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Version 1. F1000Res. 2017; 6: 444.
Published online 2017 April 7. doi:  10.12688/f1000research.10768.1
PMCID: PMC5389408

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

Abstract

During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.

Keywords: acute lymphoblastic leukaemia, ALL, chemotherapy, side effects, toxicities

Introduction

The best contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) now yields 5-year overall survival (OS) rates above 90%, which reflects intensified chemotherapy with treatment stratification directed by the somatic mutations and early response to chemotherapy, better use of conventional anti-leukemic agents, and improved supportive care, including broad-spectrum antibiotics to combat opportunistic infections 1, 2. However, a significant proportion of leukemic deaths, not least for lower-risk patients, are caused by therapy rather than by the leukemia itself, and this is just the tip of the toxicity iceberg 3. Nearly all patients encounter mucositis and serious, though manageable, infections, and although various other severe, acute toxicities individually have relatively low incidences, almost 50% of all patients will be affected by at least one of these 4. Whereas recent high-throughput, cost-effective technologies have revolutionized our insight into the somatic mutational landscape of ALL, disease pathogenesis, and drug resistance mechanisms 5, our understanding of non-infectious chemotherapy-associated acute toxicities remains limited, including how to prevent and treat them. This reflects their rarity (calling for international collaboration), diverse definitions and capture strategies across study groups, lack of tissue specimens to map pathogenesis, and uncertain associations with common germline DNA variants 6, 7. This review summarizes recent advancements in the exploration of non-infectious, chemotherapy-associated acute toxicities and outlines strategies for future research.

The toxicity scenario

Every organ can be affected by acute side effects of anti-leukemic chemotherapy, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis, ON), thromboembolism (TE), sinusoidal obstruction syndrome (SOS), endocrinopathies (especially corticosteroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate (HD-MTX)-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Other toxicities, including myopathy and some rare inflammatory toxicities (for example, epidermolysis), will not be addressed in this review.

Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and comparison of their frequency across various anti-leukemic treatment programs has been hampered by wide diversities in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences. The toxicities have traditionally been defined and graded according to the US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 8. However, these are generic in their grading and frequently inappropriate for children 9 and for the acute toxicities seen during childhood ALL therapy. Accordingly, 15 international childhood ALL study groups (Ponte di Legno Toxicity Working Group, or PTWG) have developed consensus definitions for 14 acute toxicities 7.

Mucositis

Mucositis is a debilitating adverse effect that is reported to occur in at least 40% of patients after high-dose anti-metabolites or DNA-damaging drugs, including high-dose alkylating agents given as part of conditioning therapy prior to hematopoietic stem cell transplantation (hSCT) 1013.

Risk factors for mucositis include low body weight, reduced renal function, low neutrophil counts, and elevated pre-therapeutic levels of inflammatory mediators 10, 12, 14, 15. In addition, the risk of severe mucositis has, albeit with conflicting results, been associated with common DNA polymorphisms, including the folate pathway methylenetetrahydrofolate reductase ( MTHFR, particularly C677T) 16 and DNA repair 17.

Oral mucositis ranges from soreness with erythema and edema to painful, ulcerative mucositis requiring narcotic analgesics, which may lead to poor nutritional status 18. Intestinal mucositis typically develops in parallel with abdominal pain, diarrhea or constipation, nausea, and vomiting, but oral and intestinal mucositis may not coincide 18. They both tend to peak at the time of neutrophil nadir 10 to 14 days after chemotherapy and typically resolve during the subsequent 5 to 10 days.

Gastrointestinal mucositis reflects release of damage-associated molecular patterns that are sensed by pattern recognition receptors such as Toll like-receptors, causing release of inflammatory cytokines propagating an inflammatory response 1921. This is followed by an ulceration phase and finally resolution 19. The normal intestinal microbiome may play a protective role by stimulating endothelial cell proliferation and mucous production, and intestinal dysbiosis due to chemotherapy and antibiotics could aggravate mucositis, but this awaits clinical validation 2123. Severe mucositis disrupts the intestinal immunological barrier and is a risk factor for systemic infections, although it has been most intensively studied in the hSCT setting 22, 24. Accordingly, intestinal mucositis defined by hypocitrullinemia reflecting a reduced population of functional enterocytes may be better than neutropenia at defining the risk period for bacteremia 24.

Although several studies have demonstrated temporal associations between gastrointestinal toxicity, systemic inflammation, and fever, infections can be proven in only less than 50% of febrile neutropenic episodes 25, 26, and the cause in microbiologically negative cases is more likely systemic inflammation—for example, C-reactive protein, interleukin-6, and in vitro cytokine production—than opportunistic microorganisms 13, 2729. This has led to the introduction of febrile mucositis as a complementary term to the ubiquitous febrile neutropenia 28. hSCT studies have linked systemic inflammation to adverse outcome and increased treatment-related mortality 30, 31. It is conceivable, but not yet shown, that this also holds true for ALL.

Numerous interventions have been tested for the prevention or amelioration of mucositis as reviewed and regularly updated by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology 32. Parenteral non-steroid anti-inflammatory drugs, anti-epileptics, neuroleptics, and opioids are still the mainstay of pain control, despite often being insufficiently effective 33. Probiotics containing lactobacillus species seem to reduce chemotherapy-induced diarrhea and mucositis but have been tested only in highly specific treatment settings and await formal testing in patients with chemotherapy-induced neutropenia and mucosa barrier dysfuntion 3437 (NCT02544685). Other less established interventions of some efficacy include intravenous glutamine, cryotherapy, recombinant keratinocyte growth factor-1, and low-level laser therapy for oral mucositis 32. However, most of these approaches have been studied only insufficiently (if at all) during ALL chemotherapy.

Central neurotoxicity

Central nervous system (CNS) toxicities during treatment occur in 10% to 15% of patients with childhood ALL and cover a wide spectrum of syndromes with overlapping symptoms, including seizures 38, HD-MTX-related stroke-like syndrome (MTX-SLS) 39 with or without reduced consciousness, posterior reversible encephalopathy syndrome (PRES) 40, and steroid psychosis 41, 42, and these may result in permanent or progressive neurocognitive defects (for example, attention, executive function) 4345 with or without white matter changes on magnetic resonance imaging (MRI).

Corticosteroids frequently cause transient changes in sleep pattern, mood, and cognition, and this can be quite burdensome to both patients and parents 46. Corticosteroids may affect the neurotransmitters dopamine or serotonin, deregulate the hypothalamic-pituitary-adrenal (HPA) axis, and cause hippocampal injury 47. In general, the risk of acute, severe neurotoxicity cannot be predicted, but the risk is higher for children below six years and for treatment with dexamethasone compared with prednisolone, potentially reflecting higher CNS penetration and longer half-life in CNS of dexamethasone 4850. Germline DNA polymorphisms in genes related to drug disposition or neurogenesis or both have been associated with neurotoxicity 51, but these candidate gene associations remain to be validated.

Seizures occur in approximately 10% of children with ALL 38. They can occur both as an isolated symptom, together with various other CNS toxicities (for example, intracranial hemorrhage or thrombosis, PRES, or MTX-SLS), or second to electrolyte and metabolic disturbances or to infections. Many patients subsequently require long-term anti-convulsive therapy, female sex being a significant risk factor 52.

MTX-SLS, which is characterized by focal neurological deficits or hemiparesis and often accompanied by disturbances in speech, affect, or consciousness (or a combination of these), develops within two to three weeks (usually 2 to 14 days) after HD-MTX or intrathecal MTX administration and waxes and wanes over the subsequent hours to days and then resolves within a few days 39, 53. MTX interferes with the methionine/homocysteine pathway and purine de novo synthesis pathways, disrupts myelin, causes accumulation of homocysteine and adenosine, and influences neurotransmitter status with a strong excitatory effect on the N-methyl-D-aspartate receptor (NMDAR). Vitamin B 12 deficiency can promote these disturbances 54. The incidence of SLS varies from less than 1% to 15% in the literature and appears to vary according to the scheduling and intensity of MTX and co-administration of other agents such as cyclophosphamide and Ara-C and appears more frequently in children older than 10 years 39. Most patients make a full recovery, although there are reports of persisting neurological deficits, and the risk of recurrence with subsequent MTX therapy is low 39. Dextromethorphan, a non-competitive antagonist to NMDAR, or aminophylline (more relevant for acute MTX-induced neurotoxicity) has been advocated on the basis of small series 55, 56. The effect may be dramatic, but the use of these interventions awaits formalized validation. MRI will not always be able to confirm MTX-SLS but often reveals characteristic changes allowing discrimination of MTX-SLS from PRES 57.

PRES is a clinico-radiological entity frequently seen during the first months of ALL therapy, reflecting disturbances of cerebrovascular autoregulation and inconsistently characterized by headache, altered mental status, seizures, and visual disturbances 40, 58, 59. It may have several causes, predominantly arterial hypertension, chemotherapy, and corticosteroids, but the exact cause can frequently not be determined in the individual patient 58. On cranial MRI, areas of vasogenic edema are predominant but not restricted to the posterior regions of the brain or being exclusively bilateral. Affected areas are hypointense on T1-weighted and hyperintense on T2-weighted MRI 59. In contrast to MTX-SLS, PRES is hyperintense on apparent diffusion-weighted coefficient MRI images.

Some patients develop frank psychosis during corticosteroid therapy 41, 42. There are no clear guidelines for their clinical management, but sleep medication and tranquilizers and, in severe cases, anti-psychotics (for example, risperidone) can be indicated 60.

Transverse myelitis is a very rare complication seen in children with or without hematological malignancies 61. It may occasionally be associated with malignant infiltration 62 but can also be seen as a result of intensive chemotherapy, and high-dose cytarabine, MTX, and vincristine have been suspected to play a role 63.

Peripheral neuropathy

Peripheral motor or sensory neuropathy or both are common, usually caused by vincristine, and in general completely reversible but may require many months for improvement 64, 65. In severe cases, they are occasionally associated with Charcot-Marie-Tooth disease 66, 67.

Metabolic drug-drug interactions may enhance vincristine neurotoxicity 68. Vincristine is inactivated by the major drug-metabolizing CYP isoform in humans, CYP3A4, and the azoles ketoconazole, itraconazole, and posaconazole are potent inhibitors of CYP3A4 69. The potency of the azoles fluconazole and voriconazole as CYP3A4 inhibitors are much lower but may be clinically significant at high doses. A few germline DNA variants and gene expression profiles have been associated with the risk of vincristine-induced neuropathy 64, 70.

Bone toxicities

The pathophysiology of osteoporosis during ALL therapy is uncertain, but the leukemia itself and the use of corticosteroids may cause osteoporosis and fractures, including multifocal compression fractures of the spine 7174, and osteoporosis affects up to 20% of newly diagnosed children with ALL 75. Five-year cumulative incidence of fractures has been reported to be 10% to 15% with no overall incidence difference between post-induction prednisolone or dexamethasone, although for adolescents dexamethasone seems to be associated with a higher risk 73, 76.

The most severe skeletal complication is symptomatic ON, caused by bone death resulting from poor blood supply 77. The PTWG has published a consensus definition of ON that accounts for localization of ON, joint deformation and the impact of ON on symptoms and self-care 7. If routine MRI is performed, an even higher frequency of non-symptomatic ON will be detected 78. Thus, the overall reported frequency varies from less than 5% to more than 70%, and females and adolescents have the highest risk 79, 80. ON is mainly diagnosed during the second year of ALL therapy (that is, during maintenance therapy), although presentation can occur earlier or even after cessation of therapy 78, 81. Hips and knees are most commonly affected in both subclinical and clinical cases, and often multiple joints are involved 77, 81. Many will suffer from daily pain, decreased ability of physical activity (or even need of a wheelchair), and reduced quality of life 81, 82. ON can lead to joint articular surface collapse with debilitating arthritis and need for joint-preserving or joint replacement surgery during the early phase of ON or months or years later.

So far, the only proven preventive measure for ON is giving dexamethasone intermittently rather than continuously 79. Corticosteroids contribute to the development of ON through osseous lipocyte hypertrophy with resultant increased pressure within the bone, which can cause vascular collapse and necrosis, and corticosteroids can cause direct toxicity to osteocytes. Fat emboli, vasculitis, or microthromboemboli that cause vascular occlusion can also contribute. Accordingly, hyperlipidemia induced by corticosteroids and asparaginase has been suggested to be associated with increased risk of ON, although most studies have been inconclusive 78, 83.

Genetic risk factors have been reported in pathways associated with the glutamate receptor, bone, lipid and folate metabolism, thymidylate synthase, corticosteroid disposition, and adipogenesis, but the associations have in general not been validated 78, 8486.

The benefits of prognostication of ON by imaging await validation 87, 88. Future research should focus on potential risk factors for various grades and for single-versus-multiple site ON, on the association with metabolism of drugs that may influence lipid profiles and coagulation 78, on the long-term outcome of ON, on improved guidelines for treatment adaptation and interventive surgery, and on the association of germline DNA variants with phenotype subsets.

Thromboembolisms

TE located to the venous system is most common, and half of the cases involve the CNS 8991. The cumulative incidence of symptomatic venous TE is 2 to 8% 9093, but asymptomatic cases have been reported in up to 70% of patients 92, 94. Risk factors for TE include the leukemia itself, older age, central line catheters, immobilization, infections, systemic inflammation, and therapy with asparaginase or corticosteroids or both 76, 90, 93, 95, 96, whereas inherited thrombophilia risk factors, including common germline DNA polymorphisms, do not seem to play a role or at best remain uncertain 96. The fatality rate of venous TE is highest in children with thromboses in cerebral veins, and studies on the benefits of anti-thrombotic prophylaxis, preferably with the novel oral anti-coagulants, are needed 90, 97, 98.

Sinosoidal-obstruction syndrome

Until recently, SOS, previously known as veno-occlusive disease 99, has primarily been a serious complication of hSCT and is otherwise rare during childhood ALL therapy except with continuous oral thioguanine 100, not least in patients who carry low-activity alleles for thiopurin methyl transferase 101. Doppler ultrasound showing reversed hepatic portal flow may aid the diagnosis, but a normal flow does not exclude the diagnosis and thus is not a mandatory diagnostic requirement. Instead, at least three of five criteria need to be fulfilled: that is, hepatomegaly, hyperbilirubinemia above upper normal limit (UNL), ascites, weight gain at or above 5%, and thrombocytopenia (transfusion-resistant or otherwise unexplained by treatment or both) 7.

The pathogenesis remains unclear, but drug-induced damage to hepatic endothelium and microcirculation and subsequent ischemic hepatocellular necrosis are the presumed mechanism 99, 102, 103. Previously, SOS occurred extremely rarely during 6-MP therapy 100 but recently has been described as a frequent complication to continuous polyethylene glycol-linked Escherichia coli asparaginase preparation (PEG-asparaginase) during 6-MP-based maintenance therapy when combined with pulses of either HD-MTX or vincristine/dexamethasone, probably reflecting the impact of asparaginase on 6-MP pharmacokinetics causing higher drug metabolite levels 104. Management of SOS during thiopurine therapy follows the same principles as management of SOS following hSCT: that is, fluid and sodium chloride restriction, diuretics, and, in the rare severe cases, defibrotide.

Endocrinopathies

There is a paucity of prospective longitudinal studies determining endocrine changes during ALL therapy, and the existing studies have small sample sizes. Growth retardation and relative growth hormone deficiency are common during ALL therapy, but usually an adequate growth catch-up is obtained after cessation of therapy in children who do not receive radiotherapy 105, 106, but with a trend toward reduced final height 107.

A significant weight gain is seen in up to 40% of children with ALL, primarily reflecting exposure to corticosteroids and reduced physical activity with insulin resistance, hyperglycemia, and prediabetes, which could indicate the need for dietary modifications and insulin therapy 108111. The risk of corticosteroid-induced hyperglycemia is aggravated by asparaginase therapy 112, 113. The prevalence of hyperglycemia during ALL therapy has been reported to be 10% to 20% during treatment with asparaginase and corticosteroids, most frequently in children above 10 years of age, with resolution after cessation or tapering down of these drugs 112116. Medication-induced diabetes may be a marker for metabolic disease later in life 116. Finally, hyperglycemia and obesity both have been associated with reduced event-free survival 117, 118.

Fasting hypoglycemia is common during MTX/thiopurine-based maintenance therapy, especially in children below 6 years of age, but resolves after discontinuation of therapy 119, 120. It may reflect lowered plasma levels of the gluconeogenic amino acids (alanine and glutamine) as well as impaired glycogenolysis or glyconeogenesis 119, 121.

Corticosteroids cause a suppression of the HPA axis with secondary adrenal insufficiency and impaired stress response in nearly all patients, which for some patients may last several months after cessation of corticosteroid therapy irrespective of whether prednisolone or dexamethasone has been used 122. It may be aggravated by co-administration of fluconazole 122. Thus, corticosteroid replacement is indicated during the first weeks to months after cessation of corticosteroid therapy, not least during episodes of serious stress unless a stimulation test has shown a normal adrenal response 122, 123. The duration of adrenal insufficiency has been ascribed to variants of the GR gene 124, but formal genome-wide association analyses are lacking.

HD-MTX-related nephrotoxicity

Alkalinization and vigorous hydration reduce the risk of significant nephrotoxicity with HD-MTX, but approximately 3% of patients will experience severe renal toxicity that will further compromise MTX clearance 125128. The nephrotoxicity is likely to be related to precipitation of MTX crystals in the kidneys and this is partly due to insufficient hydration and alkalization 129, 130. Plasma creatinine usually peaks within a few days after initiation of the HD-MTX infusion and returns to baseline after a few weeks. Nearly all patients will subsequently tolerate full-dose HD-MTX without recurrent nephrotoxicity 127, 128. Higher doses of folinic acid, adjusted by the plasma MTX levels, are essential to limit the risk of life-threatening myelosuppression and mucositis, but whether over-rescue could increase the risk of relapse remains an unsolved challenge 131133. In cases with extremely delayed MTX clearance, glucarpidase may be helpful to degrade MTX by enzymatic cleavage to 2,4-diamino-N10-methyl-pteroic acid (DAMPA) and glutamate 127, 128, but it does not promote restoration of renal function. Proton pump inhibitors and non-steroidal anti-inflammatory drugs 134142 as well as foodstuff (for example, licorice 143) and beverages (with low pH or sweetened with licorice extract) have been suspected to affect the MTX clearance 144. Since the introduction of 5-HT3 receptor antagonists, emesis is not a problem during HD-MTX and not linked to acute kidney injury.

Trimethroprim-sulfamethoxazole used as Pneumocystis jiroveci prophylaxis during ALL therapy does not seem to interfere with HD-MTX PK 145.

Several germline DNA variants are associated with MTX clearance, most notably in SLCO1B 146149, but none has yet been implemented in HD-MTX dosing strategies or been shown to be associated with extremely delayed MTX clearance.

Toxicities secondary to asparaginase therapy

Asparaginase causes a range of toxicities due to asparagine depletion and disturbed protein synthesis. These toxicities may occur in up to 20 to 25% of all patients 4 and may lead to discontinuation of asparaginase therapy, which may increase the risk of relapse, not least in the CNS 150, 151.

Asparaginase-associated allergy

The various asparaginase preparations and recombinant analogs differ in their biologic half-lives (shortest for Erwinia chrysanthemi-derived asparaginase and longest for PEG-asparaginase) and in their immunogenicity (lowest for PEG-asparaginase) 152, 153. Asparaginase can induce antibody formation that neutralizes asparaginase with or without (so-called silent inactivation) clinical signs of hypersensitivity 154156. Identification of silent inactivation requires measurement of plasma asparaginase activity levels.

The reported frequency of allergic reactions ranges from 3 to 75% depending on the type, dose, route, and duration of asparaginase administration, and allergic reaction primarily occurs after the first or second dose and virtually always is associated with zero asparaginase activity 150, 154, 157162. The reactions range from mild, local reactions to life-threatening systemic responses, including urticaria, symptomatic bronchospasm, edema/angioedema, and hypotension. Premedication with corticosteroid and anti-histamines and increased infusion time can reduce allergic symptoms but do not prevent asparaginase inactivation, and thus symptoms of hypersensitivity indicate the need to switch from E. coli-derived preparations to Erwinia asparaginase (or vice versa) 7, 163. Less immunogenic asparaginase preparations are emerging but are not routinely used in first-line therapy 164166.

Allergic-like reactions (for example, vomiting, stomach ache, or rash) with intact asparaginase activity can be seen but do not indicate discontinuation of the drug 7. Therapeutic drug monitoring can be helpful for differentiating allergy and allergic-like reactions 154. HLA-DRB1*07:01 and genetic variations in GRIA1 have been associated with a higher incidence of hypersensitivity and anti-asparaginase antibodies 167, 168.

Asparaginase-associated pancreatitis

Asparaginase-associated pancreatitis (AAP) has a reported incidence of 2 to 18% depending on the cumulative asparaginase dose (that is, treatment duration) and toxicity capture strategies but seemingly not on the route of administration 7, 158, 169174. AAP is most often diagnosed within two weeks of asparaginase exposure (median of 11 days with PEG-asparaginase), but the interval may be longer 175. The diagnostic criteria defined by the PTWG 7 are similar to those developed for pancreatitis in general 176 and require two of three criteria to be met: (i) abdominal symptoms suggestive of AAP, (ii) characteristic findings of pancreatitis on imaging, and (iii) serum lipase or amylase or both at least three times the UNL, and both enzymes should be measured because of a poor correlation between the two 175. If imaging shows pancreatic necrosis or hemorrhage and/or the abdomimal symptoms and elevated pancreatic enzymes at least three times the UNL persist for more than 72 hours, AAP is classified as severe and otherwise as mild.

Most AAP episodes are accompanied by systemic inflammatory responses (fever, elevated heart rate, elevated respiratory rate, or hypotension) and thus may easily be misinterpreted as sepsis. In addition to transient or permanent discontinuation of asparaginase therapy, treatment of AAP includes appropriate triage, fluid resuscitation, antibiotics (until an infection is ruled out), and monitoring for and treatment of AAP-related complications 177. The mortality rate is low, but patients systemically affected at AAP diagnosis are at increased risk of developing pseudocysts, acute or persistent diabetes mellitus, and chronic/relapsing pancreatitis 175, 178. Octreotide has been tested in few patients, but the benefit thereof remains to be determined 179, 180.

The risk of a second AAP after re-exposing patients with AAP to asparaginase is almost 50% and does not seem to be significantly lower if the first AAP episode was classified as mild 170, 174, 175.

Risk factors for AAP are few, although the incidence is associated with older age. Polymorphisms in PRSS1, SPINK1, ASNS, ULK2, RGS6, and CPA2 genes have been associated either with pediatric pancreatitis in general or with AAP 162, 174, 181, 182, although these associations await validation.

Hyperlipidemia

Elevated triglycerides and cholesterol occur frequently during ALL therapy and are associated with corticosteroid and asparaginase therapy 7, 78, 83, 183. However, patients are generally completely unaffected, even when levels are 40 to 50 times the UNL, the association with specific toxicities is very uncertain, and accordingly neither routine measurements nor interventions are recommended 7.

The hypertriglyceridemia is likely related to an increase in the endogenous hepatic synthesis of very low-density lipoprotein combined with a decreased activity in lipoprotein lipase, an enzyme involved in the removal of triglyceride-rich lipoproteins from the plasma 184.

The most common preventive measures in cases of hypertriglyceridemia are dietary restrictions (very limited effect), fibrates, insulin infusions, heparin infusions, and in extreme cases plasmapheresis, but there are no data to support that any of these interventions reduces the risk of hypertriglyceridemia-associated toxicities 83, 185189. In adults with non-malignant disorders, hypertriglyceridemia (above 10 times the UNL) has been associated with an increased risk of acute pancreatitis 185, 188, 190, but so far this has not been replicated in children with ALL 191. A few studies have indicated associations with development of ON and thrombosis 78, 83, 95, 158, 188, 192, but no randomized studies have explored whether lipid-lowering interventions prevent these complications.

Host genome variant associations

As mentioned above, multiple variants in germline DNA have been associated with the pharmacology of anti-leukemic agents, including the risk of toxicities 6, 68, 193, but their individual hazard ratios are generally low (<2.0), the variants are rare or lack validation in independent studies, and treatment alterations according to such variants so far have not been implemented in childhood ALL therapy. The main reasons for our current inability to identify clinically actionable germline variants associated with specific toxicities are lack of sufficient study power (since each toxicity is rare and few trial groups are investigating genotype variation), incomplete toxicity capture, lack of detailed phenotyping (for example, lumping all subtypes and grades of a toxicity), and exploration of single-nucleotide polymorphisms rather than biological pathways. To address these limitations, the PTWG is now collecting phenotypes of several acute toxicities (pancreatitis, ON, and CNS toxicities) in hundreds of patients for each of these toxicities to associate detailed phenotypes with germline DNA variants 175.

Leukemia predisposition syndromes

Recent research has identified several germline mutations in genes that play a critical role in hematopoiesis and lymphoid development and that are also frequently somatically mutated in ALL, such as PAX5 194, 195, ETV6 196, 197, RUNX11 198, and IKZF1 199, which align with the findings of high subtype concordance in familial cases of ALL 195, 197, 200, 201. This indicates that pure familial ALL syndromes may constitute a substantial part of ALL etiology and that more such syndromes are expected to emerge in parallel with a growing number of patients being germline-sequenced and with a deeper understanding of the impact of coding and non-coding DNA interactions 196. However, the impact of such germline DNA mutations on toxicities, not least those involving the bone marrow and immune system, remains to be determined. The risk of second malignant neoplasms may also be increased when childhood ALL arises due to a predisposition syndrome. Unusual acute toxicities and second malignant neoplasms therefore should lead to clinical suspicion of an underlying syndrome 202.

Down syndrome is the most frequent known germline mutation predisposing to ALL and is associated with enhanced gastrointestinal toxicity 203. However, reducing treatment intensity may also increase the risk of relapse 204 and should be considered only in case of excessive toxicity in the 10 to 15% of Down syndrome-ALL patients who harbor high hyperdiploidy or an ETV6-RUNX1 translocation, since these subsets have a superior cure rate 205.

Several other ALL-predisposing syndromes such as Li-Fraumeni, ataxia telangiectasia, Nijmegen breakage, biallelic mismatch repair, and Fanconi anemia can also exhibit syndrome-related toxicities when exposed to DNA-damaging anti-cancer agents or radiotherapy 206209. In such cases, a reduction of DNA-damaging drug doses must be considered on an individual basis, and at least for ataxia telangiectasia and Nijmegen breakage dose reduction may not be associated with an increased risk of relapse 210. In contrast, thiopurine-based maintenance therapy may be less efficient in patients with biallelic mismatch repair deficiency, since this pathway is critical for thiopurine cytotoxicity 211.

Future research

The low frequency and poor definitions of most of the listed organ toxicities have hampered their in-depth exploration, including the impact of specific drug dosing regimens, and identification of clear risk factors for certain phenotypic subsets. The recent PTWG consensus definitions of 14 of these toxicities have provided a platform for international collaboration on these issues 7. The results from the first of such explorations demonstrate its feasibility 175 and may allow exploration of the association between risk factors, including host DNA variants, in well-defined phenotypic subsets and provide evidence-based guidelines for treatment adaptation. Furthermore, the association of these acute toxicities with the risk of long-term organ toxicities (for example, dementia, diabetes, arthrosis, and chronic pancreatitis) remains to be mapped. Currently, event-free survival measures encompass death during induction, resistance to first-line therapy, relapse of leukemia, non-leukemic death during clinical remission, and development of a second cancer. However, many patients with a late relapse or a second cancer have a fair chance of cure 212, 213, whereas chronic toxicities are generally irreversible and challenge patients’ ability to live a normal adult life 214. This calls for new endpoint measures that include both survival and quality of life, which will require common strategies for toxicity capture and registration, and international collaboration to identify host genome variants and exposures (for example, anti-leukemic treatment, co-medication, and diet) associated with the risk of specific toxicities, but it also demands the development of a joint endpoint scoring system that encompasses OS as well as severe toxicities, both acute and long-term.

Abbreviations

6-MP, 6-mercaptopurine; AAP, asparaginase-associated pancreatitis; ALL, acute lymphoblastic leukemia; CNS, central nervous system; HD, high dose; HPA, hypothalamic-pituitary-adrenal; hSCT, hematopoietic stem cell transplantation; MRI, magnetic resonance imaging; MTX, methotrexate; NMDAR, N-methyl-D-aspartate receptor ON, osteonecrosis; OS, overall survival; PEG, polyethylene glycol; PRES, posterior reversible encephalopathy syndrome; PTWG, Ponte di Legno Toxicity Working Group; SLS, stroke-like syndrome; SOS, sinusoidal obstruction syndrome; TE, thromboembolism; UNL, upper normal limit.

Notes

[version 1; referees: 3 approved]

Funding Statement

This work was supported by the Danish Cancer Society and the Danish Childhood Cancer Foundation.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Notes

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • Jan Stary, Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic
    No competing interests were disclosed.
  • Anne Uyttebroeck, University Hospitals Leuven, Leuven, Belgium
    No competing interests were disclosed.
  • Chris Halsey, University of Glasgow, Glasgow, UK
    No competing interests were disclosed.

References

1. Starý J, Hrušák O.: Recent advances in the management of pediatric acute lymphoblastic leukemia [version 1; referees: 2 approved]. F1000Res. 2016;5(F1000 Faculty Rev):2635 10.12688/f1000research.9548.1 [Cross Ref]
2. Pui CH, Yang JJ, Hunger SP, et al. : Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol. 2015;33(27):2938–48. 10.1200/JCO.2014.59.1636 [PMC free article] [PubMed] [Cross Ref]
3. Lund B, Åsberg A, Heyman M, et al. : Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer. 2011;56(4):551–9. 10.1002/pbc.22719 [PubMed] [Cross Ref]
4. Frandsen TL, Heyman M, Abrahamsson J, et al. : Complying with the European Clinical Trials directive while surviving the administrative pressure - an alternative approach to toxicity registration in a cancer trial. Eur J Cancer. 2014;50(2):251–9. 10.1016/j.ejca.2013.09.027 [PubMed] [Cross Ref]
5. Mullighan CG.: The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012;2012:389–96. [PubMed]
6. Moriyama T, Relling MV, Yang JJ.: Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood. 2015;125(26):3988–95. 10.1182/blood-2014-12-580001 [PubMed] [Cross Ref]
7. Schmiegelow K, Attarbaschi A, Barzilai S, et al. : Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol. 2016;17(6):e231–9. 10.1016/S1470-2045(16)30035-3 [PubMed] [Cross Ref]
8. National Institutes of Health: Common Terminology Criteria for Adverse Events (CTCAE).2009; (v4.03: June 14, 2010). Reference Source
9. de Rojas T, Bautista FJ, Madero L, et al. : The First Step to Integrating Adapted Common Terminology Criteria for Adverse Events for Children. J Clin Oncol. 2016;34(18):2196–7. 10.1200/JCO.2016.67.7104 [PubMed] [Cross Ref]
10. Rask C, Albertioni F, Schrøder H, et al. : Oral mucositis in children with acute lymphoblastic leukemia after high-dose methotrexate treatment without delayed elimination of methotrexate: relation to pharmacokinetic parameters of methotrexate. Pediatr Hematol Oncol. 1996;13(4):359–67. 10.3109/08880019609030842 [PubMed] [Cross Ref]
11. Figliolia SL, Oliveira DT, Pereira MC, et al. : Oral mucositis in acute lymphoblastic leukaemia: analysis of 169 paediatric patients. Oral Dis. 2008;14(8):761–6. 10.1111/j.1601-0825.2008.01468.x [PubMed] [Cross Ref]
12. Otmani N, Alami R, Hessissen L, et al. : Determinants of severe oral mucositis in paediatric cancer patients: a prospective study. Int J Paediatr Dent. 2011;21(3):210–6. 10.1111/j.1365-263X.2011.01113.x [PubMed] [Cross Ref]
13. Rathe M, Sorensen GL, Wehner PS, et al. : Chemotherapeutic treatment reduces circulating levels of surfactant protein-D in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2017;64(3):e26253. 10.1002/pbc.26253 [PubMed] [Cross Ref]
14. Cheng KK, Goggins WB, Lee VW, et al. : Risk factors for oral mucositis in children undergoing chemotherapy: a matched case-control study. Oral Oncol. 2008;44(11):1019–25. 10.1016/j.oraloncology.2008.01.003 [PubMed] [Cross Ref]
15. Ye Y, Carlsson G, Agholme MB, et al. : Pretherapeutic plasma pro- and anti- inflammatory mediators are related to high risk of oral mucositis in pediatric patients with acute leukemia: a prospective cohort study. PLoS One. 2013;8(5):e64918. 10.1371/journal.pone.0064918 [PMC free article] [PubMed] [Cross Ref]
16. Yang L, Hu X, Xu L.: Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol. 2012;33(5):1445–54. 10.1007/s13277-012-0395-2 [PubMed] [Cross Ref]
17. Ozdemir N, Celkan T, Barış S, et al. : DNA repair gene XPD and XRCC1 polymorphisms and the risk of febrile neutropenia and mucositis in children with leukemia and lymphoma. Leuk Res. 2012;36(5):565–9. 10.1016/j.leukres.2011.10.012 [PubMed] [Cross Ref]
18. Kuiken NS, Rings EH, Tissing WJ.: Risk analysis, diagnosis and management of gastrointestinal mucositis in pediatric cancer patients. Crit Rev Oncol Hematol. 2015;94(1):87–97. 10.1016/j.critrevonc.2014.12.009 [PubMed] [Cross Ref]
19. Sonis ST.: The pathobiology of mucositis. Nat Rev Cancer. 2004;4(4):277–84. 10.1038/nrc1318 [PubMed] [Cross Ref]
20. Sonis ST.: Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol. 2007;5(9 Suppl 4):3–11. [PubMed]
21. Kornblit B, Müller K.: Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016. 10.1038/bmt.2016.263 [PubMed] [Cross Ref]
22. van Vliet MJ, Harmsen HJ, de Bont ES, et al. : The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog. 2010;6(5):e1000879. 10.1371/journal.ppat.1000879 [PMC free article] [PubMed] [Cross Ref]
23. Fijlstra M, Ferdous M, Koning AM, et al. : Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model. Support Care Cancer. 2015;23(6):1513–22. 10.1007/s00520-014-2487-6 [PubMed] [Cross Ref]
24. Herbers AH, de Haan AF, van der Velden WJ, et al. : Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2014;16(2):279–85. 10.1111/tid.12195 [PubMed] [Cross Ref]
25. Bakhshi S, Padmanjali KS, Arya LS.: Infections in childhood acute lymphoblastic leukemia: an analysis of 222 febrile neutropenic episodes. Pediatr Hematol Oncol. 2008;25(5):385–92. 10.1080/08880010802106564 [PubMed] [Cross Ref]
26. Stabell N, Nordal E, Stensvold E, et al. : Febrile neutropenia in children with cancer: a retrospective Norwegian multicentre study of clinical and microbiological outcome. Scand J Infect Dis. 2008;40(4):301–7. 10.1080/00365540701670436 [PubMed] [Cross Ref]
27. Blijlevens NM, Donnelly JP, DePauw BE.: Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients. Bone Marrow Transplant. 2005;36(8):703–7. 10.1038/sj.bmt.1705118 [PubMed] [Cross Ref]
28. van der Velden WJ, Blijlevens NM, Feuth T, et al. : Febrile mucositis in haematopoietic SCT recipients. Bone Marrow Transplant. 2009;43(1):55–60. 10.1038/bmt.2008.270 [PubMed] [Cross Ref]
29. Pontoppidan PL, Jordan K, Carlsen AL, et al. : Associations between gastrointestinal toxicity, micro RNA and cytokine production in patients undergoing myeloablative allogeneic stem cell transplantation. Int Immunopharmacol. 2015;25(1):180–8. 10.1016/j.intimp.2014.12.038 [PubMed] [Cross Ref]
30. Schots R, van Riet I, Othman TB, et al. : An early increase in serum levels of C-reactive protein is an independent risk factor for the occurrence of major complications and 100-day transplant-related mortality after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2002;30(7):441–6. 10.1038/sj.bmt.1703672 [PubMed] [Cross Ref]
31. McNeer JL, Kletzel M, Rademaker A, et al. : Early elevation of C-reactive protein correlates with severe infection and nonrelapse mortality in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16(3):350–7. 10.1016/j.bbmt.2009.10.036 [PubMed] [Cross Ref]
32. Gibson RJ, Keefe DM, Lalla RV, et al. : Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer. 2013;21(1):313–26. 10.1007/s00520-012-1644-z [PubMed] [Cross Ref]
33. White MC, Hommers C, Parry S, et al. : Pain management in 100 episodes of severe mucositis in children. Paediatr Anaesth. 2011;21(4):411–6. 10.1111/j.1460-9592.2010.03515.x [PubMed] [Cross Ref]
34. Urbancsek H, Kazar T, Mezes I, et al. : Results of a double-blind, randomized study to evaluate the efficacy and safety of Antibiophilus in patients with radiation-induced diarrhoea. Eur J Gastroenterol Hepatol. 2001;13(4):391–6. 10.1097/00042737-200104000-00015 [PubMed] [Cross Ref]
35. Delia P, Sansotta G, Donato V, et al. : Prevention of radiation-induced diarrhea with the use of VSL#3, a new high-potency probiotic preparation. Am J Gastroenterol. 2002;97(8):2150–2. 10.1111/j.1572-0241.2002.05946.x [PubMed] [Cross Ref]
36. Osterlund P, Ruotsalainen T, Korpela R, et al. : Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97(8):1028–34. 10.1038/sj.bjc.6603990 [PMC free article] [PubMed] [Cross Ref]
37. S&D Pharma SK s.r.o: Prevention of Febrile Neutropenia by Synbiotics in Pediatric Cancer Patients (FENSY).NCT02544685. Reference Source
38. Ochs JJ, Bowman WP, Pui CH, et al. : Seizures in childhood lymphoblastic leukaemia patients. Lancet. 1984;2(8417–8418):1422–4. 10.1016/S0140-6736(84)91621-0 [PubMed] [Cross Ref]
39. Bond J, Hough R, Moppett J, et al. : 'Stroke-like syndrome' caused by intrathecal methotrexate in patients treated during the UKALL 2003 trial. Leukemia. 2013;27(4):954–6. 10.1038/leu.2012.328 [PubMed] [Cross Ref]
40. de Laat P, Te Winkel ML, Devos AS, et al. : Posterior reversible encephalopathy syndrome in childhood cancer. Ann Oncol. 2011;22(2):472–8. 10.1093/annonc/mdq382 [PubMed] [Cross Ref]
41. Judd LL, Schettler PJ, Brown ES, et al. : Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects. Am J Psychiatry. 2014;171(10):1045–51. 10.1176/appi.ajp.2014.13091264 [PubMed] [Cross Ref]
42. Drozdowicz LB, Bostwick JM.: Psychiatric adverse effects of pediatric corticosteroid use. Mayo Clin Proc. 2014;89(6):817–34. 10.1016/j.mayocp.2014.01.010 [PubMed] [Cross Ref]
43. Waber DP, Carpentieri SC, Klar N, et al. : Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol. 2000;22(3):206–13. [PubMed]
44. Waber DP, McCabe M, Sebree M, et al. : Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01. Pediatr Blood Cancer. 2013;60(11):1785–91. 10.1002/pbc.24666 [PMC free article] [PubMed] [Cross Ref]
45. Halsey C, Buck G, Richards S, et al. : The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI. J Hematol Oncol. 2011;4:42. 10.1186/1756-8722-4-42 [PMC free article] [PubMed] [Cross Ref]
46. McGrath P, Holewa H.: The emotional consequences of corticosteroid use in hematology: preliminary findings. J Psychosoc Oncol. 2010;28(4):335–50. 10.1080/07347332.2010.485246 [PubMed] [Cross Ref]
47. Stuart FA, Segal TY, Keady S.: Adverse psychological effects of corticosteroids in children and adolescents. Arch Dis Child. 2005;90(5):500–6. 10.1136/adc.2003.041541 [PMC free article] [PubMed] [Cross Ref]
48. Balis FM, Lester CM, Chrousos GP, et al. : Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol. 1987;5(2):202–7. 10.1200/JCO.1987.5.2.202 [PubMed] [Cross Ref]
49. Mrakotsky CM, Silverman LB, Dahlberg SE, et al. : Neurobehavioral side effects of corticosteroids during active treatment for acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. Pediatr Blood Cancer. 2011;57(3):492–8. 10.1002/pbc.23060 [PMC free article] [PubMed] [Cross Ref]
50. Teuffel O, Kuster SP, Hunger SP, et al. : Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Leukemia. 2011;25(8):1232–8. 10.1038/leu.2011.84 [PubMed] [Cross Ref]
51. Bhojwani D, Sabin ND, Pei D, et al. : Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol. 2014;32(9):949–59. 10.1200/JCO.2013.53.0808 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
52. Khan RB, Morris EB, Pui CH, et al. : Long-term outcome and risk factors for uncontrolled seizures after a first seizure in children with hematological malignancies. J Child Neurol. 2014;29(6):774–81. 10.1177/0883073813488675 [PMC free article] [PubMed] [Cross Ref]
53. Rubnitz JE, Relling MV, Harrison PL, et al. : Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia. Leukemia. 1998;12(8):1176–81. 10.1038/sj.leu.2401098 [PubMed] [Cross Ref]
54. Forster VJ, van Delft FW, Baird SF, et al. : Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients. Cancer Chemother Pharmacol. 2016;78(5):1093–6. 10.1007/s00280-016-3153-0 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
55. Bernini JC, Fort DW, Griener JC, et al. : Aminophylline for methotrexate-induced neurotoxicity. Lancet. 1995;345(8949):544–7. 10.1016/S0140-6736(95)90464-6 [PubMed] [Cross Ref]
56. Drachtman RA, Cole PD, Golden CB, et al. : Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol. 2002;19(5):319–27. 10.1080/08880010290057336 [PubMed] [Cross Ref]
57. Haykin ME, Gorman M, van Hoff J, et al. : Diffusion-weighted MRI correlates of subacute methotrexate-related neurotoxicity. J Neurooncol. 2006;76(2):153–7. 10.1007/s11060-005-9569-8 [PubMed] [Cross Ref]
58. Kim SJ, Im SA, Lee JW, et al. : Predisposing factors of posterior reversible encephalopathy syndrome in acute childhood leukemia. Pediatr Neurol. 2012;47(6):436–42. 10.1016/j.pediatrneurol.2012.07.011 [PubMed] [Cross Ref]
59. Khan RB, Sadighi ZS, Zabrowski J, et al. : Imaging Patterns and Outcome of Posterior Reversible Encephalopathy Syndrome During Childhood Cancer Treatment. Pediatr Blood Cancer. 2016;63(3):523–6. 10.1002/pbc.25790 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
60. Ularntinon S, Tzuang D, Dahl G, et al. : Concurrent treatment of steroid-related mood and psychotic symptoms with risperidone. Pediatrics. 2010;125(5):e1241–5. 10.1542/peds.2009-1815 [PubMed] [Cross Ref]
61. Wolf VL, Lupo PJ, Lotze TE.: Pediatric acute transverse myelitis overview and differential diagnosis. J Child Neurol. 2012;27(11):1426–36. 10.1177/0883073812452916 [PubMed] [Cross Ref]
62. Yavuz H, Cakir M.: Transverse myelopathy: an initial presentation of acute leukemia. Pediatr Neurol. 2001;24(5):382–4. 10.1016/S0887-8994(01)00258-2 [PubMed] [Cross Ref]
63. Schwenn MR, Blattner SR, Lynch E, et al. : HiC-COM: a 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt's lymphoma and B-cell acute lymphoblastic leukemia. J Clin Oncol. 1991;9(1):133–8. 10.1200/JCO.1991.9.1.133 [PubMed] [Cross Ref]
64. Diouf B, Crews KR, Lew G, et al. : Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313(8):815–23. 10.1001/jama.2015.0894 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
65. Addington J, Freimer M.: Chemotherapy-induced peripheral neuropathy: an update on the current understanding [version 1; referees: 2 approved]. F1000Res. 2016;5: pii: F1000 Faculty Rev-1466. 10.12688/f1000research.8053.1 [PMC free article] [PubMed] [Cross Ref]
66. Nishikawa T, Kawakami K, Kumamoto T, et al. : Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30(7):519–21. 10.1097/MPH.0b013e31816624a4 [PubMed] [Cross Ref]
67. Graf WD, Chance PF, Lensch MW, et al. : Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77(7):1356–62. 10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-# [PubMed] [Cross Ref]
68. Davidsen ML, Dalhoff K, Schmiegelow K.: Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30(11):831–49. 10.1097/MPH.0b013e3181868570 [PubMed] [Cross Ref]
69. Venkatakrishnan K, von Moltke LL, Greenblatt DJ.: Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38(2):111–80. 10.2165/00003088-200038020-00002 [PubMed] [Cross Ref]
70. Egbelakin A, Ferguson MJ, MacGill EA, et al. : Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011;56(3):361–7. 10.1002/pbc.22845 [PMC free article] [PubMed] [Cross Ref]
71. Mitchell CD, Richards SM, Kinsey SE, et al. : Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005;129(6):734–45. 10.1111/j.1365-2141.2005.05509.x [PubMed] [Cross Ref]
72. Halton J, Gaboury I, Grant R, et al. : Advanced vertebral fracture among newly diagnosed children with acute lymphoblastic leukemia: results of the Canadian Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) research program. J Bone Miner Res. 2009;24(7):1326–34. 10.1359/jbmr.090202 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
73. Vrooman LM, Stevenson KE, Supko JG, et al. : Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013;31(9):1202–10. 10.1200/JCO.2012.43.2070 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
74. den Hoed MA, Pluijm SM, te Winkel ML, et al. : Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia. Haematologica. 2015;100(12):1564–70. 10.3324/haematol.2015.125583 [PubMed] [Cross Ref] F1000 Recommendation
75. Wilson CL, Ness KK.: Bone mineral density deficits and fractures in survivors of childhood cancer. Curr Osteoporos Rep. 2013;11(4):329–37. 10.1007/s11914-013-0165-0 [PMC free article] [PubMed] [Cross Ref]
76. 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):160–9. 10.1111/ejh.12562 [PubMed] [Cross Ref]
77. Kuhlen M, Moldovan A, Krull K, et al. : Osteonecrosis in paediatric patients with acute lymphoblastic leukaemia treated on Co-ALL-07-03 trial: a single centre analysis. Klin Padiatr. 2014;226(3):154–60. 10.1055/s-0033-1358723 [PubMed] [Cross Ref]
78. Kawedia JD, Kaste SC, Pei D, et al. : Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2011;117(8):2340–7; quiz 2556. 10.1182/blood-2010-10-311969 [PubMed] [Cross Ref] F1000 Recommendation
79. Mattano LA, Jr, Devidas M, Nachman JB, et al. : Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol. 2012;13(9):906–15. 10.1016/S1470-2045(12)70274-7 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
80. Kunstreich M, Kummer S, Laws HJ, et al. : Osteonecrosis in children with acute lymphoblastic leukemia. Haematologica. 2016;101(11):1295–305. 10.3324/haematol.2016.147595 [PubMed] [Cross Ref]
81. te Winkel ML, Pieters R, Hop WC, et al. : Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2011;29(31):4143–50. 10.1200/JCO.2011.37.3217 [PubMed] [Cross Ref]
82. Girard P, Auquier P, Barlogis V, et al. : Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. Haematologica. 2013;98(7):1089–97. 10.3324/haematol.2012.081265 [PubMed] [Cross Ref]
83. Bhojwani D, Darbandi R, Pei D, et al. : Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. Eur J Cancer. 2014;50(15):2685–94. 10.1016/j.ejca.2014.06.023 [PMC free article] [PubMed] [Cross Ref]
84. Karol SE, Yang W, van Driest SL, et al. : Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2015;126(15):1770–6. 10.1182/blood-2015-05-643601 [PubMed] [Cross Ref] F1000 Recommendation
85. Karol SE, Mattano LA, Jr, Yang W, et al. : Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood. 2016;127(5):558–64. 10.1182/blood-2015-10-673848 [PubMed] [Cross Ref] F1000 Recommendation
86. Finkelstein Y, Blonquist TM, Vijayanathan V, et al. : A thymidylate synthase polymorphism is associated with increased risk for bone toxicity among children treated for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2016. 10.1002/pbc.26393 [PubMed] [Cross Ref] F1000 Recommendation
87. Niinimäki T, Harila-Saari A, Niinimäki R.: The diagnosis and classification of osteonecrosis in patients with childhood leukemia. Pediatr Blood Cancer. 2015;62(2):198–203. 10.1002/pbc.25295 [PubMed] [Cross Ref] F1000 Recommendation
88. Niinimäki T, Niinimäki J, Halonen J, et al. : The classification of osteonecrosis in patients with cancer: validation of a new radiological classification system. Clin Radiol. 2015;70(12):1439–44. 10.1016/j.crad.2015.08.011 [PubMed] [Cross Ref] F1000 Recommendation
89. Qureshi A, Mitchell C, Richards S, et al. : Asparaginase-related venous thrombosis in UKALL 2003- re-exposure to asparaginase is feasible and safe. Br J Haematol. 2010;149(3):410–3. 10.1111/j.1365-2141.2010.08132.x [PubMed] [Cross Ref]
90. 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):452–9. 10.1111/j.1365-2141.2010.08524.x [PubMed] [Cross Ref]
91. Santoro N, Colombini A, Silvestri D, et al. : Screening for coagulopathy and identification of children with acute lymphoblastic leukemia at a higher risk of symptomatic venous thrombosis: an AIEOP experience. J Pediatr Hematol Oncol. 2013;35(5):348–55. 10.1097/MPH.0b013e31828dc614 [PubMed] [Cross Ref]
92. 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):2216–22. 10.1182/blood-2006-04-015511 [PubMed] [Cross Ref]
93. Tuckuviene R, Ranta S, Albertsen BK, et al. : Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study. J Thromb Haemost. 2016;14(3):485–94. 10.1111/jth.13236 [PubMed] [Cross Ref]
94. Farinasso L, Bertorello N, Garbarini L, et al. : Risk factors of central venous lines-related thrombosis in children with acute lymphoblastic leukemia during induction therapy: a prospective study. Leukemia. 2007;21(3):552–6. 10.1038/sj.leu.2404560 [PubMed] [Cross Ref]
95. Payne JH, Vora AJ.: Thrombosis and acute lymphoblastic leukaemia. Br J Haematol. 2007;138(4):430–45. 10.1111/j.1365-2141.2007.06677.x [PubMed] [Cross Ref]
96. De Stefano V, Za T, Ciminello A, et al. : Haemostatic alterations induced by treatment with asparaginases and clinical consequences. Thromb Haemost. 2015;113(2):247–61. 10.1160/TH14-04-0372 [PubMed] [Cross Ref] F1000 Recommendation
97. Ranta S, Tuckuviene R, Makipernaa A, et al. : Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology. Br J Haematol. 2015;168(4):547–52. 10.1111/bjh.13162 [PubMed] [Cross Ref]
98. Musgrave KM, van Delft FW, Avery PJ, et al. : Cerebral sinovenous thrombosis in children and young adults with acute lymphoblastic leukaemia - a cohort study from the United Kingdom. Br J Haematol. 2016. 10.1111/bjh.14231 [PubMed] [Cross Ref] F1000 Recommendation
99. DeLeve LD, Shulman HM, McDonald GB.: Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22(1):27–42. 10.1055/s-2002-23204 [PubMed] [Cross Ref]
100. Escherich G, Richards S, Stork LC, et al. : Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic leukaemia. Leukemia. 2011;25(6):953–9. 10.1038/leu.2011.37 [PMC free article] [PubMed] [Cross Ref]
101. Lennard L, Richards S, Cartwright CS, et al. : The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther. 2006;80(4):375–83. 10.1016/j.clpt.2006.07.002 [PubMed] [Cross Ref]
102. Helmy A.: Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome. Aliment Pharmacol Ther. 2006;23(1):11–25. 10.1111/j.1365-2036.2006.02742.x [PubMed] [Cross Ref]
103. DeLeve LD.: Vascular Liver Disease and the Liver Sinusoidal Endothelial Cell. In: Vascular liver disease deLeve LD Garcia-Tsao G; editors. New York: Springer New York;2011;25–40. 10.1007/978-1-4419-8327-5_2 [Cross Ref]
104. Toksvang LN, De Pietri S, Nielsen SN, et al. : Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukaemia is associated with continuous asparaginase therapy and mercaptopurine metabolites. Pediatr Blood Cancer. 2017, in press. [PubMed]
105. Schmiegelow M, Hertz H, Schmiegelow K, et al. : Insulin-like growth factor-I and insulin-like growth factor binding protein-3 during maintenance chemotherapy of acute lymphoblastic leukemia in children. J Pediatr Hematol Oncol. 1999;21(4):268–73. [PubMed]
106. Howard SC, Pui CH.: Endocrine complications in pediatric patients with acute lymphoblastic leukemia. Blood Rev. 2002;16(4):225–43. 10.1016/S0268-960X(02)00042-5 [PubMed] [Cross Ref]
107. Vandecruys E, Dhooge C, Craen M, et al. : Longitudinal linear growth and final height is impaired in childhood acute lymphoblastic leukemia survivors after treatment without cranial irradiation. J Pediatr. 2013;163(1):268–73. 10.1016/j.jpeds.2012.12.037 [PubMed] [Cross Ref]
108. Mohn A, Di Marzio A, Capanna R, et al. : Persistence of impaired pancreatic beta-cell function in children treated for acute lymphoblastic leukaemia. Lancet. 2004;363(9403):127–8. 10.1016/S0140-6736(03)15264-6 [PubMed] [Cross Ref]
109. White J, Flohr JA, Winter SS, et al. : Potential benefits of physical activity for children with acute lymphoblastic leukaemia. Pediatr Rehabil. 2005;8(1):53–8. 10.1080/13638490410001727428 [PubMed] [Cross Ref]
110. Esbenshade AJ, Simmons JH, Friedman DL.: BMI alterations during treatment of childhood ALL-response. Pediatr Blood Cancer. 2012;58(6):1000. 10.1002/pbc.23379 [PubMed] [Cross Ref]
111. Chow EJ, Pihoker C, Friedman DL, et al. : Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60(4):621–6. 10.1002/pbc.24364 [PMC free article] [PubMed] [Cross Ref]
112. Pui CH, Burghen GA, Bowman WP, et al. : Risk factors for hyperglycemia in children with leukemia receiving L-asparaginase and prednisone. J Pediatr. 1981;99(1):46–50. 10.1016/S0022-3476(81)80955-9 [PubMed] [Cross Ref]
113. Lowas S, Malempati S, Marks D.: Body mass index predicts insulin resistance in survivors of pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2009;53(1):58–63. 10.1002/pbc.21993 [PMC free article] [PubMed] [Cross Ref]
114. Baillargeon J, Langevin AM, Mullins J, et al. : Transient hyperglycemia in Hispanic children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2005;45(7):960–3. 10.1002/pbc.20320 [PMC free article] [PubMed] [Cross Ref]
115. Koltin D, Sung L, Naqvi A, et al. : Medication induced diabetes during induction in pediatric acute lymphoblastic leukemia: prevalence, risk factors and characteristics. Support Care Cancer. 2012;20(9):2009–15. 10.1007/s00520-011-1307-5 [PubMed] [Cross Ref]
116. Yeshayahu Y, Koltin D, Hamilton J, et al. : Medication-induced diabetes during induction treatment for ALL, an early marker for future metabolic risk? Pediatr Diabetes. 2015;16(2):104–8. 10.1111/pedi.12138 [PubMed] [Cross Ref] F1000 Recommendation
117. Sonabend RY, McKay SV, Okcu MF, et al. : Hyperglycemia during induction therapy is associated with poorer survival in children with acute lymphocytic leukemia. J Pediatr. 2009;155(1):73–8. 10.1016/j.jpeds.2009.01.072 [PubMed] [Cross Ref]
118. Butturini AM, Dorey FJ, Lange BJ, et al. : Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2007;25(15):2063–9. 10.1200/JCO.2006.07.7792 [PubMed] [Cross Ref]
119. Halonen P, Salo MK, Schmiegelow K, et al. : Investigation of the mechanisms of therapy-related hypoglycaemia in children with acute lymphoblastic leukaemia. Acta Paediatr. 2003;92(1):37–42. 10.1111/j.1651-2227.2003.tb00466.x [PubMed] [Cross Ref]
120. Bay A, Oner AF, Cesur Y, et al. : Symptomatic hypoglycemia: an unusual side effect of oral purine analogues for treatment of ALL. Pediatr Blood Cancer. 2006;47(3):330–1. 10.1002/pbc.20582 [PubMed] [Cross Ref]
121. Trelinska J, Fendler W, Szadkowska A, et al. : Hypoglycemia and glycemic variability among children with acute lymphoblastic leukemia during maintenance therapy. Leuk Lymphoma. 2011;52(9):1704–10. 10.3109/10428194.2011.580024 [PubMed] [Cross Ref]
122. Gordijn MS, Rensen N, Gemke RJ, et al. : Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2015; (8): CD008727. 10.1002/14651858.CD008727.pub3 [PubMed] [Cross Ref] F1000 Recommendation
123. Salem MA, Tantawy AA, El Sedfy HH, et al. : A prospective study of the hypothalamic-pituitary-adrenal axis in children with acute lymphoblastic leukemia receiving chemotherapy. Hematology. 2015;20(6):320–7. 10.1179/1607845414Y.0000000208 [PubMed] [Cross Ref] F1000 Recommendation
124. de Ruiter RD, Gordijn MS, Gemke RJ, et al. : Adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia is associated with glucocorticoid receptor polymorphisms ER22/23EK and BclI. Haematologica. 2014;99(8):e136–7. 10.3324/haematol.2014.105056 [PubMed] [Cross Ref]
125. Skärby T, Jönsson P, Hjorth L, et al. : High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother Pharmacol. 2003;51(4):311–20. [PubMed]
126. Christensen AM, Pauley JL, Molinelli AR, et al. : Resumption of high-dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients. Cancer. 2012;118(17):4321–30. 10.1002/cncr.27378 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
127. Widemann BC, Schwartz S, Jayaprakash N, et al. : Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy. Pharmacotherapy. 2014;34(5):427–39. 10.1002/phar.1360 [PMC free article] [PubMed] [Cross Ref]
128. Svahn T, Mellgren K, Harila-Saari A, et al. : Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2016. 10.1002/pbc.26395 [PubMed] [Cross Ref]
129. Sand TE, Jacobsen S.: Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19(6):453–6. 10.1007/BF00548590 [PubMed] [Cross Ref]
130. Garneau AP, Riopel J, Isenring P.: Acute Methotrexate-Induced Crystal Nephropathy. N Engl J Med. 2015;373(7):2691–3. 10.1056/NEJMc1507547 [PubMed] [Cross Ref] F1000 Recommendation
131. Skärby TV, Anderson H, Heldrup J, et al. : High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia. 2006;20(11):1955–62. 10.1038/sj.leu.2404404 [PubMed] [Cross Ref]
132. Cohen IJ.: Challenging the clinical relevance of folinic acid over rescue after high dose methotrexate (HDMTX). Med Hypotheses. 2013;81(5):942–7. 10.1016/j.mehy.2013.08.027 [PubMed] [Cross Ref]
133. Mikkelsen TS, Mamoudou AD, Tuckuviene R, et al. : Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions: a prospectively randomized cross-over study. Pediatr Blood Cancer. 2014;61(2):297–301. 10.1002/pbc.24623 [PubMed] [Cross Ref]
134. Treon SP, Chabner BA.: Concepts in use of high-dose methotrexate therapy. Clin Chem. 1996;42(8 Pt 2):1322–9. [PubMed]
135. Widemann BC, Adamson PC.: Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694–703. 10.1634/theoncologist.11-6-694 [PubMed] [Cross Ref]
136. Suzuki K, Doki K, Homma M, et al. : Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009;67(1):44–9. 10.1111/j.1365-2125.2008.03303.x [PMC free article] [PubMed] [Cross Ref]
137. Joerger M, Huitema AD, van den Bongard HJ, et al. : Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol. 2006;62(1):71–80. 10.1111/j.1365-2125.2005.02513.x [PMC free article] [PubMed] [Cross Ref]
138. Bauters TG, Verlooy J, Robays H, et al. : Interaction between methotrexate and omeprazole in an adolescent with leukemia: a case report. Pharm World Sci. 2008;30(4):316–8. 10.1007/s11096-008-9204-9 [PubMed] [Cross Ref]
139. Ronchera CL, Hernández T, Peris JE, et al. : Pharmacokinetic interaction between high-dose methotrexate and amoxycillin. Ther Drug Monit. 1993;15(5):375–9. 10.1097/00007691-199310000-00004 [PubMed] [Cross Ref]
140. Thyss A, Milano G, Kubar J, et al. : Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet. 1986;1(8475):256–8. 10.1016/S0140-6736(86)90786-5 [PubMed] [Cross Ref]
141. de Miguel D, García-Suárez J, Martin Y, et al. : Severe acute renal failure following high-dose methotrexate therapy in adults with haematological malignancies: a significant number result from unrecognized co-administration of several drugs. Nephrol Dial Transplant. 2008;23(12):3762–6. 10.1093/ndt/gfn503 [PubMed] [Cross Ref]
142. Loue C, Garnier N, Bertrand Y, et al. : High methotrexate exposure and toxicity in children with t(9;22) positive acute lymphoblastic leukaemia treated with imatinib. J Clin Pharm Ther. 2015. 10.1111/jcpt.12298 [PubMed] [Cross Ref] F1000 Recommendation
143. Lin SP, Tsai SY, Hou YC, et al. : Glycyrrhizin and licorice significantly affect the pharmacokinetics of methotrexate in rats. J Agric Food Chem. 2009;57(5):1854–9. 10.1021/jf8029918 [PubMed] [Cross Ref]
144. Santucci R, Levêque D, Herbrecht R.: Cola beverage and delayed elimination of methotrexate. Br J Clin Pharmacol. 2010;70(5):762–4. 10.1111/j.1365-2125.2010.03744.x [PMC free article] [PubMed] [Cross Ref]
145. Watts CS, Sciasci JN, Pauley JL, et al. : Prophylactic Trimethoprim-Sulfamethoxazole Does Not Affect Pharmacokinetics or Pharmacodynamics of Methotrexate. J Pediatr Hematol Oncol. 2016;38(6):449–52. 10.1097/MPH.0000000000000606 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
146. Treviño LR, Shimasaki N, Yang W, et al. : Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol. 2009;27(35):5972–8. 10.1200/JCO.2008.20.4156 [PMC free article] [PubMed] [Cross Ref]
147. Gregers J, Christensen IJ, Dalhoff K, et al. : The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood. 2010;115(23):4671–7. 10.1182/blood-2010-01-256958 [PubMed] [Cross Ref]
148. Mikkelsen TS, Thorn CF, Yang JJ, et al. : PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics. 2011;21(10):679–86. 10.1097/FPC.0b013e328343dd93 [PMC free article] [PubMed] [Cross Ref]
149. Ramsey LB, Panetta JC, Smith C, et al. : Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013;121(6):898–904. 10.1182/blood-2012-08-452839 [PubMed] [Cross Ref] F1000 Recommendation
150. 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):1211–8. 10.1182/blood.V97.5.1211 [PubMed] [Cross Ref]
151. Sirvent N, Suciu S, Rialland X, et al. : Prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with acute lymphoblastic leukaemia (ALL) treated without cranial irradiation: results of European Organization for Research and Treatment of Cancer (EORTC) Children Leukemia Group study 58881. Eur J Cancer. 2011;47(2):239–47. 10.1016/j.ejca.2010.10.019 [PubMed] [Cross Ref]
152. Asselin BL, Whitin JC, Coppola DJ, et al. : Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol. 1993;11(9):1780–6. 10.1200/JCO.1993.11.9.1780 [PubMed] [Cross Ref]
153. Albertsen BK, Schroder H, Ingerslev J, et al. : Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system. Br J Haematol. 2001;115(4):983–90. 10.1046/j.1365-2141.2001.03148.x [PubMed] [Cross Ref]
154. Liu C, Kawedia JD, Cheng C, et al. : Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia. 2012;26(11):2303–9. 10.1038/leu.2012.102 [PMC free article] [PubMed] [Cross Ref]
155. Fernandez CA, Smith C, Yang W, et al. : Genome-wide analysis links NFATC2 with asparaginase hypersensitivity. Blood. 2015;126(1):69–75. 10.1182/blood-2015-02-628800 [PubMed] [Cross Ref] F1000 Recommendation
156. van der Sluis IM, Vrooman LM, Pieters R, et al. : Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279–85. 10.3324/haematol.2015.137380 [PubMed] [Cross Ref] F1000 Recommendation
157. Wang B, Relling MV, Storm MC, et al. : Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia. 2003;17(8):1583–8. 10.1038/sj.leu.2403011 [PubMed] [Cross Ref]
158. Tong WH, Pieters R, de Groot-Kruseman HA, et al. : The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia. Haematologica. 2014;99(11):1716–21. 10.3324/haematol.2014.109413 [PubMed] [Cross Ref]
159. Silverman LB, Supko JG, Stevenson KE, et al. : Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood. 2010;115(7):1351–3. 10.1182/blood-2009-09-245951 [PubMed] [Cross Ref]
160. Henriksen LT, Harila-Saari A, Ruud E, et al. : PEG-asparaginase allergy in children with acute lymphoblastic leukemia in the NOPHO ALL2008 protocol. Pediatr Blood Cancer. 2015;62(3):427–33. 10.1002/pbc.25319 [PubMed] [Cross Ref]
161. Vrooman LM, Kirov II, Dreyer ZE, et al. : Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2016;63(2):228–33. 10.1002/pbc.25757 [PMC free article] [PubMed] [Cross Ref]
162. 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):2133–40. 10.1200/JCO.2015.64.5812 [PMC free article] [PubMed] [Cross Ref]
163. Ko RH, Jones TL, Radvinsky D, et al. : Allergic reactions and antiasparaginase antibodies in children with high-risk acute lymphoblastic leukemia: A children's oncology group report. Cancer. 2015;121(23):4205–11. 10.1002/cncr.29641 [PMC free article] [PubMed] [Cross Ref]
164. Offman MN, Krol M, Patel N, et al. : Rational engineering of L-asparaginase reveals importance of dual activity for cancer cell toxicity. Blood. 2011;117(5):1614–21. 10.1182/blood-2010-07-298422 [PubMed] [Cross Ref]
165. Domenech C, Thomas X, Chabaud S, et al. : l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial. Br J Haematol. 2011;153(1):58–65. 10.1111/j.1365-2141.2011.08588.x [PubMed] [Cross Ref]
166. Kumar S, Prabhu AA, Dasu VV, et al. : Batch and fed-batch bioreactor studies for the enhanced production of glutaminase-free L-asparaginase from Pectobacterium carotovorum MTCC 1428. Prep Biochem Biotechnol. 2017;47(1):74–80. 10.1080/10826068.2016.1168841 [PubMed] [Cross Ref] F1000 Recommendation
167. Chen SH, Pei D, Yang W, et al. : Genetic variations in GRIA1 on chromosome 5q33 related to asparaginase hypersensitivity. Clin Pharmacol Ther. 2010;88(2):191–6. 10.1038/clpt.2010.94 [PMC free article] [PubMed] [Cross Ref]
168. Fernandez CA, Smith C, Yang W, et al. : HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014;124(8):1266–76. 10.1182/blood-2014-03-563742 [PubMed] [Cross Ref]
169. Knoderer HM, Robarge J, Flockhart DA.: Predicting asparaginase-associated pancreatitis. Pediatr Blood Cancer. 2007;49(5):634–9. 10.1002/pbc.21037 [PubMed] [Cross Ref]
170. Kearney SL, Dahlberg SE, Levy DE, et al. : Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer. 2009;53(2):162–7. 10.1002/pbc.22076 [PMC free article] [PubMed] [Cross Ref]
171. 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):710–3. 10.1111/bjh.12407 [PubMed] [Cross Ref]
172. Raja RA, Schmiegelow K, Albertsen BK, et al. : Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol. Br J Haematol. 2014;165(1):126–33. 10.1111/bjh.12733 [PubMed] [Cross Ref]
173. 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):1677–90. 10.1016/S1470-2045(15)00363-0 [PubMed] [Cross Ref] F1000 Recommendation
174. 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):325–32. 10.1038/leu.2016.203 [PubMed] [Cross Ref]
175. Wolthers BO, Frandsen TL, Baruchel A, et al. : Asparaginase-Associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Report on Clinical Presentation and Outcome. Blood. 2016;128:585 Reference Source
176. Morinville VD, Husain SZ, Bai H, et al. : Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr. 2012;55(3):261–5. 10.1097/MPG.0b013e31824f1516 [PMC free article] [PubMed] [Cross Ref]
177. Forsmark CE, Vege SS, Wilcox CM.: Acute Pancreatitis. N Engl J Med. 2016;375(20):1972–81. 10.1056/NEJMra1505202 [PubMed] [Cross Ref]
178. Spraker HL, Spyridis GP, Pui CH, et al. : Conservative management of pancreatic pseudocysts in children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2009;31(12):957–9. 10.1097/MPH.0b013e3181ba9e6a [PMC free article] [PubMed] [Cross Ref]
179. Wu SF, Chen AC, Peng CT, et al. : Octreotide therapy in asparaginase-associated pancreatitis in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;51(6):824–5. 10.1002/pbc.21721 [PubMed] [Cross Ref]
180. Tokimasa S, Yamato K.: Does octreotide prevent L-asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia? Br J Haematol. 2012;157(3):381–2. 10.1111/j.1365-2141.2011.08971.x [PubMed] [Cross Ref]
181. 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):329–34. 10.1158/1078-0432.CCR-14-0508 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
182. Kumar S, Ooi CY, Werlin S, et al. : Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE. JAMA Pediatr. 2016;170(6):562–9. 10.1001/jamapediatrics.2015.4955 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
183. Blackett PR, Koren E, Blackstock R, et al. : Hyperlipidemia in acute lymphoblastic leukemia. Ann Clin Lab Sci. 1984;14(2):123–9. [PubMed]
184. Hoogerbrugge N, Jansen H, Hoogerbrugge PM.: Transient hyperlipidemia during treatment of ALL with L-asparaginase is related to decreased lipoprotein lipase activity. Leukemia. 1997;11(8):1377–9. 10.1038/sj.leu.2400703 [PubMed] [Cross Ref]
185. Cremer P, Lakomek M, Beck W, et al. : The effect of L-asparaginase on lipid metabolism during induction chemotherapy of childhood lymphoblastic leukaemia. Eur J Pediatr. 1988;147(1):64–7. 10.1007/BF00442614 [PubMed] [Cross Ref]
186. Dietel V, Buhrdel P, Hirsch W, et al. : Cerebral sinus occlusion in a boy presenting with asparaginase-induced hypertriglyceridemia. Klin Padiatr. 2007;219(2):95–6. 10.1055/s-2007-921455 [PubMed] [Cross Ref]
187. Kfoury-Baz EM, Nassar RA, Tanios RF, et al. : Plasmapheresis in asparaginase-induced hypertriglyceridemia. Transfusion. 2008;48(6):1227–30. 10.1111/j.1537-2995.2008.01663.x [PubMed] [Cross Ref]
188. Cohen H, Bielorai B, Harats D, et al. : Conservative treatment of L-asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2010;54(5):703–6. 10.1002/pbc.22305 [PubMed] [Cross Ref]
189. Solano-Páez P, Villegas JA, Colomer I, et al. : L-Asparaginase and steroids-associated hypertriglyceridemia successfully treated with plasmapheresis in a child with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2011;33(3):e122–4. 10.1097/MPH.0b013e3181faf7a1 [PubMed] [Cross Ref]
190. Yadav D, Pitchumoni CS.: Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol. 2003;36(1):54–62. 10.1097/00004836-200301000-00016 [PubMed] [Cross Ref]
191. Raja RA, Schmiegelow K, Sørensen DN, et al. : Asparaginase-associated pancreatitis is not predicted by hypertriglyceridemia or pancreatic enzyme levels in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2017;64(1):32–8. 10.1002/pbc.26183 [PubMed] [Cross Ref]
192. Powell C, Chang C, Gershwin ME.: Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clin Rev Allergy Immunol. 2011;41(1):102–13. 10.1007/s12016-010-8217-z [PubMed] [Cross Ref]
193. Relling MV, Ramsey LB.: Pharmacogenomics of acute lymphoid leukemia: new insights into treatment toxicity and efficacy. Hematology Am Soc Hematol Educ Program. 2013;2013:126–30. 10.1182/asheducation-2013.1.126 [PubMed] [Cross Ref]
194. Hyde RK, Liu PP.: Germline PAX5 mutations and B cell leukemia. Nat Genet. 2013;45(10):1104–5. 10.1038/ng.2778 [PubMed] [Cross Ref]
195. Shah S, Schrader KA, Waanders E, et al. : A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 2013;45(10):1226–31. 10.1038/ng.2754 [PMC free article] [PubMed] [Cross Ref]
196. Moriyama T, Metzger ML, Wu G, et al. : Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 2015;16(16):1659–66. 10.1016/S1470-2045(15)00369-1 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
197. Topka S, Vijai J, Walsh MF, et al. : Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet. 2015;11(6):e1005262. 10.1371/journal.pgen.1005262 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
198. Liew E, Owen C.: Familial myelodysplastic syndromes: a review of the literature. Haematologica. 2011;96(10):1536–42. 10.3324/haematol.2011.043422 [PubMed] [Cross Ref]
199. Churchman M, Qian M, Zhang R, et al. : Germline Genetic Variation in IKZF1 and Predisposition to Childhood Acute Lymphoblastic Leukemia. Blood. 2016;128(22):LBA–2. Reference Source
200. Schmiegelow K, Lausten Thomsen U, Baruchel A, et al. : High concordance of subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia. Leukemia. 2012;26(4):675–81. 10.1038/leu.2011.274 [PubMed] [Cross Ref]
201. Zhang MY, Churpek JE, Keel SB, et al. : Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180–5. 10.1038/ng.3177 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
202. Schmiegelow K.: Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes. Eur J Med Genet. 2016;59(12):654–60. 10.1016/j.ejmg.2016.02.006 [PubMed] [Cross Ref]
203. Buitenkamp TD, Mathôt RA, de Haas V, et al. : Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica. 2010;95(7):1106–13. 10.3324/haematol.2009.019778 [PubMed] [Cross Ref]
204. Bohnstedt C, Levinsen M, Rosthøj S, et al. : Physicians compliance during maintenance therapy in children with Down syndrome and acute lymphoblastic leukemia. Leukemia. 2013;27(4):866–70. 10.1038/leu.2012.325 [PubMed] [Cross Ref]
205. Buitenkamp TD, Izraeli S, Zimmermann M, et al. : Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. 2014;123(1):70–7. 10.1182/blood-2013-06-509463 [PubMed] [Cross Ref] F1000 Recommendation
206. Borriello A, Locasciulli A, Bianco AM, et al. : A novel Leu153Ser mutation of the Fanconi anemia FANCD2 gene is associated with severe chemotherapy toxicity in a pediatric T-cell acute lymphoblastic leukemia. Leukemia. 2007;21(1):72–8. 10.1038/sj.leu.2404468 [PubMed] [Cross Ref]
207. Wimmer K, Kratz CP, Vasen HF, et al. : Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). J Med Genet. 2014;51(6):355–65. 10.1136/jmedgenet-2014-102284 [PubMed] [Cross Ref]
208. Bougeard G, Renaux-Petel M, Flaman JM, et al. : Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015;33(21):2345–52. 10.1200/JCO.2014.59.5728 [PubMed] [Cross Ref] F1000 Recommendation
209. Schoenaker MH, Suarez F, Szczepanski T, et al. : Treatment of acute leukemia in children with ataxia telangiectasia (A-T). Eur J Med Genet. 2016;59(12):641–6. 10.1016/j.ejmg.2016.05.012 [PubMed] [Cross Ref] F1000 Recommendation
210. Bienemann K, Burkhardt B, Modlich S, et al. : Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol. 2011;155(4):468–76. 10.1111/j.1365-2141.2011.08863.x [PubMed] [Cross Ref]
211. Karran P, Attard N.: Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8(1):24–36. 10.1038/nrc2292 [PubMed] [Cross Ref]
212. Schmiegelow K, Levinsen MF, Attarbaschi A, et al. : Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 2013;31(19):2469–76. 10.1200/JCO.2012.47.0500 [PMC free article] [PubMed] [Cross Ref]
213. Oskarsson T, Soderhall S, Arvidson J, et al. : Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica. 2016;101(1):68–76. 10.3324/haematol.2015.131680 [PubMed] [Cross Ref] F1000 Recommendation
214. Armstrong GT, Kawashima T, Leisenring W, et al. : Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol. 2014;32(12):1218–27. 10.1200/JCO.2013.51.1055 [PMC free article] [PubMed] [Cross Ref]

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