Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment

Posterior Reversible Encephalopathy Syndrome in Pediatric Hematologic- Oncologic Disease: Literature Review and Case Presentation

How to Cite This Article: Arzanian MT, Shamsian BSh, Karimzadeh P, Kajiyazdi M, Malek F, Hammoud M. Posterior Reversible Encephalopathy Syndrome in Pediatric Hematologic-Oncologic Disease: Literature Review and Case Presentation. Iran J Child Neurol. 2014 Spring 8(2):1-10.ObjectivePosterior reversible encephalopathy syndrome (PRES) is a cliniconeuroradiological disease entity, which is represented by characteristic magnetic resonance imaging (MRI) findings of subcortical/cortical hyperintensity in T2-weighted sequences. It is more often seen in parietaloccipital lobes, and is accompanied by clinical neurological changes. PRES is a rare central nervous system (CNS) complication in patients with childhood hematologic-oncologic disese and shows very different neurological symptoms between patients, ranging from numbness of extremities to generalized seizure.In this article, we will review PRES presentation in hematologic-oncologic patients. Then, we will present our patient, a 7-year-old boy with Evans syndrome on treatment with cyclosporine, mycophenolate mofetil (MMF) and prednisone, with seizure episodes and MRI finding in favour of PRES. References1. De Laat P, Te Winkel ML, Devos AS, Catsman-Berrevoets CE, Pieters R, van den Heuvel-Eibrink MM. Posterior reversible encephalopathy syndrome in childhood cancer. Ann Oncol 2011;22(2):472-8.2. Siebert E, Spors B, Bohner G, Endres M, LimanTG. Posterior reversible encephalopathy syndrome in children: radiological and clinical findings - a retrospective analysis of a German tertiary care center. Eur J Paediatr Neurol 2013;17(2):169-75.3. Lucchini G, Grioni D, Colombini A, Contri M, De Grandi C, Rovelli A, et al. Encephalopathy Syndrome in Children With Hemato-Oncological Disorders Is Not Always Posterior and Reversible. Pediatr Blood Cancer 2008;51:629–33.4. Kim SJ, Im SA, Lee JW, Chung NG, Cho B, Kim HK. Predisposing Factors of Posterior Reversible Encephalopathy Syndrome in Acute Childhood Leukemia. Pediatr Neurol 2012;47(6):436-42.5. Endo A, Fuchigami T, Hasegawa M, Hashimoto K, Fujita Y, Inamo Y , et al. Posteriorreversible encephalopathy syndrome in childhood: report of four cases and review of the literature. Pediatr Emerg Care 2012;28(2):153-7.6. Won SC, Kwon SY, Han JW, Choi SY, Lyu CJ. Posterior Reversible Encephalopathy Syndrome in Childhood with Hematologic/Oncologic Diseases. J Pediatr Hematol Oncol 2009;31(7):505-8.7. Legriel S, Pico F, Azoulay E. Understanding Posterior Reversible Encephalopathy Syndrome. Annual update in intensive care and emergency medicine. Springer; 2011.P.631-653.8. Malbora B, Avcı Z, Donmez F, Alioğlu B, Alehan F, Alehan F, et al. Posterior reversible leukoencephalopathy syndrome in children with hematologic disorders. Turk J Hematol 2010;27(3):168-76.9. Komur M, Delibas A, Arslankoylu AE, Okuyaz C, Kara E.. Recurrent and atypical posterior reversible encephalopathy syndrome in a child with hypertension. Ann Indian Acad Neurol 2012;15(3):208-10.10. Dzudie A, Boissonnat P, Roussoulieres A, Cakmak, Mosbah K, Bejui FT, et al. Cyclosporine-Related Posterior Reversible Encephalopathy Syndrome After Heart Transplantation: Should We Withdraw or Reduce Cyclosporine?: Case Reports. Transplant Proc 2009;41(2):716-20.11. Fuchigami T, Inamo Y, Hashimoto K, Yoshino Y, Abe O, Ishikawa T, et al. Henoch-schönlein purpura complicated by reversible posterior leukoencephalopathy syndrome. Pediatr Emerg Care 2010;26(8):583-5.12. Incecik F, Hergüner MO, Altunbasak S, Erbey F, Leblebisatan G. Evaluation of nine children with reversible posterior encephalopathy syndrome. Neurol India 2009;57(4):475-8.13. Chandramohan V, Nagarajan VP, Sathyamoorthi MS, Kumar S, Shanmugasundaram C, Periakaruppan G, et al. Posterior reversible encephalopathy syndrome in a child with autoimmune lymphoproliferative syndrome: Case report and review of literature. J Pediatr Neurosci 2012;7(3):221-4.14. Wright KL, Polito MH, French AE. Posterior Reversible Encephalopathy Syndrome: A Case Study. Am J Nurs 2012;112(5):36-40.15. Pedraza R, Marik PE, Varon J. Posterior Reversible Encephalopathy Syndrome: A Review.Crit Care & Shock 2009;12:135-43.16. Morris EB, Laningham FH, Sandlund JT, Khan RB. Posterior reversible encephalopathy syndrome in children with cancer. Pediatr Blood Cancer 2007;48(2):152-9.

Posterior reversible encephalopathy syndrome and other severe central nervous system adverse events in the NOPHO ALL2008 protocol : clinical and radiological findings, genetic risk factors and prognosis

Background: The advances in the therapeutic protocols for pediatric acute lymphoblastic leukemia (ALL) have led to a current survival rate of more than 90% in developed countries. Treatment periods are, however, long and marked by complications and toxicity that may challenge treatment outcomes and quality of life for patients. Central nervous system (CNS) toxicity is common during pediatric ALL treatment and may implicate treatment postponement as well as long-term adverse effects. The aim of this thesis was to map CNS toxicities in pediatric ALL in patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Methods: Patients aged 1 to 17.9 years at diagnosis of B-cell-precursor and T-cell ALL who were treated according to the NOPHO ALL2008 protocol between 2008 and 2015 were included. Detailed data on CNS toxicity were collected from the NOPHO ALL2008 registry with seven participating countries and a complementary questionnaire addressing phenotypical and work-up details. Genome-wide association studies (GWAS) and candidate single nucleotide polymorphism (SNP) analyses were performed. A validation study of significant findings from GWAS and candidate SNP analyses was made in an independent Australian cohort of pediatric ALL patients (n=797) including patients with diverse CNS toxicities (n=103) and methotrexate-related CNS-toxicity (n=48). The role of minimal CNS leukemia in CNS toxicity risk was further examined by detecting leukemic blasts in cerebrospinal fluid (CSF) by flow cytometric immunophenotyping (FCI) in addition to cytomorphological analysis (CM), which is the CSF examination method specified in the NOPHO ALL2008 protocol. Results: 1464 patients were included in the study of whom 52 (3.8%) had posterior reversible encephalopathy syndrome (PRES), and 135 (9.2%) had at least one form of CNS toxicity. Overall, 82/135 patients had at least one seizure episode (60.7%). PRES was the most common form of CNS toxicity in this cohort (38.5%). Older age, defined as each extra year of age and/or as patient group >10 years of age was a significant risk factor for PRES, seizures, and all CNS toxicities. T-cell immunophenotype was significant risk factor for PRES in univariate analysis and after adjustment for age. Leukemic blasts in CSF by CM were significantly related to PRES during induction and high-risk block treatment was related to PRES after induction. Minimal CNS leukemia, detected by FCI, was a significant risk factor for PRES, seizures, and all CNS toxicities in patients without CNS leukemia by CM in univariate analyses and for PRES and seizures after adjusting for induction therapy. Genome-wide association studies did not demonstrate any significant associations with CNS toxicities, but candidate SNP analyses showed that the ATXN1rs68082256 SNP, related to epilepsy, was associated with seizures in patients <10 years. ATXN1rs68082256 was replicated in the Australian cohort in the patient group with diverse CNS toxicities. At the last follow-up, 11.7% of survivors (12/103) who had displayed CNS toxicity were reported to have had an epilepsy diagnosis. Clinical suspicion of neurocognitive impairment was reported for 10.9% of survivors (12/110) with CNS toxicity at their last follow-up, but neuropsychiatric testing was performed in only two cases. Conclusion: Central nervous system toxicity was common during pediatric ALL treatment and PRES was the most common form of CNS toxicity in this cohort. Older patients had a greater risk of CNS toxicity as well as patients with minimal CNS leukemia. The role of ATXN1rs68082256 SNP in CNS toxicity warrants further studies. Epilepsy is rather common in ALL survivors, while the neurocognitive outcome warrants more systematic follow-up

Akutna neurološka zbivanja u djece liječene od akutne limfoblastične leukemije

Complications of paediatric acute lymphoblastic leukaemia therapy in a notable number of patients include acute neurotoxicity, which presents most often as cerebrovascular disease, infection or a variety of nonspecific neurologic signs and symptoms, as well as recognizable clinical- radiological syndromes, due to admistered chemo- and radiotherapy. Although acute neurological events are rarely fatal, they usually present as emergency situations, often require treatment postponement and modifications, and can be followed by permanent sequelae in the form of epilepsy or cognitive dysfunction. We present three cases of acute neurotoxicity in childhood leukaemia patients treated at our department. Based on clinical presentation, laboratory and radiological findings, these cerebral events were characterized as ischaemia of the brain, posterior reversible encephalopathy syndrome and brain oedema with syndrome of inappropriate secretion of antidiuretic hormone. Timely and appropriate management resulted in complete neurological recovery in all three patients.U nezanemarivom broju pedijatrijskih bolesnika s akutnom limfoblastičnom leukemijom komplikacije primijenjene kemoterapije i radioterapije uključuju akutnu neurotoksičnost, koja se može manifestirati kao cerebrovaskularna bolest, infekcija, skup nespecifičnih neuroloških simptoma i znakova, ili pak kao jasno definirani i prepoznatljivi kliničko - radiološki sindrom. Iako akutna neurološka zbivanja rijetko završavaju smrtno, najčešće je ipak riječ o hitnim stanjima koja nerijetko zahtijevaju odgodu ili promjenu terapije te mogu biti praćena trajnim posljedicama, poput epilepsije i kognitivne disfunkcije. Prikazujemo tri slučaja akutne neurotoksičnosti u djece s leukemijom liječene u našem Zavodu. Temeljem kliničke slike, laboratorijskih i radioloških nalaza okarakterizirana su kao moždana ishemija, sindrom posteriorne reverzibilne encefalopatije i edem mozga sa sindromom neadekvatne sekrecije antidiuretskog hormona. Uz pravodobnu i adekvatnu terapiju u sve troje bolesnika zamijećen je potpuni neurološki oporavak

A Model of Methotrexate Encephalopathy: Neurotransmitter and Pathologic Abnormalities

Methotrexate may cause seizures, dementia, and leukoencephalopathy when given in toxic doses to children with leukemia or solid tumors. Even in therapeutic doses, treatment with this drug is associated with an increased incidence of seizures in children with leukemia. To study mechanisms of injury, juvenile rats were given multiple intraventricular injections of methotrexate and the brains were analyzed for histopathology and biogenic amine metabolites of dopamine and serotonin. Disruption of monoamine metabolism has been proposed as a cause of brain dysfunction from this chemotherapy. Multiple injections (1 or 2 mg/kg) produced convulsions in an increasingly larger percentage of animals at higher cumulative doses, and five doses produced the neuropathological changes seen in human leukoencephalopathy. A single dose reduced the concentration of brain metabolites of dopamine, but not serotonin, six hours later. The effect was less pronounced after five doses. This rodent model should be useful for studying the metabolic basis of methotrexate encephalopathy. (J Child Neurol 1986;1:351-357)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67332/2/10.1177_088307388600100406.pd

Reversible posterior leukoencephalopathy syndrome in Chinese children induced by chemotherapy: A review of five cases

This is a retrospective review of the clinico-radiological features and neurological outcomes of reversible posterior leukoencephalopathy syndrome episodes in Chinese cancer children receiving chemotherapy in a regional hospital in Hong Kong from 1998 to 2008. Five children (3 males and 2 females) with a mean age of 7 years were identified, four of whom had acute lymphoblastic leukaemia and one had a central nervous system germ cell tumour. Presenting symptoms included seizures (100%), altered mental function (100%), headache (40%), and visual disturbance (60%). The mean systolic blood pressure at presentation was 158 mm Hg. Approximately 80% had typical radiological features of reversible posterior leukoencephalopathy syndrome. All showed complete recovery after the acute stage, but one subsequently developed epilepsy. Two patients ultimately died of refractory malignant disease. Two others were followed up for a mean of 6 years, and remained neurologically normal. This report was the first case review documenting reversible posterior leukoencephalopathy syndrome in Chinese cancer children. The clinico-radiological features and neurological outcomes were similar to those reported in western series. Early recognition of the syndrome is important to facilitate appropriate treatment. The central nervous system damage may not be reversible and thus long-term follow-up is warranted.published_or_final_versio

Pharmacogenetics of the Central Nervous System—Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse

A Review of Acute and Long-Term Neurological Complications Following Haematopoietic Stem Cell Transplant for Paediatric Acute Lymphoblastic Leukaemia

Despite advances in haematopoietic stem cell transplant (HSCT) techniques, the risk of serious side effects and complications still exists. Neurological complications, both acute and long term, are common following HSCT and contribute to significant morbidity and mortality. The aetiology of neurotoxicity includes infections and a wide variety of non-infectious causes such as drug toxicities, metabolic abnormalities, irradiation, vascular and immunologic events and the leukaemia itself. The majority of the literature on this subject is focussed on adults. The impact of the combination of neurotoxic drugs given before and during HSCT, radiotherapy and neurological complications on the developing and vulnerable paediatric and adolescent brain remains unclear. Moreover, the age-related sensitivity of the nervous system to toxic insults is still being investigated. In this article, we review current evidence regarding neurotoxicity following HSCT for acute lymphoblastic leukaemia in childhood. We focus on acute and long-term impacts. Understanding the aetiology and long-term sequelae of neurological complications in children is particularly important in the current era of immunotherapy for acute lymphoblastic leukaemia (such as chimeric antigen receptor T cells and bi-specific T-cell engager antibodies), which have well-known and common neurological side effects and may represent a future treatment modality for at least a fraction of HSCT-recipients