Crisis management in the treatment of childhood acute lymphoblastic leukemia: putting right what can go wrong (emergency complications of disease and treatment)

Since the first description of pediatric acute lymphoblastic leukemia (ALL) in the 1920s, outcomes have improved^1,2  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 time^1,2 ; 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).

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.

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.

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 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 (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.

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.

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 

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 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 

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.

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 

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.