Paediatric Burkitt lymphoma patient-derived xenografts capture disease characteristics over time and are a model for therapy.

Burkitt lymphoma (BL) accounts for almost two-thirds of all B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents and is characterised by a MYC translocation and rapid cell turnover. Intensive chemotherapeutic regimens have been developed in recent decades, including the lymphomes malins B (LMB) protocol, which have resulted in a survival rate in excess of 90%. Recent clinical trials have focused on immunochemotherapy, with the addition of rituximab to chemotherapeutic backbones, showing encouraging results. Despite these advances, relapse and refractory disease occurs in up to 10% of patients and salvage options for these carry a dismal prognosis. Efforts to better understand the molecular and functional characteristics driving relapse and refractory disease may help improve this prognosis. This study has established a paediatric BL patient-derived xenograft (PDX) resource which captures and maintains tumour heterogeneity, may be used to better characterise tumours and identify cell populations responsible for therapy resistance.

Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion.

Patients with an ABL-class fusion have a high risk of relapse on standard chemotherapy but are sensitive to tyrosine kinase inhibitors (TKI). In UKALL2011, we screened patients with post-induction MRD ≥1% and positive patients (12%) received adjuvant TKI. As the intervention started during UKALL2011, not all eligible patients were screened prospectively. Retrospective screening of eligible patients allowed the outcome of equivalent ABL-class patients who did and did not receive a TKI in first remission to be compared. ABL-class patients who received a TKI in first remission had a reduced risk of relapse/refractory disease: 0% vs. 63% at four years (P = 0·009).

Multiorgan involvement and management in children with Down syndrome.

AIM: To review multiorgan involvement and management in children with Down syndrome (DS). METHODS: A literature review of articles from 1980 to 2019 using the MEDLINE interface of PubMed was performed using the following search terms- [Down syndrome] or [Trisomy 21] AND [Cardiology] or [Respiratory] or [neurodevelopment] or [epilepsy] or [musculoskeletal] or [immune system] or [haematological] or [endocrine] or [gastrointestinal] or [ophthalmological] or [Ear Nose Throat] or [dermatology] or [renal]. RESULTS: Congenital heart disease particularly septal defects occur in over 60% of infants with DS and 5%-34% of infants develop persistent pulmonary hypertension of the newborn irrespective of a diagnosis of congenital heart disease. Early recognition and management of aspiration, obstructive sleep apnoea and recurrent lower respiratory tract infections (LRTI) could reduce risk of developing pulmonary hypertension in later childhood. Children with DS have an increased risk of autistic spectrum disorder, attention deficit disorder and epilepsy particularly infantile spasms, which are associated with poor neurodevelopmental outcomes. Congenital anomalies of the gastrointestinal and renal system as well as autoimmune diseases, coeliac disease, arthropathy, thyroid dysfunction fold diabetes mellitus and dermatological conditions are more common. Hearing and visual anomalies are also well recognised association with DS (Table 1). CONCLUSION: Children with DS are at an increased risk of multiorgan comorbidities. Organ-specific health surveillance may provide holistic care for the children and families with DS throughout childhood.

Administration of G-CSF from day +6 post-allogeneic hematopoietic stem cell transplantation in children and adolescents accelerates neutrophil engraftment but does not appear to have an impact on cost savings.

G-CSF post-allogeneic HSCT accelerates neutrophil engraftment, but evidence that it impacts on cost-related outcomes is lacking. We performed a retrospective child and adolescent single-center cohort study examining G-CSF administration from Day +6 of allogeneic HSCT vs. ad hoc G-CSF use where clinically indicated. Forty consecutive children and adolescents undergoing allogeneic HSCT were included. End-points were as follows: time to engraftment; incidence of acute and chronic GvHD; number of patients alive at Day +100; 180-day TRM; post-transplant days in hospital; and cost of antimicrobials, TPN, and G-CSF usage. Neutrophil engraftment occurred earlier in the group that received G-CSF from Day +6. There was no difference between groups in any of the other end-points with the following exception: the cost of GCSF was significantly higher in the D + 6 G-CSF group. However, median G-CSF cost in this group amounted to only €280. There was a trend towards reduced cost of antimicrobials in the D + 6 G-CSF group, although this did not reach significance (p = 0.13). The median cost per patient of antimicrobial agents between groups differed by €1116. This study demonstrated the administration of G-CSF on Day +6 in pediatric HSCT to be safe. A further study using a larger cohort of patients is warranted to ascertain its true clinico-economic value.

Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation.

AIHA following allogeneic HSCT is appearing more frequently in the literature. It occurs as a result of donor cell-derived antibodies targeting donor red cell antigens. Little guidance exists on the management of such patients, particularly in the pediatric setting. First-line conventional treatment is corticosteroids and/or immunoglobulin therapy with monoclonal antibody therapy reserved for treatment failure. We report our experience of a child refractory to immunoglobulin and steroid therapy who required several infusions of rituximab and immunomodulatory therapy to obtain a clinically significant response.

Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.

Does vaccine dose predict response to the monovalent pandemic H1N1 influenza a vaccine in children with acute lymphoblastic leukemia? A single-centre study.

BACKGROUND: Vaccination against influenza is an important strategy in preventing severe infection among children with acute lymphoblastic leukemia (ALL). Successful vaccination depends on both vaccine and host-related factors. We conducted a study on factors predicting the immunogenicity of the monovalent pandemic H1N1 (pH1N1) influenza A vaccine in children with ALL. METHODS: Children with ALL in our hospital were recruited and received two doses of the inactivated split-virion AS03-adjuvanted vaccine. The serological response was measured before each vaccine dose (Day 0 and 28) and 3 months after the second dose. Antibody titres were measured using a hemagglutination-inhibition assay. Seroconversion was defined as a ≥fourfold increase in antibody titre and a post-vaccination titre ≥1:40. RESULTS: Pre and post-vaccination titres were available from 45 children with ALL after one dose of the vaccine and 39 children after two doses. The seroconversion rate was 11.1% after one dose and 25.6% after the second dose. Univariate analysis demonstrated a significantly higher (P = 0.01) seroconversion rate among children who received the adult dose (0.5 ml) of the vaccine and a trend towards increased seroconversion (P = 0.07) by multivariate analysis. Factors including age, gender, lymphocyte count, treatment phase and regimen did not significantly affect the seroconversion rate. Children who received the adult dose demonstrated a significantly greater magnitude of serological response after both one dose (P = 0.04) and two doses (P = 0.001). CONCLUSIONS: These data suggest that the immunogenicity of the pH1N1 vaccine among children with ALL is improved by repeated and adult doses of the vaccine.

Invasive intracerebral fungal infection in a leukaemic patient.

Intracerebral abscesses secondary to Zygomycosis are potentially fatal. A 12-year-old girl with acute promyelocytic leukaemia was successfully treated for intracerebral abscess caused by Zygomycosis with complete surgical excision and combination antifungal therapy.

Post-transplant lymphoproliferative disorder presenting as supraglottitis following pediatric heart transplantation treated with EBV-specific cytotoxic T-lymphocytes.

We present the case of a 4 year-old boy post heart transplantation who presented with signs and symptoms of critical airway obstruction and was initially diagnosed with infective supraglottitis. Following re-presentation and biopsy, this was confirmed as post-transplant lymphoproliferative disorder (PTLD) in an unusual site; laryngeal PTLD is rare. The patient failed standard therapy and ultimately was successfully treated with EBV-specific cytotoxic T lymphocytes (CTL). This case describes a rare presentation of PTLD which required a novel treatment approach including elective tracheostomy prior to CTL therapy. The treatment was successful and the patient was decannulated prior to discharge following 4 negative biopsies, the most recent 6 months following treatment completion. The case also highlights the importance of extra-vigilance in the post-transplant population and of a collaborative approach between multiple specialties across two separate countries including the transplant center and the referral center.

Esophageal strictures during treatment for acute lymphoblastic leukemia.

Esophageal stricture is a rare complication of paediatric cancer treatment that usually occurs after esophageal exposure to radiotherapy. We describe 4 cases of esophageal stricture during chemotherapy for acute lymphoblastic leukemia. All patients presented with refractory vomiting and were diagnosed with radiologic contrast studies. None of the patients had received radiotherapy. Esophageal candidiasis was seen in 2 patients but the remaining 2 patients had earlier systemic candidiasis. High-dose dexamethasone may predispose these children to both esophageal candidiasis and peptic esophagitis. The etiology of esophageal strictures during treatment for acute leukemia is likely to be multifactorial but systemic candidiasis may play a significant role.

Survival of childhood and adolescent/young adult (AYA) cancer patients in Ireland during 1994-2013: comparisons by age.

BACKGROUND: Some studies indicate that survival of adolescents and young adults (AYA) with cancer may be inferior to that of younger children with similar cancers, possibly related (in part) to differences in access to centralized or standardized treatment. AIMS: This study aims to evaluate differences in survival for AYA patients when compared with paediatric patients treated in Ireland over a 20-year time period. METHODS: This study compares relative survival for patients diagnosed in Ireland at ages 0-15 (paediatric group) and 16-24 (AYA group) during 1994-2013, followed to the end of 2014, for cancers defined by the International Classification of Childhood Cancer (ICCC) (Third Edition) group or subgroup. Five-year relative survival estimates, and excess hazard ratios (EHR) comparing excess mortality associated with a cancer diagnosis among AYA with that in the paediatric group, are presented. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. RESULTS: Significantly higher excess mortality was found for AYA with leukaemias, lymphomas, astrocytomas, malignant bone tumours, and Ewing and related bone sarcomas, soft tissue sarcomas and 'other/unspecified' epithelial cancers, rhabdomyosarcomas, and 'other and unspecified' carcinomas. In contrast, lower excess mortality was found in the AYA group for all cancers and intracranial/intraspinal tumours, and for gliomas other than astrocytomas or ependymomas. Comparing 1994-2003 and 2004-2013 cohorts, age-related survival differences narrowed for lymphoid leukaemias, but widened for all cancers combined and intracranial/intraspinal tumours combined. Centralization of services varied depending upon cancer subtype, with leukaemias, CNS tumours and bone sarcomas most centralized. Within these, improvements in survival for leukaemias and CNS tumours have been seen for the AYA population. CONCLUSIONS: Reasons for age-related survival differences, and differences in time-trend by age group, are not clear. The significant narrowing of survival differences by age in more recent years for lymphoid leukaemias reflects a more marked recent increase in survival among AYA. More work is required to explain and improve other age-related survival differences.

A retrospective study of myeloid leukaemia in children with Down syndrome in Ireland.

BACKGROUND: Acute megakaryoblastic leukaemia (AMKL) is a subtype of myeloid leukaemia and is the most common leukaemia type in children with Down syndrome (DS) under 4 years of age. AMKL is often preceded by a transient neonatal pre-leukaemic syndrome, transient myeloproliferative disorder (TMD). Although TMD often spontaneously resolves, 20-30% of these patients subsequently develop AMKL within the first 4 years of life. AIMS: To perform a retrospective consecutive national audit of all documented cases of childhood TMD and AMKL-DS from 1990 to 2018 at Our Lady's Children's Hospital, Crumlin (OLCHC), Ireland. METHODS: All patients with a diagnosis of AMKL treated consecutively at (OLCHC) between 1990 and 2018 were reviewed. Kaplan-Meier survival curves were constructed. RESULTS: Twenty-seven patients with AMKL-DS were identified. A prior neonatal diagnosis of TMD was described in 10 patients (37%). Nineteen patients (70%) are alive and well, in complete remission, at a median follow-up of 11.4 years. Overall survival (OS) of this cohort has risen from 54% from those treated between the years 1990 and 2004 (n = 13) to 93% for those treated between the years 2005 and 2018 (n = 14). CONCLUSION: High cure rates are observed in AMKL-DS using current polychemotherapy protocols. The finding of a low platelet count at time of diagnosis is in keeping with the knowledge that AMKL-DS is a malignancy of platelet progenitor cells.

Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches.

In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual disease (MRD) detected by real time quantitative polymerase chain reaction (RQ-PCR) and 3-colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time-points during treatment (93.38%), and a combined use of both approaches allowed a multi time-point evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0.01% were identified by RQ-PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ-PCR and FC approach, the evaluation of 367 follow-up BM samples revealed that the detection of MRD >1% at Day 15 (P = 0.04), >0.01% at the end of induction (P = 0.02), >0.01% at the end of consolidation (P = 0.01), >0.01% prior to the first delayed intensification (P = 0.01), and >0.1% prior to the second delayed intensification and continued maintenance (P = 0.001) were all associated with relapse and, based on early time-points (end of induction and consolidation) a significant log-rank trend (P = 0.0091) was noted between survival curves for patients stratified into high, intermediate and low-risk MRD groups.

Mediastinal and neck kaposiform hemangioendothelioma: report of three cases.

Kaposiform hemangioendothelioma is an aggressive vascular tumor, named for its striking histologic resemblance to Kaposi sarcoma and locally invasive growth. Mortality is high, and ranges from 10% to 24% for all kaposiform hemangioendothelioma lesions, with a significantly higher mortality for deep soft-tissue or visceral lesions occurring in infants less than 6 months. Mediastinal and neck kaposiform hemangioendothelioma in particular merit special discussion, as involvement of these critical anatomic locations results in significant site-specific therapeutic challenges due to invasion of vital structures, inherent delays in establishing histopathologic confirmation, and difficulties in monitoring disease status. We report our experience with three cases of mediastinal and neck kaposiform hemangioendothelioma, emphasizing the unique diagnostic and management challenges, variable response to treatment and outcome of this anatomic variant of kaposiform hemangioendothelioma.