorphisms 
  GSTP1, MTHFR, SHMT1 (methotrexate encephalopathy)22  
  RGS6, UKL2, ASNS, CPA2 (pancreatitis)31,33  
  TPMT, NUDT15 (6-mercaptopurine toxicity)46,47  
Acquired 
 Age (discussed below) 
 Preexisting comorbidities 
 Obesity (particularly avascular necrosis) 
 Regimen intensity, including allogeneic transplant 
 Presence of central venous catheter (line-related infection, thrombosis) 
 Exposure to specific drugs 
Etiology and risk factors
Inherent 
 Syndromes5  
  Down syndrome (increased risk of gastrointestinal toxicity and infections) 
  Li Fraumeni (increased risk of induction death, death in remission, and second malignancies) 
  Ataxia telangiectasia (increased risk of toxic death, cyclophosphamide-induced cystitis, and second malignancies) 
 Polymorphisms 
  GSTP1, MTHFR, SHMT1 (methotrexate encephalopathy)22  
  RGS6, UKL2, ASNS, CPA2 (pancreatitis)31,33  
  TPMT, NUDT15 (6-mercaptopurine toxicity)46,47  
Acquired 
 Age (discussed below) 
 Preexisting comorbidities 
 Obesity (particularly avascular necrosis) 
 Regimen intensity, including allogeneic transplant 
 Presence of central venous catheter (line-related infection, thrombosis) 
 Exposure to specific drugs 
Table 3.

Specific toxicities

ToxicityEtiology/risk factorsManagement
At presentation   
 Fever Usually disease related and resolves on initiation of ALL therapy Infection screen 
May be caused by infection (impossible to distinguish from disease related and may be present as a result of neutropenia and immune dysregulation) Broad spectrum antibiotics until fever resolved and infection excluded 
Hypoxia in vital organs as a result of increased blood viscosity and microvasculature damage Maintain euvolemia 
 Leucostasis More likely in infants, males, high white count, T-cell disease, and KMT2A or BCR-ABL rearrangements Avoid red cell transfusions until white count reduced 
 Platelet transfusion to reduce risk of CNS bleeding 
 Early cytoreduction (steroids with or without vincristine) 
 Management of concomitant tumor lysis or sepsis 
 Leucopheresis no longer generally used 
 Beware: pseudohyperkalemia 
Sudden tumor cell death with release of intracellular cytokines Hyperhydration 
 TLS 
More likely in those with preexisting renal impairment or high tumor burden Correction of metabolic abnormalities 
 Management of seizures, arrhythmias, and renal insufficiency 
 Prevention: Allopurinol if white count <100 × 109/L, Raspuricase if white count >100 × 109/L (beware: check G6PD) 
  Nurse in semiupright position 
 Compression of superior vena cava and/or large airways Mediastinal mass composed of blasts, primarily seen in T-cell ALL Avoid imaging requiring the patient to lay flat, because this may result in cardiac arrest 
 Immediate administration of corticosteroids and early initiation of chemotherapy 
 Disseminated intravascular coagulation Rapid release of procoagulants resulting in uncontrolled systemic activation of coagulation pathways; this may cause (1) microvascular thrombosis and multiorgan dysfunction and (2) hemorrhage because of consumption of clotting factors and platelets Initiation of all chemotherapy 
 Replacement of coagulation factors (eg, fibrin concentrate, fresh frozen plasma) if there is bleeding and to cover procedures (eg, bone marrow biopsy, lumbar punctures) 
 Management of thrombosis is rarely required (eg, LMWH) 
During chemotherapy   
 Infection Down syndrome, age (infants and adolescents at higher risk than children ages 1-9 y), female sex, higher-intensity regimens, failure to achieve neutrophilia after dexamethasone pulses, and white race Early recognition of sepsis, rapid access to expert care, and early institution of antimicrobials 
 Intravenous immunoglobulin may be considered for those with hypogammaglobulinemia or recurrent infections 
Mechanism poorly understood? CNS folate homeostasis disruption Supportive care with control of seizures, correction of electrolytes, maintenance of airway 
 Methotrexate encephalopathy More common with children >10 y, more intensive regimes, concomitant administration of cyclophosphamide and cytarabine Exclude CNS thrombosis, hemorrhage, or infection 
 Folinica acid, aminophylline, or dextromethorphan may be effective in severe cases 
 Reexposure to methotrexate safe >80% but avoid concomitant administration with cyclophosphamide or cytarabine 
 LMWH 
 Caution around procedures 
 Thrombosis Prothrombotic state because of a combination of the leukemia itself, host factors, and exposure to asparaginase; other risk factors include increasing age, presence of a central venous catheter, concomitant administration of anthracycline and prednisolone, and inherited thrombophilic syndromes Reexposure to asparaginase is safe once thrombosis symptoms have resolved and the patient is fully anticoagulated 
 Insufficient evidence currently exists for thromboprophylaxis in newly diagnosed patients 
 Deferring insertion of a central venous catheter until the end of induction should be considered where possible 
Pathophysiology is unknown Fluid resuscitation, analgesia, and antibiotics for infected pancreatic necrosis ? Octreotide to reduce pancreatic inflammation 
 Pancreatitis Asparaginase is the primary etiology  
Higher cumulative dose or duration of asparaginase exposure, older age, concomitant steroid and anthracycline administration, severe hypertriglyceridemia, and genetic predisposition (RGS6, UKL2, ASNS, and CPA2 genes)  
Pathophysiology unknown Supportive care, including careful fluid balance (to prevent fluid overload but ensuring adequate intravascular volume to prevent renal injury), small volume ascetic taps, hemodialysis, intensive care unit support 
 Veno-occlusive disease (VOD) of the liver (sinusoidal obstruction syndrome) Risk factors include thiopurine exposure, thiopurine methyltransferase polymorphisms, hemopoietic stem cell transplantation Defibrotide 
Small hepatic vessel thrombi classically lead to acute VOD with painful hepatomegaly, ascites, hyperbilirubinemia, thrombocytopenia, multiorgan failure, and a high risk of mortality  
The use of thiopurines may result in chronic veno-occlusive disease, which presents with disproportionate thrombocytopenia and evidence of chronic portal hypertension  
Pathophysiology is unknown Supportive care with intravenous fluids, parenteral nutrition, gut rest, correction of electrolyte imbalance, analgesia, and broad spectrum antibiotics 
 Neutropenic enterocolitis (typhlitis) Transmural inflammation primarily of the cecum; the ascending and transverse colon may also be involved Omit chemotherapy and consider the use of granulocyte colony stimulating factor (GCSF) 
 The role of surgery is controversial and generally avoided unless typhlitis is complicated (eg, by perforation, bowel necrosis, uncontrolled bleeding, or abscess formation) 
ToxicityEtiology/risk factorsManagement
At presentation   
 Fever Usually disease related and resolves on initiation of ALL therapy Infection screen 
May be caused by infection (impossible to distinguish from disease related and may be present as a result of neutropenia and immune dysregulation) Broad spectrum antibiotics until fever resolved and infection excluded 
Hypoxia in vital organs as a result of increased blood viscosity and microvasculature damage Maintain euvolemia 
 Leucostasis More likely in infants, males, high white count, T-cell disease, and KMT2A or BCR-ABL rearrangements Avoid red cell transfusions until white count reduced 
 Platelet transfusion to reduce risk of CNS bleeding 
 Early cytoreduction (steroids with or without vincristine) 
 Management of concomitant tumor lysis or sepsis 
 Leucopheresis no longer generally used 
 Beware: pseudohyperkalemia 
Sudden tumor cell death with release of intracellular cytokines Hyperhydration 
 TLS 
More likely in those with preexisting renal impairment or high tumor burden Correction of metabolic abnormalities 
 Management of seizures, arrhythmias, and renal insufficiency 
 Prevention: Allopurinol if white count <100 × 109/L, Raspuricase if white count >100 × 109/L (beware: check G6PD) 
  Nurse in semiupright position 
 Compression of superior vena cava and/or large airways Mediastinal mass composed of blasts, primarily seen in T-cell ALL Avoid imaging requiring the patient to lay flat, because this may result in cardiac arrest 
 Immediate administration of corticosteroids and early initiation of chemotherapy 
 Disseminated intravascular coagulation Rapid release of procoagulants resulting in uncontrolled systemic activation of coagulation pathways; this may cause (1) microvascular thrombosis and multiorgan dysfunction and (2) hemorrhage because of consumption of clotting factors and platelets Initiation of all chemotherapy 
 Replacement of coagulation factors (eg, fibrin concentrate, fresh frozen plasma) if there is bleeding and to cover procedures (eg, bone marrow biopsy, lumbar punctures) 
 Management of thrombosis is rarely required (eg, LMWH) 
During chemotherapy   
 Infection Down syndrome, age (infants and adolescents at higher risk than children ages 1-9 y), female sex, higher-intensity regimens, failure to achieve neutrophilia after dexamethasone pulses, and white race Early recognition of sepsis, rapid access to expert care, and early institution of antimicrobials 
 Intravenous immunoglobulin may be considered for those with hypogammaglobulinemia or recurrent infections 
Mechanism poorly understood? CNS folate homeostasis disruption Supportive care with control of seizures, correction of electrolytes, maintenance of airway 
 Methotrexate encephalopathy More common with children >10 y, more intensive regimes, concomitant administration of cyclophosphamide and cytarabine Exclude CNS thrombosis, hemorrhage, or infection 
 Folinica acid, aminophylline, or dextromethorphan may be effective in severe cases 
 Reexposure to methotrexate safe >80% but avoid concomitant administration with cyclophosphamide or cytarabine 
 LMWH 
 Caution around procedures 
 Thrombosis Prothrombotic state because of a combination of the leukemia itself, host factors, and exposure to asparaginase; other risk factors include increasing age, presence of a central venous catheter, concomitant administration of anthracycline and prednisolone, and inherited thrombophilic syndromes Reexposure to asparaginase is safe once thrombosis symptoms have resolved and the patient is fully anticoagulated 
 Insufficient evidence currently exists for thromboprophylaxis in newly diagnosed patients 
 Deferring insertion of a central venous catheter until the end of induction should be considered where possible 
Pathophysiology is unknown Fluid resuscitation, analgesia, and antibiotics for infected pancreatic necrosis ? Octreotide to reduce pancreatic inflammation 
 Pancreatitis Asparaginase is the primary etiology  
Higher cumulative dose or duration of asparaginase exposure, older age, concomitant steroid and anthracycline administration, severe hypertriglyceridemia, and genetic predisposition (RGS6, UKL2, ASNS, and CPA2 genes)  
Pathophysiology unknown Supportive care, including careful fluid balance (to prevent fluid overload but ensuring adequate intravascular volume to prevent renal injury), small volume ascetic taps, hemodialysis, intensive care unit support 
 Veno-occlusive disease (VOD) of the liver (sinusoidal obstruction syndrome) Risk factors include thiopurine exposure, thiopurine methyltransferase polymorphisms, hemopoietic stem cell transplantation Defibrotide 
Small hepatic vessel thrombi classically lead to acute VOD with painful hepatomegaly, ascites, hyperbilirubinemia, thrombocytopenia, multiorgan failure, and a high risk of mortality  
The use of thiopurines may result in chronic veno-occlusive disease, which presents with disproportionate thrombocytopenia and evidence of chronic portal hypertension  
Pathophysiology is unknown Supportive care with intravenous fluids, parenteral nutrition, gut rest, correction of electrolyte imbalance, analgesia, and broad spectrum antibiotics 
 Neutropenic enterocolitis (typhlitis) Transmural inflammation primarily of the cecum; the ascending and transverse colon may also be involved Omit chemotherapy and consider the use of granulocyte colony stimulating factor (GCSF) 
 The role of surgery is controversial and generally avoided unless typhlitis is complicated (eg, by perforation, bowel necrosis, uncontrolled bleeding, or abscess formation) 

The overall risk of a child developing at least one serious adverse event during first-line ALL therapy is around 30% to 50% (Table 1), but varies with age. The etiology and management of life-threatening complications of ALL and its treatment are summarized in Table 3. Determining the exact frequency of different toxicities and comparing these across the different study group protocols are very challenging, because each uses different definition criteria, data capture procedures, and reporting strategies.6 

Leucostasis

Leucostasis arises in patients with a high circulating white cell count caused by increase blood viscosity and reduced deformability of blast cells, which causes ischemic injury to vital organs, primarily the central nervous system (CNS), lungs, and kidneys,7  and is often compounded by hyperuricemia caused by tumor lysis. The clinical features range from mild visual disturbance, headache, cough, or dyspnea to coma, acute respiratory distress syndrome, or renal failure. The incidence of hyperleucocytosis is around 5% to 10% of newly diagnosed children with ALL,8  with leucostasis being more likely in those with a high white count (>200 × 109/L), males, those with a T-cell immunophenotype, infants, and those with KMT2A or BCR-ABL rearrangements.8,9  The risk of leucostasis is lower in ALL compared with acute myeloid leukemia.

Historically, leucostasis was associated with a high mortality of up to 20%. More recently, the outcome has markedly improved with hydration, judicious blood product support (avoidance of red cell transfusions until the white count is below 100 × 109/L and platelet transfusions to reduce the risk of CNS bleeding), early institution of cytoreduction with steroids with or without low-dose chemotherapy (vincristine), and aggressive treatment of coexistent sepsis or tumor lysis. Leucopheresis has been previously used to reduce the circulating white count quickly. However, it may increase the risk of hypocalcemia, catheter-related thrombosis or malfunction, and coagulopathy without reducing the frequency or severity of the complications of leucostasis; leucopheresis is, therefore, not generally used in children with ALL.8 

Tumor lysis syndrome

Tumor lysis syndrome (TLS) occurs when there is simultaneous destruction of a large number of rapidly dividing tumor cells, which causes the sudden release of intracellular metabolites. This results in an acute metabolic disturbance, which may include hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, or uremia. These abnormalities can develop spontaneously and be present at diagnosis or may develop within 12 to 72 hours after initiation of chemotherapy. Tumor lysis may be asymptomatic but can cause seizures, cardiac arrhythmias, acute renal failure, and death. Patients with preexisting renal impairment or a high tumor burden (white cell count >100 × 109/L, large mediastinal mass, high urate, and high lactate dehydrogenase) are at greatest risk. All patients with ALL should be considered to be at risk of TLS irrespective of white cell count and should receive prophylactic Allopurinol (a xanthine oxidase inhibitor) and hyperhydration before and for a few days after starting treatment. Patients with a white count above 100 × 109/L should receive prophylactic Rasburicase (recombinant urate oxidase) on initiation of therapy (after excluding glucose 6 phosphate dehydrogenase (G6PD) deficiency, because these patients can develop methemoglobinemia and hemolysis). The prophylactic use of Rasburicase in those with a white count <100 × 109/L but with a high lactate dehydrogenase10  is more controversial, and it may be reasonable to reserve this for situations in which TLS develops, despite prophylactic Allopurinol and hyperhydration.11  Immediate supportive care of TLS, including hyperhydration, correction of electrolyte abnormalities, antiepileptics and renal support if necessary, is essential.

Infection

Infections are the most frequent complications of ALL chemotherapy and constitute the greatest cause of treatment-related mortality. Medical Research Council (MRC) Working Party on Leukaemia in Children UK National Acute Lymphoblastic Leukaemia (ALL) Trial, UKALL2003, the 5-year cumulative incidence of infection-related mortality was 2.4% and accounted for 30% of all deaths and 64% of treatment-related deaths.12  Bacterial and fungal infections are most frequently seen during the intensive phases of treatment when neutropenia is more likely, whereas viral infections are seen throughout the treatment course, often increasing toward the end of therapy.12,13  The risk of opportunistic infection with Pneumocystis jiroveci is greatest between days 50 and 120 after diagnosis but may occur throughout therapy.14 

In UKALL2003, 68% of infection-related deaths were caused by bacterial infection (64% gram negative), and 20% were caused by fungal infection. Viral infections, sufficiently severe to be reported as “serious adverse events,” were seen in 5% of patients and resulted in 12% of infection-related deaths.12,15  The risk factors for infections and infection-related mortality include Down syndrome, age (infants and adolescents are at higher risk than patients ages 1-9 years old), higher-intensity regimens, and failure to achieve neutrophilia after dexamethasone pulses.12,13,15  The risk of treatment-related mortality, primarily caused by sepsis, may be around sevenfold higher in children with Down syndrome compared with non–Down syndrome children (21.6% at 5 years vs 3.3%, P < .00005),16  with the greatest risk being immediately after glucocorticoid therapy.17 

Management of infections requires prompt recognition and early institution of antimicrobial therapy determined by local bacterial prevalence and resistance patterns. There are no consensus recommendations on antimicrobial prophylaxis or replacement immunoglobulin infusions in children receiving chemotherapy for ALL other than routine prophylaxis for Pneumocystis Jiroveci. Trimethoprim-sulfamethoxazole is now universally recommended, albeit with different schedules, and it is highly effective at preventing this life-threatening opportunistic infection.18 

The use of Fluoroquinolone prophylaxis in children receiving chemotherapy for ALL is highly controversial. Although it may reduce the risk of bacterial infections19  and is recommended in some adult ALL guidelines,20  this potential benefit must be weighed against the risk of development of antibiotic-resistant organisms and Clostridium difficile infections. Additional efficacy and safety data are required before antibiotic prophylaxis can be routinely recommended in children receiving chemotherapy for ALL. Similarly, the use of azoles in preventing fungal infections is complicated by the potential for interaction with vincristine. Until randomized, prospective evaluations of antimicrobial prophylaxis answer these questions definitively, clinicians must rely on a high index of suspicion of infection (even in afebrile patients during dexamethasone blocks and those in lower-intensity phases of treatment, such as maintenance chemotherapy), with rapid access to the hospital and prompt administration of antimicrobials. Patients with Down syndrome should be monitored especially closely and may be the best candidates for antimicrobial prophylaxis and replacement immunoglobulin.

Methotrexate neurotoxicity

The use of intrathecal methotrexate has provided effective CNS-directed therapy, such that craniospinal irradiation with its associated long-term complications is generally no longer required.21  Asymptomatic leucoencephalopathy is demonstrable in around 20% of children undergoing contemporary chemotherapy for ALL.22  However, the incidence of symptomatic methotrexate leucoencephalopathy is around 4% to 8% and more likely in those over the age of 10 years old, those receiving higher-intensity regimens, and during treatment blocks where there is concomitant administration of cytarabine and cyclophosphamide (eg, delayed intensification).15,22,23 

Methotrexate neurotoxicity typically occurs around 2 to 14 days after exposure to oral, intrathecal, or high-dose intravenous methotrexate. Clinical features include headache, seizures, change in affect, speech disturbance, cerebellar syndrome, stroke-like syndrome, altered conscious level, and rarely, death. The classical waxing and waning nature of the neurological signs helps to distinguish it from other differential diagnoses, including thrombosis, hemorrhage, and infection. The immediate management is to exclude these alternative diagnoses (magnetic resonance imaging/venogram classically shows increased white matter signal on T2 weighted images with or without electroencephalogram), control seizures, correct electrolyte imbalances, and protect the airway, depending of the conscious level. Generally, the neurological abnormalities will fully resolve within hours or a few days (usually up to 9 days) spontaneously. In severely affected individuals, folinic acid, aminophylline, and dextromethorphan may be considered; small case series suggest potential benefit of these agents,24,25  although definitive data are lacking.

In general, >80% of patients may be safely re-exposed to methotrexate without additional toxicity, although a small number of patients may have recurrent or long-term significant neurological deficits.22,23  In these rare patients, the balance between additional exposure to methotrexate and potential exacerbation of neurological injury needs to be carefully weighed against replacement of methotrexate with intrathecal hydrocortisone and cytarabine and a potential higher risk of CNS relapse.

The mechanism of methotrexate encephalopathy remains poorly understood but may be caused by disruption of the folate homeostatic mechanisms in the CNS with or without direct neuronal injury.22  Genome-wide single-nucleotide polymorphism studies are beginning to find interesting polymorphisms in genes enriched for neuronal development pathways, which may also be linked to migraine, autism, attention deficit disorder, and Alzheimer disease.22 

Thrombosis

Symptomatic thrombosis during treatment of ALL is a significant complication, with an incidence of around 4% to 6%; 54% of these events occur in the CNS, and 28% are related to central venous catheters.26  The pathogenesis of thrombosis is poorly understood and likely contributed to by the leukemia itself, host factors, and chemotherapy (in particular, asparaginase exposure). Asparaginase causes reduced synthesis of many proteins involved in the coagulation and fibrinolytic pathways, and thrombotic events in children with ALL primarily occur during the asparaginase-containing intensive blocks of therapy (particularly induction), with events being more likely the longer the duration of asparaginase exposure.26  Other risk factors include increasing age, presence of a central venous catheter, concomitant administration of anthracycline and prednisolone, and inherited thrombophilic syndromes.26  The management of thrombosis is complicated by the presence of coexisting hemorrhage (in CNS thrombosis), the need for frequent procedures (lumbar punctures and bone marrow aspirates), and intermittent thrombocytopenia caused by chemotherapy. Low–molecular weight heparin (LMWH) is the most commonly used anticoagulant, and it is omitted around the time of procedures, is dose-reduced or omitted during periods of thrombocytopenia, and may be delayed if there is CNS hemorrhage secondary to thrombosis. Asparaginase can usually be safely administered after the clinical symptoms have resolved and the patient is fully anticoagulated.27,28  LMWH is generally continued until at least 3 weeks after the last dose of pegylated asparaginase is given and for a variable period thereafter determined by the site of thrombosis. There are no data to suggest that prophylaxis with low-dose warfarin, LMWH, or antithrombin replacement is effective in preventing thrombosis in this context. However, prospective randomized clinical trials of thromboprophylaxis (for example, using intermediate-dose LMWH, LMWH with antithrombin replacement, or nonvitamin K antagonist oral anticoagulants) are much needed.

Pancreatitis

Pancreatitis is a severe complication of asparaginase therapy, occurring in 1.5% to 10% children receiving ALL chemotherapy.29  Presenting features include abdominal pain, nausea and vomiting, fever and back pain arising between 6 and 14 days after asparaginase administration; this ranges in severity from a mild self-limiting illness to a fulminant form, with systemic inflammatory response syndrome, failure of pancreatic function, and multiorgan failure, with around one-third of patients requiring admission to the intensive care unit. The diagnosis is confirmed using raised biochemical markers (pancreatic amylase and lipase) and imaging (ultrasound, computerized tomography, or magnetic resonance imaging scans). Immediate management includes fluid resuscitation, analgesia, and antibiotics for infected pancreatic necrosis. Octreotide may be useful in decreasing pancreatic inflammation, although experience in children is limited.30  Long-term complications can arise, particularly after severe pancreatitis, including pseudocyst formation in 25% to 28% of patients, recurrent abdominal pain in 7%, and exogenous insulin dependency in 8%.31,32  Risk factors for the development of pancreatitis include a higher cumulative dose or duration of asparaginase exposure, older age, concomitant steroid and anthracycline administration, severe hypertriglyceridemia, and genetic predisposition (RGS6, UKL2, ASNS, and CPA2 genes).29-34  Re-exposure to asparaginase may be possible in children who have, within 48 hours from the onset of symptoms, resolution of their symptoms, amylase and lipase levels below 3 times the upper limit of normal, and no pancreatic pseudocysts or necrosis on ultrasound.30,32  However, for the majority of patients, additional exposure to asparaginase is contraindicated; it is unclear whether this impacts on subsequent relapse risk.32,35 

Impact of age on toxicity

Since the mid-2000s, the upper age limit of many pediatric ALL studies has increased in response to the observation that adolescents and young adults have a 10% to 15% superior event-free survival when treated on pediatric rather than adult ALL protocols.36-40  The treatment of children, adolescents, and young adults on the same protocol in prospective trial settings has facilitated detailed study of the impact of age on the frequency of different toxicities.4,15  In patients treated on the UKALL2003,15  the risks of death in remission, treatment delays, infections, thrombosis, and psychosis increased with increasing age; age had no impact on some complications, including vincristine-related neuropathy, line-related thrombosis, and line-related sepsis, implying that other risk factors (genetic polymorphisms or presence of central venous catheter, respectively) are more dominant risk factors for these toxicities. Interestingly, avascular necrosis was primarily restricted to patients ages between 10 and 20 years old, suggesting the importance of an interplay between steroid and asparaginase exposure and host factors present in the peripubertal patient (such as rapid bone growth and changes in sex hormones). A final group of toxicities appeared to be more common in patients ages 10 years old or older compared with younger patients, with no increasing risk in the young adults compared with adolescents. These include pancreatitis, mucositis, methotrexate encephalopathy, and hyperglycemia and were not solely accounted for by differences in treatment regimen.

What next?

The improvement in overall survival in pediatric ALL is a great success story. The reduction in relapses is now exposing the high morbidity and mortality associated with current chemotherapy regimens. Successive trials have facilitated a reduction in the use of hemopoietic stem cell transplantation, largely obviated the need for cranial radiotherapy, and enabled the safe de-escalation of some regimens for patients with low-risk disease.

As we become more sophisticated in our ability to define those at low, intermediate, and high risks of relapse41  and novel agents (such as inotuzumab, blinatumomab, and chimeric antigen receptor T cells [CAR]) with different mechanisms of action become available, we are presented with new opportunities to reduce toxicity. Additional de-escalation of conventional chemotherapy for low-risk patients with an expected event-free survival in excess of 95% should be possible, because these patients are likely overtreated at present. For those with extremely poor–risk disease, intensive chemotherapy with allogeneic transplant or use of CAR T cells in first-line therapy seems to be justified. Intermediate-risk patients may benefit from the incorporation of newer agents alongside conventional chemotherapy, with the potential for increased efficacy without undue toxicity, given the different mechanisms of action and different toxicity profiles of these agents.

It is also clear that gaining additional understanding of the pathogenesis and risk factors for specific rare toxicities in a rare disease, such as pediatric ALL, will necessitate international collaboration to agree on definition sets for the most important toxicities, explore the pharmacogenetic basis for complications, and ask randomized supportive care questions with the aim of reducing both short- and long-term toxicities.6 

Correspondence

Rachael Hough, Department of Haematology, University College London Hospital’s National Health Service Foundation Trust, 250 Euston Rd, London NW1 2PG, United Kingdom; e-mail: rachael.hough@uclh.nhs.uk.

References

References
1.
Pui
CH
,
Pei
D
,
Campana
D
, et al
.
A revised definition for cure of childhood acute lymphoblastic leukemia
.
Leukemia
.
2014
;
28
(
12
):
2336
-
2343
.
2.
Hunger
SP
,
Lu
X
,
Devidas
M
, et al
.
Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group
.
J Clin Oncol
.
2012
;
30
(
14
):
1663
-
1669
.
3.
Essig
S
,
Li
Q
,
Chen
Y
, et al
.
Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort
.
Lancet Oncol
.
2014
;
15
(
8
):
841
-
851
.
4.
Toft
N
,
Birgens
H
,
Abrahamsson
J
, et al
.
Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia
.
Eur J Haematol
.
2016
;
96
(
2
):
160
-
169
.
5.
Schmiegelow
K
.
Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes
.
Eur J Med Genet
.
2016
;
59
(
12
):
654
-
660
.
6.
Schmiegelow
K
,
Attarbaschi
A
,
Barzilai
S
, et al
;
Ponte di Legno toxicity working group
.
Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus
.
Lancet Oncol
.
2016
;
17
(
6
):
e231
-
e239
.
7.
Lam
WA
,
Rosenbluth
MJ
,
Fletcher
DA
.
Increased leukaemia cell stiffness is associated with symptoms of leucostasis in paediatric acute lymphoblastic leukaemia
.
Br J Haematol
.
2008
;
142
(
3
):
497
-
501
.
8.
Nguyen
R
,
Jeha
S
,
Zhou
Y
, et al
.
The role of leukapheresis in the current management of hyperleukocytosis in newly diagnosed childhood acute lymphoblastic leukemia
.
Pediatr Blood Cancer
.
2016
;
63
(
9
):
1546
-
1551
.
9.
Kong
SG
,
Seo
JH
,
Jun
SE
,
Lee
BK
,
Lim
YT
.
Childhood acute lymphoblastic leukemia with hyperleukocytosis at presentation
.
Blood Res
.
2014
;
49
(
1
):
29
-
35
.
10.
Cairo
MS
,
Coiffier
B
,
Reiter
A
,
Younes
A
;
TLS Expert Panel
.
Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus
.
Br J Haematol
.
2010
;
149
(
4
):
578
-
586
.
11.
Agrawal
AK
,
Feusner
JH
.
Management of tumour lysis syndrome in children: what is the evidence for prophylactic rasburicase in non-hyperleucocytic leukaemia?
Br J Haematol
.
2011
;
153
(
2
):
275
-
277
.
12.
O’Connor
D
,
Bate
J
,
Wade
R
, et al
.
Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003
.
Blood
.
2014
;
124
(
7
):
1056
-
1061
.
13.
Inaba
H
,
Pei
D
,
Wolf
J
, et al
.
Infection-related complications during treatment for childhood acute lymphoblastic leukemia
.
Ann Oncol
.
2017
;
28
(
2
):
386
-
392
.
14.
Siegel
SE
,
Nesbit
ME
,
Baehner
R
,
Sather
H
,
Hammond
GD
.
Pneumonia during therapy for childhood acute lymphoblastic leukemia
.
Am J Dis Child
.
1980
;
134
(
1
):
28
-
34
.
15.
Hough
R
,
Rowntree
C
,
Goulden
N
, et al
.
Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: results from UKALL 2003
.
Br J Haematol
.
2016
;
172
(
3
):
439
-
451
.
16.
Patrick
K
,
Wade
R
,
Goulden
N
, et al
.
Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol
.
Br J Haematol
.
2014
;
165
(
4
):
552
-
555
.
17.
Ceppi
F
,
Stephens
D
,
den Hollander
BS
, et al
.
Clinical presentation and risk factors of serious infections in children with Down syndrome treated for acute lymphoblastic leukemia
.
Pediatr Blood Cancer
.
2016
;
63
(
11
):
1949
-
1953
.
18.
Agrawal
AK
,
Chang
PP
,
Feusner
J
.
Twice weekly Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole in pediatric patients with acute lymphoblastic leukemia
.
J Pediatr Hematol Oncol
.
2011
;
33
(
1
):
e1
-
e4
.
19.
Yeh
TC
,
Liu
HC
,
Hou
JY
, et al
.
Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis
.
Cancer
.
2014
;
120
(
8
):
1255
-
1262
.
20.
Baden
LR
,
Bensinger
W
,
Angarone
M
, et al
;
National Comprehensive Cancer Network
.
Prevention and treatment of cancer-related infections
.
J Natl Compr Canc Netw
.
2012
;
10
(
11
):
1412
-
1445
.
21.
Richards
S
,
Pui
CH
,
Gayon
P
;
Childhood Acute Lymphoblastic Leukemia Collaborative Group (CALLCG)
.
Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia [published correction appears in Pediatr Blood Cancer. 2013;60(10):1729]
.
Pediatr Blood Cancer
.
2013
;
60
(
2
):
185
-
195
.
22.
Bhojwani
D
,
Sabin
ND
,
Pei
D
, et al
.
Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia
.
J Clin Oncol
.
2014
;
32
(
9
):
949
-
959
.
23.
Bond
J
,
Hough
R
,
Moppett
J
,
Vora
A
,
Mitchell
C
,
Goulden
N
.
‘Stroke-like syndrome’ caused by intrathecal methotrexate in patients treated during the UKALL 2003 trial
.
Leukemia
.
2013
;
27
(
4
):
954
-
956
.
24.
Bernini
JC
,
Fort
DW
,
Griener
JC
,
Kane
BJ
,
Chappell
WB
,
Kamen
BA
.
Aminophylline for methotrexate-induced neurotoxicity
.
Lancet
.
1995
;
345
(
8949
):
544
-
547
.
25.
Drachtman
RA
,
Cole
PD
,
Golden
CB
, et al
.
Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity
.
Pediatr Hematol Oncol
.
2002
;
19
(
5
):
319
-
327
.
26.
Caruso
V
,
Iacoviello
L
,
Di Castelnuovo
A
, et al
.
Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients
.
Blood
.
2006
;
108
(
7
):
2216
-
2222
.
27.
Qureshi
A
,
Mitchell
C
,
Richards
S
,
Vora
A
,
Goulden
N
.
Asparaginase-related venous thrombosis in UKALL 2003- re-exposure to asparaginase is feasible and safe
.
Br J Haematol
.
2010
;
149
(
3
):
410
-
413
.
28.
Grace
RF
,
Dahlberg
SE
,
Neuberg
D
, et al
.
The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols
.
Br J Haematol
.
2011
;
152
(
4
):
452
-
459
.
29.
Oparaji
JA
,
Rose
F
,
Okafor
D
, et al
.
Risk factors for asparaginase-associated pancreatitis: a systematic review [published online ahead of print 3 April 2017]
.
J Clin Gastroenterol
.
30.
Raja
RA
,
Schmiegelow
K
,
Frandsen
TL
.
Asparaginase-associated pancreatitis in children
.
Br J Haematol
.
2012
;
159
(
1
):
18
-
27
.
31.
Wolthers
BO
,
Frandsen
TL
,
Abrahamsson
J
, et al
.
Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol
.
Leukemia
.
2017
;
31
(
2
):
325
-
332
.
32.
Samarasinghe
S
,
Dhir
S
,
Slack
J
, et al
.
Incidence and outcome of pancreatitis in children and young adults with acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003
.
Br J Haematol
.
2013
;
162
(
5
):
710
-
713
.
33.
Liu
C
,
Yang
W
,
Devidas
M
, et al
.
Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia
.
J Clin Oncol
.
2016
;
34
(
18
):
2133
-
2140
.
34.
Ben Tanfous
M
,
Sharif-Askari
B
,
Ceppi
F
, et al
.
Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia
.
Clin Cancer Res
.
2015
;
21
(
2
):
329
-
334
.
35.
Silverman
LB
,
Gelber
RD
,
Dalton
VK
, et al
.
Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01
.
Blood
.
2001
;
97
(
5
):
1211
-
1218
.
36.
Ramanujachar
R
,
Richards
S
,
Hann
I
, et al
.
Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials
.
Pediatr Blood Cancer
.
2007
;
48
(
3
):
254
-
261
.
37.
Hallböök
H
,
Gustafsson
G
,
Smedmyr
B
,
Söderhäll
S
,
Heyman
M
;
Swedish Adult Acute Lymphocytic Leukemia Group
;
Swedish Childhood Leukemia Group
.
Treatment outcome in young adults and children >10 years of age with acute lymphoblastic leukemia in Sweden: a comparison between a pediatric protocol and an adult protocol
.
Cancer
.
2006
;
107
(
7
):
1551
-
1561
.
38.
Boissel
N
,
Auclerc
MF
,
Lhéritier
V
, et al
.
Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials
.
J Clin Oncol
.
2003
;
21
(
5
):
774
-
780
.
39.
de Bont
JM
,
Holt
B
,
Dekker
AW
,
van der Does-van den Berg
A
,
Sonneveld
P
,
Pieters
R
.
Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands
.
Leukemia
.
2004
;
18
(
12
):
2032
-
2035
.
40.
Stock
W
,
La
M
,
Sanford
B
, et al
;
Children’s Cancer Group
;
Cancer and Leukemia Group B studies
.
What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies
.
Blood
.
2008
;
112
(
5
):
1646
-
1654
.
41.
O’Connor
D
,
Moorman
AV
,
Wade
R
, et al
.
Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia
.
J Clin Oncol
.
2017
;
35
(
6
):
660
-
667
.
42.
Stary
J
,
Zimmermann
M
,
Campbell
M
, et al
.
Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002
.
J Clin Oncol
.
2014
;
32
(
3
):
174
-
184
.
43.
Pui
CH
,
Pei
D
,
Raimondi
SC
, et al
.
Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy
.
Leukemia
.
2017
;
31
(
2
):
333
-
339
.
44.
Place
AE
,
Stevenson
KE
,
Vrooman
LM
, et al
.
Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial
.
Lancet Oncol
.
2015
;
16
(
16
):
1677
-
1690
.
45.
Veerman
AJ
,
Kamps
WA
,
van den Berg
H
, et al
;
Dutch Childhood Oncology Group
.
Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004)
.
Lancet Oncol
.
2009
;
10
(
10
):
957
-
966
.
46.
Kim
MG
,
Ko
M
,
Kim
IW
,
Oh
JM
.
Meta-analysis of the impact of thioprine S-methyltransferase polymorphisms on the tolerable 6-mercaptopurine dose considering initial dose and ethnic difference
.
Onco Targets Ther
.
2016
;
9
:
7133
-
7139
.
47.
Moriyama
T
,
Yang
YL
,
Nishii
R
, et al
.
Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry
.
Blood
.
2017
;
130
(
10
):
1209
-
1212
.

Competing Interests

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Author notes

Off-label drug use: None disclosed.